Pharmacokinetics of Psychotropic Drugs€¦ · (solution > suspension > capsule > tab > enteric...
Transcript of Pharmacokinetics of Psychotropic Drugs€¦ · (solution > suspension > capsule > tab > enteric...
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Pharmacokinetics of Psychotropic Drugs
Terence A Ketter MDStanford University School of Medicine
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Teaching Pointsbull Key pharmacokinetic parameters include volume of
distribution half life and clearance
bull Most drugs undergo hepatic metabolism and are thus at risk for drug interactions related to hepatic metabolism but a few drugs (such as lithium) have renal excretion and are thus at risk for drug interactions related to renal excretion
bull Characterizing medications as substrates inducers and inhibitors of specific cytochrome p450 metabolic enzymes can help predict and prevent adverse events related to drug interactions
bull The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are CYP2D6 and CYP3A34
3
Pre Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
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Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
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Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
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Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
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Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
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Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
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Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
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Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
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Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
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Outline
bull CONCEPTSPharmacokinetics Pharmacodynamics
bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers
bull MOOD STABILIZERS Li CBZ VPA
bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs
bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers
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PHARMACOKINETICS
bullTime course of drug absorption distribution metabolism amp excretion
bullDrug transport to amp from receptors
bullWhat the body does to the drug
15
PHARMACODYNAMICS
bull Relationships between drug concentrations amp responses
bull Drug activity at receptors
bull What the drug does to the body
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CONCEPT DEFINITION
V (vol of distrib) Volume needed to contain drug at concentration same as plasma
t12 Time for [drug] to darr 50(half life)
Cl Volume of blood cleared(clearance) of drug per unit time
PHARMACOKINETIC CONCEPTS
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CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
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CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait
Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure
PHARMACOKINETIC CONCEPTS
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ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)
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DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
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EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
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METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
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bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
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ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
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ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
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CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
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DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
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INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
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CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
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KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
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CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
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CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
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INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
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INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
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GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
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SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
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DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
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LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
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LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
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CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
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Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
2
Teaching Pointsbull Key pharmacokinetic parameters include volume of
distribution half life and clearance
bull Most drugs undergo hepatic metabolism and are thus at risk for drug interactions related to hepatic metabolism but a few drugs (such as lithium) have renal excretion and are thus at risk for drug interactions related to renal excretion
bull Characterizing medications as substrates inducers and inhibitors of specific cytochrome p450 metabolic enzymes can help predict and prevent adverse events related to drug interactions
bull The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are CYP2D6 and CYP3A34
3
Pre Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
4
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
5
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
6
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
7
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
8
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
9
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
10
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
13
Outline
bull CONCEPTSPharmacokinetics Pharmacodynamics
bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers
bull MOOD STABILIZERS Li CBZ VPA
bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs
bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers
14
PHARMACOKINETICS
bullTime course of drug absorption distribution metabolism amp excretion
bullDrug transport to amp from receptors
bullWhat the body does to the drug
15
PHARMACODYNAMICS
bull Relationships between drug concentrations amp responses
bull Drug activity at receptors
bull What the drug does to the body
16
CONCEPT DEFINITION
V (vol of distrib) Volume needed to contain drug at concentration same as plasma
t12 Time for [drug] to darr 50(half life)
Cl Volume of blood cleared(clearance) of drug per unit time
PHARMACOKINETIC CONCEPTS
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait
Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure
PHARMACOKINETIC CONCEPTS
19
ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
3
Pre Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
4
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
5
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
6
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
7
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
8
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
9
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
10
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
13
Outline
bull CONCEPTSPharmacokinetics Pharmacodynamics
bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers
bull MOOD STABILIZERS Li CBZ VPA
bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs
bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers
14
PHARMACOKINETICS
bullTime course of drug absorption distribution metabolism amp excretion
bullDrug transport to amp from receptors
bullWhat the body does to the drug
15
PHARMACODYNAMICS
bull Relationships between drug concentrations amp responses
bull Drug activity at receptors
bull What the drug does to the body
16
CONCEPT DEFINITION
V (vol of distrib) Volume needed to contain drug at concentration same as plasma
t12 Time for [drug] to darr 50(half life)
Cl Volume of blood cleared(clearance) of drug per unit time
PHARMACOKINETIC CONCEPTS
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait
Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure
PHARMACOKINETIC CONCEPTS
19
ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
4
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
5
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
6
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
7
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
8
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
9
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
10
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
13
Outline
bull CONCEPTSPharmacokinetics Pharmacodynamics
bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers
bull MOOD STABILIZERS Li CBZ VPA
bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs
bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers
14
PHARMACOKINETICS
bullTime course of drug absorption distribution metabolism amp excretion
bullDrug transport to amp from receptors
bullWhat the body does to the drug
15
PHARMACODYNAMICS
bull Relationships between drug concentrations amp responses
bull Drug activity at receptors
bull What the drug does to the body
16
CONCEPT DEFINITION
V (vol of distrib) Volume needed to contain drug at concentration same as plasma
t12 Time for [drug] to darr 50(half life)
Cl Volume of blood cleared(clearance) of drug per unit time
PHARMACOKINETIC CONCEPTS
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait
Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure
PHARMACOKINETIC CONCEPTS
19
ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
5
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
6
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
7
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
8
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
9
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
10
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
13
Outline
bull CONCEPTSPharmacokinetics Pharmacodynamics
bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers
bull MOOD STABILIZERS Li CBZ VPA
bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs
bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers
14
PHARMACOKINETICS
bullTime course of drug absorption distribution metabolism amp excretion
bullDrug transport to amp from receptors
bullWhat the body does to the drug
15
PHARMACODYNAMICS
bull Relationships between drug concentrations amp responses
bull Drug activity at receptors
bull What the drug does to the body
16
CONCEPT DEFINITION
V (vol of distrib) Volume needed to contain drug at concentration same as plasma
t12 Time for [drug] to darr 50(half life)
Cl Volume of blood cleared(clearance) of drug per unit time
PHARMACOKINETIC CONCEPTS
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait
Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure
PHARMACOKINETIC CONCEPTS
19
ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
6
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
7
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
8
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
9
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
10
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
13
Outline
bull CONCEPTSPharmacokinetics Pharmacodynamics
bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers
bull MOOD STABILIZERS Li CBZ VPA
bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs
bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers
14
PHARMACOKINETICS
bullTime course of drug absorption distribution metabolism amp excretion
bullDrug transport to amp from receptors
bullWhat the body does to the drug
15
PHARMACODYNAMICS
bull Relationships between drug concentrations amp responses
bull Drug activity at receptors
bull What the drug does to the body
16
CONCEPT DEFINITION
V (vol of distrib) Volume needed to contain drug at concentration same as plasma
t12 Time for [drug] to darr 50(half life)
Cl Volume of blood cleared(clearance) of drug per unit time
PHARMACOKINETIC CONCEPTS
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait
Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure
PHARMACOKINETIC CONCEPTS
19
ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
7
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
8
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
9
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
10
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
13
Outline
bull CONCEPTSPharmacokinetics Pharmacodynamics
bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers
bull MOOD STABILIZERS Li CBZ VPA
bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs
bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers
14
PHARMACOKINETICS
bullTime course of drug absorption distribution metabolism amp excretion
bullDrug transport to amp from receptors
bullWhat the body does to the drug
15
PHARMACODYNAMICS
bull Relationships between drug concentrations amp responses
bull Drug activity at receptors
bull What the drug does to the body
16
CONCEPT DEFINITION
V (vol of distrib) Volume needed to contain drug at concentration same as plasma
t12 Time for [drug] to darr 50(half life)
Cl Volume of blood cleared(clearance) of drug per unit time
PHARMACOKINETIC CONCEPTS
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait
Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure
PHARMACOKINETIC CONCEPTS
19
ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
8
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
9
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
10
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
13
Outline
bull CONCEPTSPharmacokinetics Pharmacodynamics
bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers
bull MOOD STABILIZERS Li CBZ VPA
bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs
bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers
14
PHARMACOKINETICS
bullTime course of drug absorption distribution metabolism amp excretion
bullDrug transport to amp from receptors
bullWhat the body does to the drug
15
PHARMACODYNAMICS
bull Relationships between drug concentrations amp responses
bull Drug activity at receptors
bull What the drug does to the body
16
CONCEPT DEFINITION
V (vol of distrib) Volume needed to contain drug at concentration same as plasma
t12 Time for [drug] to darr 50(half life)
Cl Volume of blood cleared(clearance) of drug per unit time
PHARMACOKINETIC CONCEPTS
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait
Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure
PHARMACOKINETIC CONCEPTS
19
ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
9
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
10
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
13
Outline
bull CONCEPTSPharmacokinetics Pharmacodynamics
bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers
bull MOOD STABILIZERS Li CBZ VPA
bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs
bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers
14
PHARMACOKINETICS
bullTime course of drug absorption distribution metabolism amp excretion
bullDrug transport to amp from receptors
bullWhat the body does to the drug
15
PHARMACODYNAMICS
bull Relationships between drug concentrations amp responses
bull Drug activity at receptors
bull What the drug does to the body
16
CONCEPT DEFINITION
V (vol of distrib) Volume needed to contain drug at concentration same as plasma
t12 Time for [drug] to darr 50(half life)
Cl Volume of blood cleared(clearance) of drug per unit time
PHARMACOKINETIC CONCEPTS
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait
Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure
PHARMACOKINETIC CONCEPTS
19
ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
10
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
13
Outline
bull CONCEPTSPharmacokinetics Pharmacodynamics
bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers
bull MOOD STABILIZERS Li CBZ VPA
bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs
bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers
14
PHARMACOKINETICS
bullTime course of drug absorption distribution metabolism amp excretion
bullDrug transport to amp from receptors
bullWhat the body does to the drug
15
PHARMACODYNAMICS
bull Relationships between drug concentrations amp responses
bull Drug activity at receptors
bull What the drug does to the body
16
CONCEPT DEFINITION
V (vol of distrib) Volume needed to contain drug at concentration same as plasma
t12 Time for [drug] to darr 50(half life)
Cl Volume of blood cleared(clearance) of drug per unit time
PHARMACOKINETIC CONCEPTS
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait
Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure
PHARMACOKINETIC CONCEPTS
19
ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
13
Outline
bull CONCEPTSPharmacokinetics Pharmacodynamics
bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers
bull MOOD STABILIZERS Li CBZ VPA
bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs
bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers
14
PHARMACOKINETICS
bullTime course of drug absorption distribution metabolism amp excretion
bullDrug transport to amp from receptors
bullWhat the body does to the drug
15
PHARMACODYNAMICS
bull Relationships between drug concentrations amp responses
bull Drug activity at receptors
bull What the drug does to the body
16
CONCEPT DEFINITION
V (vol of distrib) Volume needed to contain drug at concentration same as plasma
t12 Time for [drug] to darr 50(half life)
Cl Volume of blood cleared(clearance) of drug per unit time
PHARMACOKINETIC CONCEPTS
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait
Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure
PHARMACOKINETIC CONCEPTS
19
ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
13
Outline
bull CONCEPTSPharmacokinetics Pharmacodynamics
bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers
bull MOOD STABILIZERS Li CBZ VPA
bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs
bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers
14
PHARMACOKINETICS
bullTime course of drug absorption distribution metabolism amp excretion
bullDrug transport to amp from receptors
bullWhat the body does to the drug
15
PHARMACODYNAMICS
bull Relationships between drug concentrations amp responses
bull Drug activity at receptors
bull What the drug does to the body
16
CONCEPT DEFINITION
V (vol of distrib) Volume needed to contain drug at concentration same as plasma
t12 Time for [drug] to darr 50(half life)
Cl Volume of blood cleared(clearance) of drug per unit time
PHARMACOKINETIC CONCEPTS
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait
Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure
PHARMACOKINETIC CONCEPTS
19
ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
13
Outline
bull CONCEPTSPharmacokinetics Pharmacodynamics
bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers
bull MOOD STABILIZERS Li CBZ VPA
bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs
bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers
14
PHARMACOKINETICS
bullTime course of drug absorption distribution metabolism amp excretion
bullDrug transport to amp from receptors
bullWhat the body does to the drug
15
PHARMACODYNAMICS
bull Relationships between drug concentrations amp responses
bull Drug activity at receptors
bull What the drug does to the body
16
CONCEPT DEFINITION
V (vol of distrib) Volume needed to contain drug at concentration same as plasma
t12 Time for [drug] to darr 50(half life)
Cl Volume of blood cleared(clearance) of drug per unit time
PHARMACOKINETIC CONCEPTS
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait
Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure
PHARMACOKINETIC CONCEPTS
19
ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
14
PHARMACOKINETICS
bullTime course of drug absorption distribution metabolism amp excretion
bullDrug transport to amp from receptors
bullWhat the body does to the drug
15
PHARMACODYNAMICS
bull Relationships between drug concentrations amp responses
bull Drug activity at receptors
bull What the drug does to the body
16
CONCEPT DEFINITION
V (vol of distrib) Volume needed to contain drug at concentration same as plasma
t12 Time for [drug] to darr 50(half life)
Cl Volume of blood cleared(clearance) of drug per unit time
PHARMACOKINETIC CONCEPTS
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait
Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure
PHARMACOKINETIC CONCEPTS
19
ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
15
PHARMACODYNAMICS
bull Relationships between drug concentrations amp responses
bull Drug activity at receptors
bull What the drug does to the body
16
CONCEPT DEFINITION
V (vol of distrib) Volume needed to contain drug at concentration same as plasma
t12 Time for [drug] to darr 50(half life)
Cl Volume of blood cleared(clearance) of drug per unit time
PHARMACOKINETIC CONCEPTS
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait
Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure
PHARMACOKINETIC CONCEPTS
19
ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
16
CONCEPT DEFINITION
V (vol of distrib) Volume needed to contain drug at concentration same as plasma
t12 Time for [drug] to darr 50(half life)
Cl Volume of blood cleared(clearance) of drug per unit time
PHARMACOKINETIC CONCEPTS
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait
Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure
PHARMACOKINETIC CONCEPTS
19
ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait
Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure
PHARMACOKINETIC CONCEPTS
19
ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait
Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure
PHARMACOKINETIC CONCEPTS
19
ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
19
ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs
bull darr binding in renal d amp hyperthyroidism
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine
bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate
PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
trazodone anxiolytic)
METABOLITES COMPARED TOPARENT DRUGS
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
24
ACTIVE METABOLITES
Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)
valproate 2-ene-valproate 4-ene-valproate (toxic)
amitriptyline nortriptyline hydroxynortiptyline
IMIDMI imipramine desipramine hydroxy-IMI and DMI
amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)
citalopramdidesmethylcitalopram
venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion
trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
25
ACTIVE METABOLITES
diazepam N-desmethyldiazepamclorazepate N-
desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam
desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)
chlorpromazine hydroxychlorpromazinethioridazine mesoridazine
haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)
risperidone 9-hydroxyrisperidone aripiprazole dehydo-
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Tolerance BZ (sedation anticonvulsant) opiates (analgesia)
Withdrawal BZ (insomnia anxiety)
Response latency BZ - minutesLi CBZ VPA - days to wks
PHARMACODYNAMIC CONCEPTS
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
28
DRUG INTERACTIONS
PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion
PHARMACODYNAMIC- Direct - at same receptor site
(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites
(MAOI + SSRI serotonin toxicity)
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
31
KEY ISOFORMS FOR DRUG METABOLISM
ISOFORM
CYP1A2
CYP2C910
CYP2C19
CYP2D6
CYP2E1
CYP3A457
SUBSTRATES
TCAsclozolanz
phenytoinTHCS-warfarin
BZsTCAs
TCAsparoxmirtaz venla plusmnfluox
Etoh
BZsCBZSertraline
NefazodoneTCAs mirtazCa blockers
Oral contraceptives
INHIBITORScipro
fluvoxamine
fluvoxamine
fluoxfluvox
paroxfluox plusmnfluvox
plusmnsertradisulfiram
fluoxetine fluvoxaminenefazodone
diltiazemverapamil
macrolides
INDUCERS
Cig smokeomep
rifambarb
rifampin
-
EtohINH
CBZphenytoin phenobarb
rifampin St Johnrsquos wort
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
32
CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine
2deg amp 3deg tricyclics(hydroxylation)
trazodone
plusmn clozapine haloperidol
fluphenazineperphenazine risperidonethioridazine
codeinemexiletine
IC antiarrhythmicsβ blockers
INHIBITORS
bupropionfluoxetine
plusmn fluvoxamine paroxetineplusmn sertraline
moclobemide
fluphenazine haloperidol
perphenazine thioridazine
amiodaronecimetidinemethadonequinidine
Ritonavir et al
INDUCERS
-
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
33
CYP3A457SUBSTRATES
plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline
3deg tricyclics (demethylation)
alprazolam diazepam
midazolamtriazolam
buspironeCBZ
Ca blockersH1 blockers
local anestheticsmacrolides quinidinesteroids
INHIBITORS
fluvoxamine
nefazodone
diltiazemverapamil
cimetidineimidazolesmacrolidesnaringenin
INDUCERS
CBZphenobarbital
phenytoin
dexamethasonerifampin
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
34
INHIBITION PROFILES
POTENCY
highest
intermediate
lowest
CYP2D6
quinidine paroxetine fluoxetinebupropion
sertraline
fluvoxaminenefazodone venlafaxine
erythromycinketoconazole
CYP3A457
ketoconazoleclarithromycin
nefazodone
fluvoxamine
sertraline desmethylsertraline
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
35
INHIBITORS
barbituratescarbamazepine
phenytoinprimidone
cigarette smokechronic ethanol
isoniazidrifampin
glutethimideomeprazole
azole antifungalschloramphenicol
ciprofloxacincotrimoxazole
macrolidesmetronidazole
allopurinolcimetidine
omeprazolephenylbutazone
propranololpropoxyphene
quinidine
TCAs MAOIsbupropionfluoxetine
fluvoxamineparoxetineplusmn sertralinenefazodone
antipsychoticsacute ethanol
disulfirammethylphenidate
diltiazemverapamilvalproate
INDUCERS
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
36
GENETIC POLYMORPHISMS
CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox
venla plusmn fluox thioridazineIC antiarrhythmics β-blockers
CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates
omeprazole S-mephenytoin
N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
CARBAMAZEPINE METABOLISM
CYP3A34 EPOXIDEHYDROLASE
+
darr CBZ LEVELS WITHCARBAMAZEPINE (++)
FELBAMATE (+)PHENOBARBITAL (++)
PHENYTOIN (++)PRIMIDONE (++)
darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)
phenytoin (+)primidone (+)
uarrCBZ LEVELS WITHACETAZOLAMIDE
cimetidineCLARITHROMYCIN
DANAZOLDILTIAZEM
ERYTHROMYCINFLUOXETINE
FLUVOXAMINEgemfibrozilISONIAZID
NEFAZODONEnicotinamide
PROPOXYPHENEVERAPAMIL
uarr CBZ-E LEVELS WITHlamotrigine (-)
progabide (-)VALPROATE (-)
VALPROMIDE (--)
N
2NHO
CBZ
ACTIVEPARENT
DRUG
- -
+
molecular bichemical evidence supports CYP3A34
ACTIVEEPOXIDE
METABOLITE
CBZ-E
N
2NHO
O
INACTIVEDIOL
METABOLITE
CBZ-D
N
2NHO
OHHO
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
43
Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone
Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()
Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones
Methadone Warfarin RapacuroniumTramadol Rocuronium
Vecuronium
CarbamazepineDecreases Levels of Other Drugs
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
44
Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip
bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)
47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56
VALPROATE METABOLISM
VPA glucuronide
Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION
3-oxo-VPA
2-ene-VPA
VPA
3-ene-VPA
23-diene-VPA
CO H2
[3-OH-VPA]
40VPACONJUGATION P450 OXIDATION
VPA
4-ene-VPA
O
OHOHHO
CO H2OO
CO H2
24-diene-VPA
3-OH-VPA 4-OH-VPA 5-OH-VPA
PGAPSA4-oxo-VPA
50 503 4woxidw-1 oxidddehyrdro
CO H2
O
48
VPAPLASMA PROTEIN BINDING INTERACTIONS
VPA rarruarr FREE DRUG
CBZdiazepamphenytointiagabine
tolbutamidewarfarin
DRUG rarruarr FREE VPA
ASANSAIDs
49
DVPX METABOLIC INTERACTIONS
VPA rarruarr DRUG
amitriptylineCBZ-E
diazepamethosuximidelamotriginelorazepam
nortriptylinephenobarbital
phenytoinzidovudine
DRUG rarruarr VPA
ASAcimetidinefluoxetinefelbamate
erythromycinphenothiazines
DRUG rarrdarr VPA
CBZplusmn lamotriginemefloquine
phenobarbitalphenytoinrifampin
50
KEY ISOFORMS FORANTIDEPRESSANT METABOLISM
ISOFORM
CYP1A2
CYP2C19
CYP2D6
CYP3A457
SUBSTRATES
TCAs plusmn mirtazdulox
plusmn citalopram TCAs
plusmn fluoxetineplusmn mirtazapine
paroxetine duloxvenlafaxineTCAs trazodone
plusmn citalopramplusmn mirtazapinenefazodonereboxetine
sertraline TCAs
INHIBITORS
fluvoxamine
fluox fluvox
bupropionfluoxetine
plusmn fluvoxamineparoxetineplusmn sertraline
fluvoxaminenefazodoneplusmn sertraline
INDUCERS
cigs omep
rifampin
-
CBZphenytoin
phenobarbrifampin
51
TRICYCLIC ANTIDEPRESSANTS
bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)
75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs
amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI
(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]
(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)
52
TRICYCLIC INTERACTIONS
VIA 2D6
fluoxetineplusmn sertraline paroxetinehaloperidol
phenothiazinesmethadone
propafenonequinidine
DRUG rarruarr TCA
VIA
methylphenidate()disulfiram
acute ethanolvalproate ()
azole antifungals ()BCPs ()
cimetidinechloramphenicol
53
TRICYCLIC INTERACTIONS
DRUG rarrdarr TCA
carbamazepinechronic ethanolcigarette smokephenobarbital
phenytoinrifampin ()
TCA rarruarr DRUG
phenytoin ()warfarin ()
54
IMIPRAMINE METABOLISM
ACTIVE 2-HYDROXY METABOLITE
2-OH-IMI
IMI
ACTIVE PARENT
DRUG
N N
N N
OH
N N
DMI
ACTIVE N-DEMETHYL METABOLITE
2D6
-
2D6-
2-OH-DMIOH
N N
1A2 2C19 3A4- +
1A2 2C19 3A4
SSRIs HALOPERIDOL
PHENOTHIAZINES
SSRIs
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
RATE LIMITING REACTION GLUCURONIDES
ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
- +
SSRIs
SSRIs HALOPERIDOL
PHENOTHIAZINES
55
SSRIs amp SNRIs
DrugInhibits
SubstrateMetabolite
bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine
bullSNRI - duloxetine venlafaxine
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
59
PAROXETINE INTERACTIONS
PAROXETINE rarruarr DRUG
VIA 2D6AMI IMI
NORT DMIphenothiazinesIC antiarrhythmics
(propafenone flecainide encainide)beta blockersatomoxetine
60
FLUVOXAMINE
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip
bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)
47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56
VALPROATE METABOLISM
VPA glucuronide
Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION
3-oxo-VPA
2-ene-VPA
VPA
3-ene-VPA
23-diene-VPA
CO H2
[3-OH-VPA]
40VPACONJUGATION P450 OXIDATION
VPA
4-ene-VPA
O
OHOHHO
CO H2OO
CO H2
24-diene-VPA
3-OH-VPA 4-OH-VPA 5-OH-VPA
PGAPSA4-oxo-VPA
50 503 4woxidw-1 oxidddehyrdro
CO H2
O
48
VPAPLASMA PROTEIN BINDING INTERACTIONS
VPA rarruarr FREE DRUG
CBZdiazepamphenytointiagabine
tolbutamidewarfarin
DRUG rarruarr FREE VPA
ASANSAIDs
49
DVPX METABOLIC INTERACTIONS
VPA rarruarr DRUG
amitriptylineCBZ-E
diazepamethosuximidelamotriginelorazepam
nortriptylinephenobarbital
phenytoinzidovudine
DRUG rarruarr VPA
ASAcimetidinefluoxetinefelbamate
erythromycinphenothiazines
DRUG rarrdarr VPA
CBZplusmn lamotriginemefloquine
phenobarbitalphenytoinrifampin
50
KEY ISOFORMS FORANTIDEPRESSANT METABOLISM
ISOFORM
CYP1A2
CYP2C19
CYP2D6
CYP3A457
SUBSTRATES
TCAs plusmn mirtazdulox
plusmn citalopram TCAs
plusmn fluoxetineplusmn mirtazapine
paroxetine duloxvenlafaxineTCAs trazodone
plusmn citalopramplusmn mirtazapinenefazodonereboxetine
sertraline TCAs
INHIBITORS
fluvoxamine
fluox fluvox
bupropionfluoxetine
plusmn fluvoxamineparoxetineplusmn sertraline
fluvoxaminenefazodoneplusmn sertraline
INDUCERS
cigs omep
rifampin
-
CBZphenytoin
phenobarbrifampin
51
TRICYCLIC ANTIDEPRESSANTS
bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)
75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs
amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI
(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]
(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)
52
TRICYCLIC INTERACTIONS
VIA 2D6
fluoxetineplusmn sertraline paroxetinehaloperidol
phenothiazinesmethadone
propafenonequinidine
DRUG rarruarr TCA
VIA
methylphenidate()disulfiram
acute ethanolvalproate ()
azole antifungals ()BCPs ()
cimetidinechloramphenicol
53
TRICYCLIC INTERACTIONS
DRUG rarrdarr TCA
carbamazepinechronic ethanolcigarette smokephenobarbital
phenytoinrifampin ()
TCA rarruarr DRUG
phenytoin ()warfarin ()
54
IMIPRAMINE METABOLISM
ACTIVE 2-HYDROXY METABOLITE
2-OH-IMI
IMI
ACTIVE PARENT
DRUG
N N
N N
OH
N N
DMI
ACTIVE N-DEMETHYL METABOLITE
2D6
-
2D6-
2-OH-DMIOH
N N
1A2 2C19 3A4- +
1A2 2C19 3A4
SSRIs HALOPERIDOL
PHENOTHIAZINES
SSRIs
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
RATE LIMITING REACTION GLUCURONIDES
ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
- +
SSRIs
SSRIs HALOPERIDOL
PHENOTHIAZINES
55
SSRIs amp SNRIs
DrugInhibits
SubstrateMetabolite
bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine
bullSNRI - duloxetine venlafaxine
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
59
PAROXETINE INTERACTIONS
PAROXETINE rarruarr DRUG
VIA 2D6AMI IMI
NORT DMIphenothiazinesIC antiarrhythmics
(propafenone flecainide encainide)beta blockersatomoxetine
60
FLUVOXAMINE
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56
VALPROATE METABOLISM
VPA glucuronide
Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION
3-oxo-VPA
2-ene-VPA
VPA
3-ene-VPA
23-diene-VPA
CO H2
[3-OH-VPA]
40VPACONJUGATION P450 OXIDATION
VPA
4-ene-VPA
O
OHOHHO
CO H2OO
CO H2
24-diene-VPA
3-OH-VPA 4-OH-VPA 5-OH-VPA
PGAPSA4-oxo-VPA
50 503 4woxidw-1 oxidddehyrdro
CO H2
O
48
VPAPLASMA PROTEIN BINDING INTERACTIONS
VPA rarruarr FREE DRUG
CBZdiazepamphenytointiagabine
tolbutamidewarfarin
DRUG rarruarr FREE VPA
ASANSAIDs
49
DVPX METABOLIC INTERACTIONS
VPA rarruarr DRUG
amitriptylineCBZ-E
diazepamethosuximidelamotriginelorazepam
nortriptylinephenobarbital
phenytoinzidovudine
DRUG rarruarr VPA
ASAcimetidinefluoxetinefelbamate
erythromycinphenothiazines
DRUG rarrdarr VPA
CBZplusmn lamotriginemefloquine
phenobarbitalphenytoinrifampin
50
KEY ISOFORMS FORANTIDEPRESSANT METABOLISM
ISOFORM
CYP1A2
CYP2C19
CYP2D6
CYP3A457
SUBSTRATES
TCAs plusmn mirtazdulox
plusmn citalopram TCAs
plusmn fluoxetineplusmn mirtazapine
paroxetine duloxvenlafaxineTCAs trazodone
plusmn citalopramplusmn mirtazapinenefazodonereboxetine
sertraline TCAs
INHIBITORS
fluvoxamine
fluox fluvox
bupropionfluoxetine
plusmn fluvoxamineparoxetineplusmn sertraline
fluvoxaminenefazodoneplusmn sertraline
INDUCERS
cigs omep
rifampin
-
CBZphenytoin
phenobarbrifampin
51
TRICYCLIC ANTIDEPRESSANTS
bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)
75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs
amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI
(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]
(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)
52
TRICYCLIC INTERACTIONS
VIA 2D6
fluoxetineplusmn sertraline paroxetinehaloperidol
phenothiazinesmethadone
propafenonequinidine
DRUG rarruarr TCA
VIA
methylphenidate()disulfiram
acute ethanolvalproate ()
azole antifungals ()BCPs ()
cimetidinechloramphenicol
53
TRICYCLIC INTERACTIONS
DRUG rarrdarr TCA
carbamazepinechronic ethanolcigarette smokephenobarbital
phenytoinrifampin ()
TCA rarruarr DRUG
phenytoin ()warfarin ()
54
IMIPRAMINE METABOLISM
ACTIVE 2-HYDROXY METABOLITE
2-OH-IMI
IMI
ACTIVE PARENT
DRUG
N N
N N
OH
N N
DMI
ACTIVE N-DEMETHYL METABOLITE
2D6
-
2D6-
2-OH-DMIOH
N N
1A2 2C19 3A4- +
1A2 2C19 3A4
SSRIs HALOPERIDOL
PHENOTHIAZINES
SSRIs
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
RATE LIMITING REACTION GLUCURONIDES
ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
- +
SSRIs
SSRIs HALOPERIDOL
PHENOTHIAZINES
55
SSRIs amp SNRIs
DrugInhibits
SubstrateMetabolite
bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine
bullSNRI - duloxetine venlafaxine
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
59
PAROXETINE INTERACTIONS
PAROXETINE rarruarr DRUG
VIA 2D6AMI IMI
NORT DMIphenothiazinesIC antiarrhythmics
(propafenone flecainide encainide)beta blockersatomoxetine
60
FLUVOXAMINE
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
48
VPAPLASMA PROTEIN BINDING INTERACTIONS
VPA rarruarr FREE DRUG
CBZdiazepamphenytointiagabine
tolbutamidewarfarin
DRUG rarruarr FREE VPA
ASANSAIDs
49
DVPX METABOLIC INTERACTIONS
VPA rarruarr DRUG
amitriptylineCBZ-E
diazepamethosuximidelamotriginelorazepam
nortriptylinephenobarbital
phenytoinzidovudine
DRUG rarruarr VPA
ASAcimetidinefluoxetinefelbamate
erythromycinphenothiazines
DRUG rarrdarr VPA
CBZplusmn lamotriginemefloquine
phenobarbitalphenytoinrifampin
50
KEY ISOFORMS FORANTIDEPRESSANT METABOLISM
ISOFORM
CYP1A2
CYP2C19
CYP2D6
CYP3A457
SUBSTRATES
TCAs plusmn mirtazdulox
plusmn citalopram TCAs
plusmn fluoxetineplusmn mirtazapine
paroxetine duloxvenlafaxineTCAs trazodone
plusmn citalopramplusmn mirtazapinenefazodonereboxetine
sertraline TCAs
INHIBITORS
fluvoxamine
fluox fluvox
bupropionfluoxetine
plusmn fluvoxamineparoxetineplusmn sertraline
fluvoxaminenefazodoneplusmn sertraline
INDUCERS
cigs omep
rifampin
-
CBZphenytoin
phenobarbrifampin
51
TRICYCLIC ANTIDEPRESSANTS
bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)
75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs
amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI
(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]
(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)
52
TRICYCLIC INTERACTIONS
VIA 2D6
fluoxetineplusmn sertraline paroxetinehaloperidol
phenothiazinesmethadone
propafenonequinidine
DRUG rarruarr TCA
VIA
methylphenidate()disulfiram
acute ethanolvalproate ()
azole antifungals ()BCPs ()
cimetidinechloramphenicol
53
TRICYCLIC INTERACTIONS
DRUG rarrdarr TCA
carbamazepinechronic ethanolcigarette smokephenobarbital
phenytoinrifampin ()
TCA rarruarr DRUG
phenytoin ()warfarin ()
54
IMIPRAMINE METABOLISM
ACTIVE 2-HYDROXY METABOLITE
2-OH-IMI
IMI
ACTIVE PARENT
DRUG
N N
N N
OH
N N
DMI
ACTIVE N-DEMETHYL METABOLITE
2D6
-
2D6-
2-OH-DMIOH
N N
1A2 2C19 3A4- +
1A2 2C19 3A4
SSRIs HALOPERIDOL
PHENOTHIAZINES
SSRIs
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
RATE LIMITING REACTION GLUCURONIDES
ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
- +
SSRIs
SSRIs HALOPERIDOL
PHENOTHIAZINES
55
SSRIs amp SNRIs
DrugInhibits
SubstrateMetabolite
bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine
bullSNRI - duloxetine venlafaxine
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
59
PAROXETINE INTERACTIONS
PAROXETINE rarruarr DRUG
VIA 2D6AMI IMI
NORT DMIphenothiazinesIC antiarrhythmics
(propafenone flecainide encainide)beta blockersatomoxetine
60
FLUVOXAMINE
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
49
DVPX METABOLIC INTERACTIONS
VPA rarruarr DRUG
amitriptylineCBZ-E
diazepamethosuximidelamotriginelorazepam
nortriptylinephenobarbital
phenytoinzidovudine
DRUG rarruarr VPA
ASAcimetidinefluoxetinefelbamate
erythromycinphenothiazines
DRUG rarrdarr VPA
CBZplusmn lamotriginemefloquine
phenobarbitalphenytoinrifampin
50
KEY ISOFORMS FORANTIDEPRESSANT METABOLISM
ISOFORM
CYP1A2
CYP2C19
CYP2D6
CYP3A457
SUBSTRATES
TCAs plusmn mirtazdulox
plusmn citalopram TCAs
plusmn fluoxetineplusmn mirtazapine
paroxetine duloxvenlafaxineTCAs trazodone
plusmn citalopramplusmn mirtazapinenefazodonereboxetine
sertraline TCAs
INHIBITORS
fluvoxamine
fluox fluvox
bupropionfluoxetine
plusmn fluvoxamineparoxetineplusmn sertraline
fluvoxaminenefazodoneplusmn sertraline
INDUCERS
cigs omep
rifampin
-
CBZphenytoin
phenobarbrifampin
51
TRICYCLIC ANTIDEPRESSANTS
bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)
75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs
amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI
(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]
(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)
52
TRICYCLIC INTERACTIONS
VIA 2D6
fluoxetineplusmn sertraline paroxetinehaloperidol
phenothiazinesmethadone
propafenonequinidine
DRUG rarruarr TCA
VIA
methylphenidate()disulfiram
acute ethanolvalproate ()
azole antifungals ()BCPs ()
cimetidinechloramphenicol
53
TRICYCLIC INTERACTIONS
DRUG rarrdarr TCA
carbamazepinechronic ethanolcigarette smokephenobarbital
phenytoinrifampin ()
TCA rarruarr DRUG
phenytoin ()warfarin ()
54
IMIPRAMINE METABOLISM
ACTIVE 2-HYDROXY METABOLITE
2-OH-IMI
IMI
ACTIVE PARENT
DRUG
N N
N N
OH
N N
DMI
ACTIVE N-DEMETHYL METABOLITE
2D6
-
2D6-
2-OH-DMIOH
N N
1A2 2C19 3A4- +
1A2 2C19 3A4
SSRIs HALOPERIDOL
PHENOTHIAZINES
SSRIs
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
RATE LIMITING REACTION GLUCURONIDES
ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
- +
SSRIs
SSRIs HALOPERIDOL
PHENOTHIAZINES
55
SSRIs amp SNRIs
DrugInhibits
SubstrateMetabolite
bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine
bullSNRI - duloxetine venlafaxine
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
59
PAROXETINE INTERACTIONS
PAROXETINE rarruarr DRUG
VIA 2D6AMI IMI
NORT DMIphenothiazinesIC antiarrhythmics
(propafenone flecainide encainide)beta blockersatomoxetine
60
FLUVOXAMINE
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
50
KEY ISOFORMS FORANTIDEPRESSANT METABOLISM
ISOFORM
CYP1A2
CYP2C19
CYP2D6
CYP3A457
SUBSTRATES
TCAs plusmn mirtazdulox
plusmn citalopram TCAs
plusmn fluoxetineplusmn mirtazapine
paroxetine duloxvenlafaxineTCAs trazodone
plusmn citalopramplusmn mirtazapinenefazodonereboxetine
sertraline TCAs
INHIBITORS
fluvoxamine
fluox fluvox
bupropionfluoxetine
plusmn fluvoxamineparoxetineplusmn sertraline
fluvoxaminenefazodoneplusmn sertraline
INDUCERS
cigs omep
rifampin
-
CBZphenytoin
phenobarbrifampin
51
TRICYCLIC ANTIDEPRESSANTS
bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)
75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs
amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI
(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]
(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)
52
TRICYCLIC INTERACTIONS
VIA 2D6
fluoxetineplusmn sertraline paroxetinehaloperidol
phenothiazinesmethadone
propafenonequinidine
DRUG rarruarr TCA
VIA
methylphenidate()disulfiram
acute ethanolvalproate ()
azole antifungals ()BCPs ()
cimetidinechloramphenicol
53
TRICYCLIC INTERACTIONS
DRUG rarrdarr TCA
carbamazepinechronic ethanolcigarette smokephenobarbital
phenytoinrifampin ()
TCA rarruarr DRUG
phenytoin ()warfarin ()
54
IMIPRAMINE METABOLISM
ACTIVE 2-HYDROXY METABOLITE
2-OH-IMI
IMI
ACTIVE PARENT
DRUG
N N
N N
OH
N N
DMI
ACTIVE N-DEMETHYL METABOLITE
2D6
-
2D6-
2-OH-DMIOH
N N
1A2 2C19 3A4- +
1A2 2C19 3A4
SSRIs HALOPERIDOL
PHENOTHIAZINES
SSRIs
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
RATE LIMITING REACTION GLUCURONIDES
ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
- +
SSRIs
SSRIs HALOPERIDOL
PHENOTHIAZINES
55
SSRIs amp SNRIs
DrugInhibits
SubstrateMetabolite
bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine
bullSNRI - duloxetine venlafaxine
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
59
PAROXETINE INTERACTIONS
PAROXETINE rarruarr DRUG
VIA 2D6AMI IMI
NORT DMIphenothiazinesIC antiarrhythmics
(propafenone flecainide encainide)beta blockersatomoxetine
60
FLUVOXAMINE
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
51
TRICYCLIC ANTIDEPRESSANTS
bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)
75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs
amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI
(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]
(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)
52
TRICYCLIC INTERACTIONS
VIA 2D6
fluoxetineplusmn sertraline paroxetinehaloperidol
phenothiazinesmethadone
propafenonequinidine
DRUG rarruarr TCA
VIA
methylphenidate()disulfiram
acute ethanolvalproate ()
azole antifungals ()BCPs ()
cimetidinechloramphenicol
53
TRICYCLIC INTERACTIONS
DRUG rarrdarr TCA
carbamazepinechronic ethanolcigarette smokephenobarbital
phenytoinrifampin ()
TCA rarruarr DRUG
phenytoin ()warfarin ()
54
IMIPRAMINE METABOLISM
ACTIVE 2-HYDROXY METABOLITE
2-OH-IMI
IMI
ACTIVE PARENT
DRUG
N N
N N
OH
N N
DMI
ACTIVE N-DEMETHYL METABOLITE
2D6
-
2D6-
2-OH-DMIOH
N N
1A2 2C19 3A4- +
1A2 2C19 3A4
SSRIs HALOPERIDOL
PHENOTHIAZINES
SSRIs
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
RATE LIMITING REACTION GLUCURONIDES
ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
- +
SSRIs
SSRIs HALOPERIDOL
PHENOTHIAZINES
55
SSRIs amp SNRIs
DrugInhibits
SubstrateMetabolite
bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine
bullSNRI - duloxetine venlafaxine
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
59
PAROXETINE INTERACTIONS
PAROXETINE rarruarr DRUG
VIA 2D6AMI IMI
NORT DMIphenothiazinesIC antiarrhythmics
(propafenone flecainide encainide)beta blockersatomoxetine
60
FLUVOXAMINE
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
52
TRICYCLIC INTERACTIONS
VIA 2D6
fluoxetineplusmn sertraline paroxetinehaloperidol
phenothiazinesmethadone
propafenonequinidine
DRUG rarruarr TCA
VIA
methylphenidate()disulfiram
acute ethanolvalproate ()
azole antifungals ()BCPs ()
cimetidinechloramphenicol
53
TRICYCLIC INTERACTIONS
DRUG rarrdarr TCA
carbamazepinechronic ethanolcigarette smokephenobarbital
phenytoinrifampin ()
TCA rarruarr DRUG
phenytoin ()warfarin ()
54
IMIPRAMINE METABOLISM
ACTIVE 2-HYDROXY METABOLITE
2-OH-IMI
IMI
ACTIVE PARENT
DRUG
N N
N N
OH
N N
DMI
ACTIVE N-DEMETHYL METABOLITE
2D6
-
2D6-
2-OH-DMIOH
N N
1A2 2C19 3A4- +
1A2 2C19 3A4
SSRIs HALOPERIDOL
PHENOTHIAZINES
SSRIs
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
RATE LIMITING REACTION GLUCURONIDES
ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
- +
SSRIs
SSRIs HALOPERIDOL
PHENOTHIAZINES
55
SSRIs amp SNRIs
DrugInhibits
SubstrateMetabolite
bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine
bullSNRI - duloxetine venlafaxine
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
59
PAROXETINE INTERACTIONS
PAROXETINE rarruarr DRUG
VIA 2D6AMI IMI
NORT DMIphenothiazinesIC antiarrhythmics
(propafenone flecainide encainide)beta blockersatomoxetine
60
FLUVOXAMINE
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
53
TRICYCLIC INTERACTIONS
DRUG rarrdarr TCA
carbamazepinechronic ethanolcigarette smokephenobarbital
phenytoinrifampin ()
TCA rarruarr DRUG
phenytoin ()warfarin ()
54
IMIPRAMINE METABOLISM
ACTIVE 2-HYDROXY METABOLITE
2-OH-IMI
IMI
ACTIVE PARENT
DRUG
N N
N N
OH
N N
DMI
ACTIVE N-DEMETHYL METABOLITE
2D6
-
2D6-
2-OH-DMIOH
N N
1A2 2C19 3A4- +
1A2 2C19 3A4
SSRIs HALOPERIDOL
PHENOTHIAZINES
SSRIs
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
RATE LIMITING REACTION GLUCURONIDES
ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
- +
SSRIs
SSRIs HALOPERIDOL
PHENOTHIAZINES
55
SSRIs amp SNRIs
DrugInhibits
SubstrateMetabolite
bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine
bullSNRI - duloxetine venlafaxine
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
59
PAROXETINE INTERACTIONS
PAROXETINE rarruarr DRUG
VIA 2D6AMI IMI
NORT DMIphenothiazinesIC antiarrhythmics
(propafenone flecainide encainide)beta blockersatomoxetine
60
FLUVOXAMINE
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
54
IMIPRAMINE METABOLISM
ACTIVE 2-HYDROXY METABOLITE
2-OH-IMI
IMI
ACTIVE PARENT
DRUG
N N
N N
OH
N N
DMI
ACTIVE N-DEMETHYL METABOLITE
2D6
-
2D6-
2-OH-DMIOH
N N
1A2 2C19 3A4- +
1A2 2C19 3A4
SSRIs HALOPERIDOL
PHENOTHIAZINES
SSRIs
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
RATE LIMITING REACTION GLUCURONIDES
ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN CIGS
- +
SSRIs
SSRIs HALOPERIDOL
PHENOTHIAZINES
55
SSRIs amp SNRIs
DrugInhibits
SubstrateMetabolite
bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine
bullSNRI - duloxetine venlafaxine
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
59
PAROXETINE INTERACTIONS
PAROXETINE rarruarr DRUG
VIA 2D6AMI IMI
NORT DMIphenothiazinesIC antiarrhythmics
(propafenone flecainide encainide)beta blockersatomoxetine
60
FLUVOXAMINE
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
55
SSRIs amp SNRIs
DrugInhibits
SubstrateMetabolite
bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine
bullSNRI - duloxetine venlafaxine
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
59
PAROXETINE INTERACTIONS
PAROXETINE rarruarr DRUG
VIA 2D6AMI IMI
NORT DMIphenothiazinesIC antiarrhythmics
(propafenone flecainide encainide)beta blockersatomoxetine
60
FLUVOXAMINE
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
59
PAROXETINE INTERACTIONS
PAROXETINE rarruarr DRUG
VIA 2D6AMI IMI
NORT DMIphenothiazinesIC antiarrhythmics
(propafenone flecainide encainide)beta blockersatomoxetine
60
FLUVOXAMINE
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
59
PAROXETINE INTERACTIONS
PAROXETINE rarruarr DRUG
VIA 2D6AMI IMI
NORT DMIphenothiazinesIC antiarrhythmics
(propafenone flecainide encainide)beta blockersatomoxetine
60
FLUVOXAMINE
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
59
PAROXETINE INTERACTIONS
PAROXETINE rarruarr DRUG
VIA 2D6AMI IMI
NORT DMIphenothiazinesIC antiarrhythmics
(propafenone flecainide encainide)beta blockersatomoxetine
60
FLUVOXAMINE
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
59
PAROXETINE INTERACTIONS
PAROXETINE rarruarr DRUG
VIA 2D6AMI IMI
NORT DMIphenothiazinesIC antiarrhythmics
(propafenone flecainide encainide)beta blockersatomoxetine
60
FLUVOXAMINE
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
60
FLUVOXAMINE
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
66
CITALOPRAM INTERACTIONS
VIA 2D6
DMI(citalopram given with IMI)
metoprolol
CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM
VIA
cimetidineCMI
fluvoxamine
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
67
PHARMACOKINETICS OFSSRIs AND SNRIs
fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram
drug t12 4 d 26 h 21 h 16 h 5 h 35 h
metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80
Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d
bull 85 MAO inhibition neededbull Therapeutic index
ndash Phenelzine - lowndash Tranylcypromine - low-mod
bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism
ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
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- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
72
MAO INHIBITORS
SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)
SERIOUS drug interactionsSSRI CMI stimulants
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
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- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
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- Nuacutemero de diapositiva 52
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- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
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- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
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- Nuacutemero de diapositiva 93
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- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
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- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite
(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine
bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
76
NEFAZODONE INTERACTIONS
NEFAZODONE rarruarr DRUG
VIA 3A34alprazolamtriazolam
carbamazepinecyclosporin
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
77
ANTIHISTAMINE INTERACTIONS
DRUG rarruarr ANTIHISTAMINE
VIA 3A34ketoconazoleitraconazolefluconazole
erythromycinclarithromycintroleandomycinnefazodone fluvoxamine
ANTIHISTAMINES
METABOLIZED VIA 3A34
loratadine (Claritin)cetirizine (Zyrtec)
fexofenadine (Allegra)
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite
110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam
bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)
bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam
desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)
7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
VIA 2C19 3A34fluoxetine
fluvoxaminedisulfiram
BCPsketoconazole
cimetidineisoniazid
omeprazolepropranolol
DRUG rarruarr TRIAZOLO BZalprazolam triazolam
VIA 3A34 fluoxetine
fluvoxaminenefazodone
diltiazemBCPs
ketoconazolecimetidine
erythromycinpropoxyphene
BENZODIAZEPINE INTERACTIONS
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
83
TRIAZOLOalprazolamtriazolam
4-hydroxylation [3A4]-hydroxylation [3A4]
uarr metabolism withCBZ
darr metabolism with fluoxetine fluvoxamine
nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene
2-KETOclorazepate diazepam
flurazepam
N-dealkylation [2C19] rarr3-hydroxylation [3A4]
uarr metabolism withcigs barbiturate
rifampin
darr metabolism withfluoxetine fluvoxamine
disulfiram isoniazidBCPs cimetidine
ketoconazoleomeprazolepropranolol
BZ INTERACTIONS
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
84
DIAZEPAM METABOLISM
OXAZEPAM
2C19 (3A4)
ACTIVE 3-HYDROXY-BZ
(DIRECTLY CONJUGATED)
+ - + -
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
ACTIVE 2-KETO-BZ
N
N
O
ClN
HN
O
Cl
ACTIVE METABOLITE
N
O
Cl
HN
N-DEALKYLATION 3-HYDROXYLATION
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
DIAZEPAM N-DESMETHYL-DIAZEPAM
3A4 (2C19)
BCPs CIMETIDINE FLUOXETINE
FLUVOXAMINE OMEPRAZOLE
OH
CH3
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
85
ALPRAZOLAM METABOLISM
ALPRAZOLAM
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
+ -3A4
α-HYDROXYLATION
α-HYDROXY-ALPRAZOLAM
N
N
Cl
N
N
N
N
Cl
N
N
N
N
Cl
H3C
N
N
4-HYDROXY-ALPRAZOLAM+ -
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
CARBAMAZEPINE PHENOBARBITAL
PHENYTOIN RIFAMPIN
3A4
4-HYDROXYLA
TION
CIMETIDINE FLUOXETINE
FLUVOXAMINE KETOCONAZOLE
NEFAZODONE
OH
H3C
HO
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
86
DRUG
haloperidolfluphenazineperphenazinethioridazine
clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine
SUBSTRATE OF
2D62D6+-1A2
2D62D6
1A2 plusmn 2D62D6 3A4UGTs1A2
Aldehyde ox3A4 plusmn 1A22D6 3A4
3A4
INHIBITS
2D62D62D62D6
----
ANTIPSYCHOTIC METABOLISM
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull Low therapeutic index (neurotoxicity)
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
88
TYPICAL ANTIPSYCHOTIC INTERACTIONS
DRUGrarrdarrAPcarbamazepinephenobarbital
phenytoincigarettesrifampin
AP rarruarr DRUGtricyclics
DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)
bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
(in 2 divided doses)bull Metabolism
ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)
bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels
ZIPRASIDONE
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
ARIPIPRAZOLE
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
96
DRUG
carbamazepinevalproatefelbamategabapentinlamotriginetopiramate
tiagabineoxcarbazepinevigabatrinzonisamide
SUBSTRATE OF
3A4conjgt-oxidgtP450oxid
renalgtconjoxid renal excretion
conjugationrenalgthydroxhydrolconj
3A4 conjugationreduction
renal excretion3A4 (reduction)
INDUCES INHIBITS
induces 3A4 UGTsweak inhibitorinduces 3A4
-Weak inducer UGTs
plusmn inhibits 2C19 induces 3A4
-induces 3A4
--
ANTICONVULSANT ELIMINATION
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]
bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity
(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives
TOPIRAMATE
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
103
ZONISAMIDE
bull 15 bound
bull t12 = 60 h with monoRx
t12 = 30 h with inducers
bull Cl = 20 mL min
bull Reduced to 2-sulfamoylacetylphenol (SMAP)
bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd
bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
-
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
- Nuacutemero de diapositiva 1
- Teaching Points
- Pre Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Outline
- Nuacutemero de diapositiva 14
- Nuacutemero de diapositiva 15
- Nuacutemero de diapositiva 16
- Nuacutemero de diapositiva 17
- Nuacutemero de diapositiva 18
- Nuacutemero de diapositiva 19
- Nuacutemero de diapositiva 20
- Nuacutemero de diapositiva 21
- Nuacutemero de diapositiva 22
- Nuacutemero de diapositiva 23
- Nuacutemero de diapositiva 24
- Nuacutemero de diapositiva 25
- Nuacutemero de diapositiva 26
- Nuacutemero de diapositiva 27
- Nuacutemero de diapositiva 28
- Nuacutemero de diapositiva 29
- Nuacutemero de diapositiva 30
- Nuacutemero de diapositiva 31
- Nuacutemero de diapositiva 32
- Nuacutemero de diapositiva 33
- Nuacutemero de diapositiva 34
- Nuacutemero de diapositiva 35
- Nuacutemero de diapositiva 36
- Nuacutemero de diapositiva 37
- Nuacutemero de diapositiva 38
- LITHIUM
- Nuacutemero de diapositiva 40
- CARBAMAZEPINE
- Nuacutemero de diapositiva 42
- Nuacutemero de diapositiva 43
- Nuacutemero de diapositiva 44
- Nuacutemero de diapositiva 45
- VALPROATE
- Nuacutemero de diapositiva 47
- Nuacutemero de diapositiva 48
- Nuacutemero de diapositiva 49
- Nuacutemero de diapositiva 50
- Nuacutemero de diapositiva 51
- Nuacutemero de diapositiva 52
- Nuacutemero de diapositiva 53
- Nuacutemero de diapositiva 54
- SSRIs amp SNRIs
- FLUOXETINE
- Nuacutemero de diapositiva 57
- PAROXETINE
- Nuacutemero de diapositiva 59
- Nuacutemero de diapositiva 60
- Nuacutemero de diapositiva 61
- SERTRALINE
- VENLAFAXINE
- DULOXETINE
- CITALOPRAM-racemic mixtureescitalopram-enantiomer
- Nuacutemero de diapositiva 66
- PHARMACOKINETICS OFSSRIs AND SNRIs
- BUPROPION
- Nuacutemero de diapositiva 69
- Nuacutemero de diapositiva 70
- Nuacutemero de diapositiva 71
- MAO INHIBITORS
- MAO INHIBITOR INTERACTIONS
- Nuacutemero de diapositiva 74
- Nuacutemero de diapositiva 75
- Nuacutemero de diapositiva 76
- Nuacutemero de diapositiva 77
- Nuacutemero de diapositiva 78
- Nuacutemero de diapositiva 79
- BENZODIAZEPINES
- Nuacutemero de diapositiva 81
- Nuacutemero de diapositiva 82
- Nuacutemero de diapositiva 83
- Nuacutemero de diapositiva 84
- Nuacutemero de diapositiva 85
- Nuacutemero de diapositiva 86
- TYPCIAL ANTIPSYCHOTICS
- Nuacutemero de diapositiva 88
- Nuacutemero de diapositiva 89
- Nuacutemero de diapositiva 90
- Nuacutemero de diapositiva 91
- Nuacutemero de diapositiva 92
- Nuacutemero de diapositiva 93
- Nuacutemero de diapositiva 94
- Nuacutemero de diapositiva 95
- Nuacutemero de diapositiva 96
- Nuacutemero de diapositiva 97
- Nuacutemero de diapositiva 98
- Lamotrigine Titration Influenced by Valproate and Carbamazepine
- Nuacutemero de diapositiva 100
- Nuacutemero de diapositiva 101
- OXCARBAZEPINE
- Nuacutemero de diapositiva 103
- Nuacutemero de diapositiva 104
- Nuacutemero de diapositiva 105
- CONCLUSIONS
- Nuacutemero de diapositiva 107
- Post Lecture ExamQuestion 1
- Question 2
- Question 3
- Question 4
- Question 5
- Question 6
- Question 7
- Question 8
- Question 9
- Question 10
- Answers to Pre amp PostCompetency Exams
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