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Transcript of 1 Antipsychotics and Mood Stabilizers: Pharmacokinetics Adverse Effects Drug Interactions Philip G....
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Antipsychotics andAntipsychotics andMood Stabilizers:Mood Stabilizers:
PharmacokineticsPharmacokineticsAdverse EffectsAdverse Effects
Drug InteractionsDrug Interactions
Philip G. Janicak, MDPhilip G. Janicak, MD
Professor of PsychiatryProfessor of Psychiatry
Rush University Medical CenterRush University Medical Center
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GoalsGoals AntipsychoticsAntipsychotics
Diagnostic indicationsDiagnostic indications Classification Classification Relevant PharmacokineticsRelevant Pharmacokinetics Serious Adverse EffectsSerious Adverse Effects Drug InteractionsDrug Interactions
Mood StabilizersMood Stabilizers Diagnostic indicationsDiagnostic indications Classification Classification Relevant PharmacokineticsRelevant Pharmacokinetics Serious Adverse EffectsSerious Adverse Effects Drug InteractionsDrug Interactions
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Antipsychotics:Antipsychotics:Diagnostic IndicationsDiagnostic Indications
PsychiatricPsychiatric SchizophreniaSchizophrenia Schizoaffective disorderSchizoaffective disorder Mood disorders with psychosisMood disorders with psychosis Delusional disorderDelusional disorder
NonpsychiatricNonpsychiatric Dementia/DeliriumDementia/Delirium Psychosis secondary to a non-psychiatric medical disorder Psychosis secondary to a non-psychiatric medical disorder Developmental disability with psychosis and/or aggressionDevelopmental disability with psychosis and/or aggression Tourette’s disorderTourette’s disorder Nausea, vomitingNausea, vomiting
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Positive symptoms:
Delusions*Hallucinations*Disorganized speechCatatonia
Cognitive symptoms:
AttentionMemoryExecutive functions
Moodsymptoms:
DysphoriaSuicidalityHelplessness
Negativesymptoms:
Affective flatteningAlogiaAvolitionAnhedoniaSocial inattentiveness
Occupational
Interpersonal
Self- care
Social
Work
Impact of Schizophrenic Impact of Schizophrenic Symptoms on Overall Symptoms on Overall
FunctioningFunctioning
*Schneiderian First Rank Symptoms4
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Pharmacokinetics of Pharmacokinetics of AntipsychoticsAntipsychotics
ADME profilesADME profiles All are readily absorbedAll are readily absorbed All are metabolized by the hepatic cytochrome All are metabolized by the hepatic cytochrome
P450 systemP450 system prone to drug interactionsprone to drug interactions
TT1/21/2 is generally 20 hours except: is generally 20 hours except: ziprasidone, quetiapine, aripiprazole ziprasidone, quetiapine, aripiprazole
Dosing adjustment in elderly renal and/or Dosing adjustment in elderly renal and/or hepatic impairmenthepatic impairment
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Antipsychotic AgentsAntipsychotic Agents
© Janicak
Class/Trade Name Generic Name Dosage (average range; PO, qd)
Phenothiazines
Aliphatics
Thorazine Chlorpromazine 100-1000 mg
Sparine Promazine 25-1000 mg
Vesprin Triflupromazine 20-150 mg
Piperidines
Mellaril Thioridazine 30-800 mg
Serentil Mesoridazine 20-200 mg
Quide Piperacetazine 20-160 mg
Piperazines
Stelazine Trifluoperazine 2-60 mg
Prolixin Fluphenzine 5-40 mg
Trilafon Perphenazine 2-60 mg
Tindal Acetophenazine 40-80 mg
Compazine Prochlorperazine 15-125 mg
Thioxanthenes
Navane Thiothixene 6-60 mg
Taractan Chlorprothixene 10-600 mg
Dibenzoxapines
Loxitane Loxapine 20-250 mg
Butyrophenones
Haldol Haloperidol 3-50 mg
Inapsine Droperidol 2.5-10 mg (IM)
Dihydroindolones
Moban Molindone 15-225 mg
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Antipsychotic Agents (con’t)Antipsychotic Agents (con’t)Class/Trade Name Generic Name Dosage (average range; PO, qd)
Dibenzodiazepines
Clozaril Clozapine 100-900 mg
Benzisoxazole
Risperdal
Invega
Risperidone
Paliperidone
2-10 mg
3-12 mg
Thienobenzodiazepines
Zyprexa Olanzapine 5-20 mg
Dibenzothiazepines
Seroquel Quetiapine 75-750 mg
Benzisothiazolyls
Geodon Ziprasidone 40-160 mg
Quinolinones
Abilify Aripiprazole 10-30 mg
Diphenytbutyrylpiperidines
Semap Penfluridol 100 mg/wk
Orap Pimozide 1-10 mg© Janicak 7
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EPS*EPS* HPDLHPDL CLOZCLOZ RISPRISP OLZOLZ QTPQTP ZIPZIP ARIPARIP
NeurologicalNeurological ++++++ 00 ++ 0/+0/+ 00 0/+0/+ 0/+0/+
Weight gain/ Weight gain/ EndocrineEndocrine
++ ++++++ ++++ ++++++ ++++ 0/+0/+ 0/+0/+
AnticholinergicAnticholinergic 00 ++++++ 0/+0/+ +/+++/++ 0/+0/+ 0/+0/+ 00
HematologicalHematological 00 ++++++ 00 00 00 00 00
CardiovascularCardiovascular ++ 0/+0/+ ++ ++ ++ ++++ 00
ProlactinProlactin ++++ 0/+0/+ ++++++ 0/+0/+ 0/+0/+ 0/+0/+ 00
SedationSedation ++ ++++++ ++ +/+++/++ ++++ ++++ ++
PALIPALI
++
++++
0/+0/+
00
++
++++++
++
Adapted from Masand PS et al. Handbook of Psychiatry in Primary Care. 1998.
Antipsychotics:Antipsychotics:Adverse Effect ProfilesAdverse Effect Profiles
*At appropriate doses; 0 = none; + = mild; ++ = moderate; +++ = substantial*At appropriate doses; 0 = none; + = mild; ++ = moderate; +++ = substantial
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Maximum Minimum
HIGH POTENCY RISPERIDONE OLANZAPINE CLOZAPINEFGAs PALIPERIDONE ZIPRASIDONE
(DOSE-RELATED) QUETIAPINE ARIPIPRAZOLE*
ADVERSE EFFECTS OF ANTIPSYCHOTICSADVERSE EFFECTS OF ANTIPSYCHOTICS
Acute EPSAcute EPS
*Based on clinical trial data
• Psuedoparkinsonism
• Dystonia
• Akathisia
• Tardive Dyskinesia
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Dementia PatientsDementia Patients RisksRisks
Mortality rateMortality rate CVA in 4% vs 2%CVA in 4% vs 2% Risks may be Risks may be
higher for all APshigher for all APs
RecommendationsRecommendations Avoid in those with Avoid in those with
vascular dementiavascular dementia Avoid with TIA, Avoid with TIA,
hypertension, Afibhypertension, Afib Use low doses Use low doses
Monitor for Monitor for hypotension, hypotension, sedation, EPSsedation, EPS
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Weight Gain: OverviewWeight Gain: Overview General populationGeneral population
Increased morbidity and mortalityIncreased morbidity and mortality StigmatizationStigmatization Major mental disordersMajor mental disorders
This This adverse effect adverse effect is more common with someis more common with some recent recent antipsychoticsantipsychotics
Recognized problem since chlorpromazineRecognized problem since chlorpromazine PolypharmacyPolypharmacy may contribute may contribute
Divalproex sodiumDivalproex sodium LithiumLithium AntidepressantsAntidepressants AntipsychoticsAntipsychotics
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The Metabolic SyndromeThe Metabolic Syndrome
Insulin Insulin resistanceresistance HyperinsulinemiaHyperinsulinemia Decreased Decreased beta cellbeta cell function function Postprandial Postprandial hyperglycemiahyperglycemia
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SGAs and Metabolic SGAs and Metabolic AbnormalitiesAbnormalities
+ = increase effect; - = no effect; D = discrepant results.*Newer drugs with limited long-term data.Diabetes Care. 2004.
Risk for Worsening Drug Weight Gain Diabetes Lipid Profile
Clozapine +++ + +
Olanzapine +++ + +
Risperidone ++ D D
Quetiapine ++ D D
Aripiprazole* +/- - -
Ziprasidone* +/- - -
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Baseline MonitoringBaseline Monitoring
HistoryHistory (personal or family) of obesity, (personal or family) of obesity, diabetes, dyslipidemia, hypertension, CVDdiabetes, dyslipidemia, hypertension, CVD
BMIBMI WaistWaist circumference circumference Blood pressureBlood pressure Fasting Fasting lipid profilelipid profile Fasting plasma Fasting plasma glucoseglucose
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Anticholinergic EffectsAnticholinergic Effects
Most common with:Most common with: ClozapineClozapine OlanzapineOlanzapine QuetiapineQuetiapine Low-potency FGAsLow-potency FGAs
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HematologicalHematological
Clozapine-induced agranulocytosisClozapine-induced agranulocytosis ManagementManagement
Stop agentStop agent
Reverse isolation; supportive Reverse isolation; supportive measures measures
GSCF (filgastrim)GSCF (filgastrim) Rechallenging strategies Rechallenging strategies
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CardiovascularCardiovascular
Related to both Related to both alphaalpha11 adrenergic adrenergic and and
muscarinicmuscarinic effects effects HypotensionHypotension TachycardiaTachycardia
MyocarditisMyocarditis ArrhythmogenicArrhythmogenic potential possible with all potential possible with all
antipsychoticsantipsychotics
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Royal College of Psychiatrists. 1997.
QTc prolongation
Ventricular fibrillation(sudden death)
Rarely
Rarely
(syncope)
Torsade de pointes arrhythmia
Potential Consequences of Potential Consequences of QTc Interval ProlongationQTc Interval Prolongation
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QT intervalQT interval
Time between onset Time between onset of depolarization and of depolarization and repolarizationrepolarization
Affected by diet, Affected by diet, alcohol intake, time of alcohol intake, time of day, heart rateday, heart rate
Usually corrected for Usually corrected for heart rate = QTcheart rate = QTc
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Antipsychotics:Antipsychotics:Drug InteractionsDrug Interactions
PharmacodynamicPharmacodynamic AnticholinergicAnticholinergic HypotensionHypotension
PharmacokineticPharmacokinetic P450 inhibition (quinidine)P450 inhibition (quinidine) P450 induction (carbamazepine)P450 induction (carbamazepine)
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Bipolar Disorder:Bipolar Disorder:Symptom DomainsSymptom Domains
ManiaManiaEuphoriaEuphoriaGrandiosityGrandiosityPressured speechPressured speechImpulsivityImpulsivityExcessive libidoExcessive libidoRecklessnessRecklessnessDiminished need for sleepDiminished need for sleep
DepressionDepressionDepressionDepressionAnxietyAnxietyIrritabilityIrritabilityHostilityHostilityViolence or suicideViolence or suicide
Manic, depressed or mixed
Psychosis•Delusions•Hallucinations•Sensory hyperactivity
Cognition•Racing thoughts•Distractability•Poor insight•Disorganization•Inattentiveness•Confusion
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Lithium* (A, M)
Anticonvulsants
Valproate* (A)
Lamotrigine* (M)
Carbamazepine (A)
Oxcarbazepine*
Topiramate
Gabapentin
Psychotherapy
Cognitive behavioral therapy Marital/family counseling
Interpersonal therapy Group therapy
Pharmacological/Somatic
Antidepressants; OLZ/FLU* (D)
Quetiapine* (D)
Electroconvulsive therapy
Possibly:» Bright light therapy» Transcranial magnetic stimulation » Vagal nerve stimulation» Sleep deprivation
Mood Disorders:Mood Disorders:Therapeutic OptionsTherapeutic Options
First generation antipsychotics
Second generation antipsychotics
Clozapine
Olanzapine* (A, M)
Risperidone* (A)
Quetiapine* (A)
Ziprasidone* (A)
Aripiprazole* (A)
* FDA approved© Janicak 22
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Mood Stabilizer PharmacokineticsMood Stabilizer Pharmacokinetics
DrugDrug Desired Desired CpCp
DistributioDistributionn
MetabolisMetabolismm
EliminatioEliminationn
LithiumLithium 0.6-1.0 0.6-1.0
mEq/LmEq/L
No PBNo PBkidneys, kidneys, thyroidthyroid
NoneNone Renally,Renally,
18-20 18-20 hourshours
CBZCBZ 6-12 6-12 mcg/mlmcg/ml
CompleteComplete Hepatic,Hepatic,
autoinducautoinducerer
10,1110,11 epoxide epoxide
15-28 15-28 hourshours
VPAVPA 50-120 50-120
mcg/mlmcg/ml
Rapid in Rapid in
CNSCNS
Hepatic, Hepatic,
Inhibitor or Inhibitor or
InducerInducer
8-17 8-17 hourshours
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LITHIUMLITHIUM
Narrow therapeutic indexNarrow therapeutic index Slow Slow onset of actiononset of action Numerous Numerous adverse effectsadverse effects
DISADVANTAGES
BIPOLAR DISORDERBIPOLAR DISORDER
© Janicak 24
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Factors Affecting Lithium CpFactors Affecting Lithium Cp
Impaired Renal FunctionImpaired Renal Function PregnancyPregnancy Sodium balanceSodium balance MedicationsMedications
Diuretics Diuretics → Na depletion → Li reabsorption→ Na depletion → Li reabsorption Caffeine Caffeine ↓ lithium levels↓ lithium levels ACE Inhibitors → ↓ GFR → increase Li ACE Inhibitors → ↓ GFR → increase Li
concentrationconcentration
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Lithium: Adverse EffectsLithium: Adverse EffectsOrgan SystemOrgan System Clinical PresentationClinical Presentation CommentsComments
CardiovascularCardiovascular ECG changesECG changes T wave suppression, delayed or irregular rhythm, increase in PVCsT wave suppression, delayed or irregular rhythm, increase in PVCs
Sick sinus node syndrome (SSNS)Sick sinus node syndrome (SSNS)
MyocarditisMyocarditis
DermatologicDermatologic AcneAcne
PsoriasisPsoriasis
RashesRashes
WorsensWorsens
Treatment-refractory worseningTreatment-refractory worsening
Maculopapular and follicularMaculopapular and follicular
EndocrineEndocrine Hypothyroid stateHypothyroid state About 5% goiter; about 4% clinically significant hypothyroidismAbout 5% goiter; about 4% clinically significant hypothyroidism
Hyperparathyroid stateHyperparathyroid state Clinically nonsignificantClinically nonsignificant
Fetus (teratogenic)Fetus (teratogenic) Tricuspid valve malformationTricuspid valve malformation
Atrial septal defectAtrial septal defect
Ebstein’s anomalyEbstein’s anomaly
GastrointestinalGastrointestinal AnorexiaAnorexia
Nausea (10-30%)Nausea (10-30%)
VomitingVomiting
Diarrhea (5-20%)Diarrhea (5-20%)
Usually early in treatment and usually transient; may be early sign Usually early in treatment and usually transient; may be early sign of toxicityof toxicity
Slow release preparations may helpSlow release preparations may help
HematologicalHematological GranulocytosisGranulocytosis May be useful in disorders such as Felty’s syndrome, iatrogenic May be useful in disorders such as Felty’s syndrome, iatrogenic neutropenia. May counter CBZ-induced leukopenianeutropenia. May counter CBZ-induced leukopenia
RenalRenal Polyuria-polydipsia Polyuria-polydipsia (Nephrogenic diabetes (Nephrogenic diabetes insipidus)insipidus)
May be an indication of morphologic changesMay be an indication of morphologic changes
Requires adequate hydrationRequires adequate hydration
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Neurological Neurological Cognitive; tremorsCognitive; tremors
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Anticonvulsants for Mood DisordersAnticonvulsants for Mood Disorders
Valproate (VPA)Valproate (VPA)
Lamotrigine (LTG)Lamotrigine (LTG)
Carbamazepine (CBZ)Carbamazepine (CBZ)
OxcarbazepineOxcarbazepine
Gabapentin (GBN)Gabapentin (GBN)
Topiramate (TOP)Topiramate (TOP)
OthersOthers
BIPOLAR DISORDERBIPOLAR DISORDER
© Janicak 27
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VALPROATEVALPROATE
Adverse effectsAdverse effects Weight gainWeight gain TremorsTremors HyperammonemiaHyperammonemia PCOS (?)PCOS (?)
DISADVANTAGES
BIPOLAR DISORDERBIPOLAR DISORDER
© Janicak 28
PancreatitisPancreatitis
HepatotoxicityHepatotoxicity
TeratogenicityTeratogenicity
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Valproic Acid Valproic Acid PharmacokineticsPharmacokinetics
Usually inhibits hepatic metabolismUsually inhibits hepatic metabolism Occasionally induces hepatic metabolismOccasionally induces hepatic metabolism
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CBZ PharmacokineticsCBZ Pharmacokinetics
Oxidation to CBZ-10,11-epoxideOxidation to CBZ-10,11-epoxide Potent enzyme inducerPotent enzyme inducer
antidepressants, anticonvulsants, antidepressants, anticonvulsants, antipsychoticsantipsychotics
AutoinductionAutoinduction serum level should stabilize within 4 weeksserum level should stabilize within 4 weeks
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Carbamazepine MetabolismCarbamazepine Metabolism
10,11 epoxide metabolite10,11 epoxide metabolite
CarbamazepineCarbamazepine
Further metabolismFurther metabolism
→→ ToxicityToxicity
XXValproic acidValproic acid
oxidationoxidation
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LAMOTRIGINELAMOTRIGINE
Slow titration to avoid rashSlow titration to avoid rash Adverse effectsAdverse effects
Serious rashesSerious rashes SJSSJS TENTEN
BIPOLAR DISORDERBIPOLAR DISORDER
DISADVANTAGES
© Janicak 32
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GoalsGoals AntipsychoticsAntipsychotics
Diagnostic indicationsDiagnostic indications Classification Classification Relevant PharmacokineticsRelevant Pharmacokinetics Serious Adverse EffectsSerious Adverse Effects Drug InteractionsDrug Interactions
Mood StabilizersMood Stabilizers Diagnostic indicationsDiagnostic indications Classification Classification Relevant PharmacokineticsRelevant Pharmacokinetics Serious Adverse EffectsSerious Adverse Effects Drug InteractionsDrug Interactions
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