Drug interactions in psychiatry
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Transcript of Drug interactions in psychiatry
Drug Interactions In Psychiatry
PRESENTER: DR.PJ.CHAKMA,PGT,AMCH
MODERATOR: DR.R.U.ZAMAN,ASSOC. PROF. AMCH
21/06/2013
Plan of presentation• Introduction• Importance of drug interaction• Risk factor• Type of interaction• Different drug interaction in
psychiatry• Clinical consequences• Management • Conclusion• bibliography
introduction
• A drug interaction, defined as the modification of the action of one drug by another, can be beneficial or harmful, or it can have no significant effect.This action can be synergistic or antagonistic
• The risk that a pharmacological interaction will appear increases as a function of the no of combinations of drugs administered to a patient at the same time
importance
Recognition of beneficial effects and
Recognition and prevention of adverse drug interactions
Basic principles of drug-drug interactions in planning a therapeutic regimen.
Risk factor
– Old age – Polydrug misusers– Polypharmacy– Psychiatric patients taking high doses
ofmedication– people in developing countries in which
there is a high prevalence of self-medication
– Irresponsible dispensing by a small minority of pharmacists
Role of Genetics• An individual's genetic makeup can
alter their response to a drug.• A common example is the metabolism
of ethanol .There are ethnic differences in the metabolism of ethanol by alcohol dehydrogenase.
Presentation of drug interactions
A multitude of different types of serious adverse
events (SAEs), such as sudden death,
seizures,cardiac rhythm disturbances,delirium
Poor tolerability (ie, patient is “sensitive” to
adverse drug effect)
Lack of efficacy (ie, patient is “resistant” to
beneficial drug effect)
Symptoms that mimic or lead to a misdiagnosis of a
new disease The apparent worsening of the disease being
treated
Withdrawal symptoms or drug-seeking behavior on
the part of the patient
Epidemiology of Drug Interactions
• The overall prevalence of drug
interactions is 50% to 60%.
• Those that affect pharmacodynamics or
pharmacokinetics have a prevalence of
approximately 5% to 9%.
• About 7% of hospitalizations are due to
drug interactions.
Challenges in Anticipating Interactions
Drug potency, strength, doseDrug purity – contaminants, adulterantsResearch studies lacking, inconclusive, unethicalDrug interaction information based on unproven theory or case reports with incomplete dataClients not forthcomingOver-the-counter drugs, herbal products and grapefruit juice not often reported by clients
Type of interaction
Pharmaceutical
Pharmocokinetics
AbsorptionDistributionEliminationMetabolism
Pharmacodynamic
Agonist & antagonists
Pharmaceutical
When drugs are mixed outside the body prior to administration.
For example, mixing chemically incompatible drugs
before intravenous infusion can result In precipitation or inactivation.
Pharmacokinetic Interactions• One drug changes how the body handles other
drugs, either increasing or decreasing blood levels of one or both drugs
Absorption: (gut,skin)– drug movement from administration site to bloodstream (P-Glycoproteins, protein binding)
Distribution– drug movement from bloodstream to the rest of the body– psychotropics must cross the blood brain barrier to reach
their site of action
Metabolism– transformation of drug by chemical processes(phase 1
metabolism= CYP450)PHASE II= conjugation
Excretion or Elimination(urine,bile,gut)– routes of leaving the body for drug and drug metabolites
Effect of interaction at absorption
• Delay n the rate of absorption- Antacid can decrease the rate of absorption of chlordizapoxide by increasing the pH
• Alteration of dissolution of tablets • Elevation of gastric PH with antacids above
the Pka of chlordiazepoxide (4.8) may reduce the dissolution rate
• Change in the amount of drug absorbed– Decreased serum concentration – Increased serum concentration – Precipitation of the drug
• Precipitation :Iron may decrease the antibacterial efficacy of tetracycline by chelation
• Enzymatic reaction : Monoamine oxidase inhibitor and tyramine.(drugs-food interactions)
Pharmacodynamic Interactions:
• Based on the way the drug works on the body
Additive / Synergistic - two drugs with the same effect– increased drug effects (e.g. euphoria,
relaxation)– increased side effects (e.g. drowsiness,
nausea, overdose)
Opposing – two drugs with opposite effects– do not necessarily ‘cancel each other out’
Counterproductive – drug exacerbates underlying condition; more of a disease/drug interaction than true drug interaction
Pharamacodynamics:Where Drugs Act
Four sites of action
Receptors (those sites to which a neurotransmitter can specifically adhere to produce a change in the cell membranes)
Ion channels
Enzymes
carrier Proteins
Biological action depends on how its structure interacts with a receptor
Receptors
Types of Action Agonist: same biologic
action Antagonist: opposite effect
Interactions with a receptor Selectivity: specific for a receptorAffinity: degree of attractionIntrinsic activity: ability to produce a
biologic response once it is attached to receptor
Protein Binding
• Not as clinically relevant as previously believed.
• Properties of a drug that predict clinically relevant displacement by protein binding:
– Low clearance drugs– Low therapeutic index– Small volume of distribution– Examples: warfarin, tolbutamide, phenytoin
Protein Binding and Urinary Excretion of SRIs
The Pharmacological Basis of Therapeutics; Goodman & Gilman; 10th Edition; 2001*From Physician’s Desk Reference; 2004; page 1302
Distribution of drug
When the drug leaves the systemic circulation and moves to various parts of the body
• Drugs in the bloodstream are often bound to plasma proteins; only unbound drugs can leave the blood and affect target organs
• Low serum albumin can increase availability of drugs and potentiate their effects
Factors affecting volume of distribution
Lipid solubility
Degree of plasma protein binding
Affinity for different tissue
eg duration of action of thiopental,
first dose lorazepam and diazepam.
Drug metabolism
• Primarily in the liver; cytochrome P-450 enzyme system facilitates drug metabolism; metabolism generally changes fat soluble compounds to water soluble compounds that can be excreted
– Enzyme mediated biotransformation– Cytochrome P450
Elimination
Clearance: Total amount of blood, serum, or plasma from which a drug is completely removed per unit time
Half-life: Time required for plasma concentrations of the drug to be reduced by 50%
kidneys (responsible for excreating all water soluble substances)
Some excreted via the liver,urine,faeces,saliva& sweat,milk, bile and delivered to the intestine
may be reabsorbed in intestine and “re-circulate” (up to 20%)
Elimination Interactions
– Glomerular filtration: Chloral derivatives – Tubular re-absorption:
• Alkalizing agent may enhance the excretion of Lithium or Tranylcypromine
• Urinary acidifier such as may enhance excretion of imipramine, amitriptyline or amphetamines
• (NSAIDs), angiotensin-converting enzyme (ACE) inhibitors, or angiotensin II receptor blockers (ARBs) should be used cautiously, if at all, in patients already receiving lithium.
Cytochrome P450
– Oxidase system– Metabolize endogenous compounds such as
steroids and neuropeptides – Contain red pigmented heme– Absorb light at a wave length of 450 nm if
bound to CO– Encoded by one particular gene – Grouped into families and subfamilies on the
basis of amino acid sequences
Cytochrome P450• Largest class of enzymes catalyzing oxidation of organic
substances in all living things
11,550+ identified ; 57 in humansHigh affinity for fat-soluble drugsInvolved in metabolism of most psychiatric medicationsInactivate drugs (or in some cases activate them)Chemicals may increase or decrease CYP activity
Example: SSRIs inhibitors of the subfamily CYP2D6Compounds in grapefruit juice inhibit CYP3A4Tobacco induces CYP1A2
Cytochrome P450Category meaning Examples
Family numeral
CYP450 1
Subfamily numeral + capital letter
CYP450 1A
Single gene or protein
Arabic numeral + capital letter + numeral for individual gene
CYP450 1A2
cytochrome p450
• Substrate– any drug metabolized by P450 enzymes
• Inhibitor– any drug that inhibits the metabolism of
a P450 substrate (strong, moderate, weak)
• Inducer– anything that increases the amount of
P450 enzymes (strong, moderate, weak)
P450 Variations
• Some people have more than normal amounts of certain P450 enzymes (ultra-rapid metabolizers)
• Some people have normal amounts (extensive metabolizers)
• Some people have less than normal amounts (poor metabolizers
Effects of Drug Interaction
Different types of serious adverse effects
Poor tolerabilityLack of efficacySymptoms that mimic or lead to a
misdiagnosis of a new diseaseThe apparent worsening of the disease
being treatedWithdrawal symptoms or drug-seeking
behavior on the part of the patient
Cytochrome P450 1A2
Antidepressant
fluvoxamine
Antibiotics
ciprofloxacin
fluoroquinolones
furafylline
Other
cimetidine
amiodarone
interferon
omeprazole
tobacco
Insulin
Modafinil
broccoli
brussel sprouts
char-grilled meat
methylcholanthrene
nafcillin
INHIBITOR INDUCER
Cytochrome P450 2D6
AntidepressantbupropionfluoxetineparoxetinesertralineDuloxetineAntipsychoticsChlorpromazineOtherquinidineterbinafineamiodaronecimetidine
dexamethasonerifampin
INHIBITOR INDUCER
Cytochrome P450 2C19
PPIlansoprazoleomeprazoleAnticonvulsantoxcarbazepineTopiramate
Otherchloramphenicolcimetidineindomethacinketoconazolemodafinil
carbamazepinepentobarbitalprednisonerifampin
INHIBITOR INDUCER
Cytochrome P450 3A4
HIV AntiviralsindinavirnelfinavirritonavirAntibioticsclarithromycinitraconazoleketoconazolenefazodonesaquinavirtelithromycinerythromycinfluconazole
AntidepressantFluvoxamine Other verapamil,cimetidineamioderon
nevirapinebarbituratescarbamazepineoxcarbazepineglucocorticoidsmodafinilphenobarbitalphenytoinpioglitazonerifabutinrifampinSt. John's wort
INHIBITOR INDUCER
Interaction of antipsychotics
Clozapine
1A2
3A4
2D6
Fluoroquinolones,
Fluvoxamine,sertralineErythromycin,ketoconazole, ritonavir,cimetidine
Ritonavir, quinidine,risperidone,fluoxetine, sertraline
Smoking,
Rifampin,carbamazepine,phenytoin,barbiturates
Drug & CYP450 Inhibitor Inducer
contd
Risperidone (2D6)
Olanzepine( 1A2,2D6)
Quetiapine (3A4)
Ziprasidone (3A4)
Aripiprazole (3A4,2D6)
FLUOXETINE,PAROXETINE
Fluvoxamine
Ketoconazole,Erythromycin
NONE
NONE
Rifampin,carbamazepinePhenytoin,PHB.
Smoking,Carbamaz
epine
Rifampin,carbamazepine,phenytoin,BarbituratesNONENONE
Drug & CYP450 Inhibitor Inducer
contd
• others common interaction antacids dopamine agonists or
antiparkinson”s Rx CNSdepressants such as analgesics,
anxiolytics, and hypnotics
Antidepressants and the Cytochrome P450 System
• Antidepressants and mood stabilizers may be inhibitors, inducers or substrates of one or more cytochrome P450 isoenzymes
• Knowledge of their P450 profile is useful in predicting drug-drug interactions
• When some isoenzymes are absent of inhibited, others may offer a secondary metabolic pathway
• P450 1A2, 2C (subfamily), 2D6 and 3A4 are especially important to antidepressant metabolism and drug-drug interactions
TCA
• Phenytoin,valproate,carbamazepine• Verapamil,diltiazem,ketoconazole,cimetadine. smoking Inhibit P450-3A4• Adrenergic receptor blockade can worsen the
orthostatic hypotension• antiarrhythmics and anticholinergic
medications
Monoamine Oxidase Inhibitors
• The combination of MAOIs and narcotics, particularly meperidine may cause a fatal interaction
• With SSRIs can cause the serotonin syndrome.
Drug Interactions with Lithium• (ACE) inhibitors• Alprazolam• Amiloride• Antipsychotic agents• Fluoxetine • Ibuprofen • Indomethacin• Mefenamic acid• Nonsteroidal anti-inflammatory drugs
(NSAIDs)• Phenylbutazone• Thiazides diuretics• Spironolactone• Tetracycline, aminophyline
Increase lithium level
contd
• Caffeine• Carbonic anhydrase inhibitors• Laxatives• Osmotic diuretics• Theobromine• Theophylline
Decrease lithium level
Increase Adverse Reactions
• Atracurium• ECT• Carbamazepine• Fluoxetine• Fluvoxamine• Methyl DOPA• Verapamil• Succinyl choline
Benzodiazepine Drug Interactions
Increased metabolism Decreased metabolism
CarbamazepineRifampinCorticosteroids,phenobarbitone,phenytoin
CimetidineAzole antifungals (ketoconazole,miconazole, itraconazole)ErythromycinDisulfiramOral contraceptives,FluvoxamineFluoxetinisoniazide
Phenytoin
• carbamazapine, phenobarbital will decrease plasma levels;
• Isoniazide,cimetadine,warfarin, alcohol, diazapam, methylphenidate will increase plasma levels--- precipitate toxicity
• Induces microsomal enzymes failure of ocp,digitoxin,doxycycline,theophyline
Valproate
Drugs increased valproate level
aspirinCimetidineErythromycinFluoxetinFluvoxamineibuprofen
Drugs that decreased valproate level
CarbamazepinePhenobarbitoneRifampinethosuximide
Carbamazepine
Phenobarbital Primidone Phenytoin
Cimetidine Diltiazem Erythromycin Fluoxetine Fluvoxamine Isoniazid Propoxyphene Valproic acid Verapamil
increased decreased
Reduce efficacy of haloperidol,ocp,& other antiepileptics drugs
Lamotrigine
• Carbamazepine
• Oxcarbazepine
• Phenobarbital
• Phenytoin
Fluoxetin,valproate,erythromycin
Drug interaction with ECT
Drugs seizure duration threshold
TCA”s Increased decreased
MAOIs minimal effect no effect
Lithium increased combination may lead
delirium
BZD”s Reduced raised
SSRIs mild increase safe
Venlafaxine minimal epileptogenic
Propofol decrease increase
Antipsychotics some increase decrease
Drug-Drug Interactions: approach
• Take a medication history
• Remember high risk patients • Evaluate therapeutic alternative
– Dose spacing– Decreasing dose– Discontinue the drug– Add another agent to counter the
interaction
Management of Drug Interactions
• Inform all prescribers about current medications - GP’s, psychiatrists, dentist
• When possible take all prescriptions to one pharmacy so there is one computer record
• Ask pharmacist about OTC meds & check ingredient list on combination products (will sometimes change!!)
• Scheduling different dosing times can sometimes minimize interaction (but not always)
• Some interactions cannot be avoided, so close monitoring and dosage adjustment is essential
contd
• Some websites have drug interaction programs, but significance of each interaction needs to be assessed and put in proper context by MD or pharmacist
• Some interactions are more theoretical, and may not have clinical significance
• Some drug interactions are good– Using a 2nd drug to decrease a “bad”
metabolite of the first drug• Not all combinations can be anticipated or
tested, so new drug interactions are being discovered every day!!
How to avoid drug interaction
• Beware and follow good clinical
practice
• Avoid multi target medication
• Use available literature
• When in doubt start low and go
slow
• Monitor for adverse out come
conclusions
• Drug Interactions are inevitable .There is also a lack of knowledge of the size of the problem and of the many pharmacological and host factors that determine whether or not an individual will have a particular interaction
• Future research has been carried out into potentially hazardous interactions with different drugs, yet there is much that remains unknown.
bibliography• Kaplan and Sadock’s Comprehensive Textbook
of Psychiatry vol.1 by Benjamin J. Sadock and Virginia A Sadock 9th edition 2005, Williams and Wilkins
• Textbook of Postgraduate Psychiatry, Vol.1 by J.N. Vyas and Niraj Ahuja, 2nd edition 2003 Jaypee Brothers Medical Publishers (P) Ltd
• The south london and maudsley NHS foundation trust prescribing guidelines 10th edition
• Jerald kay,Allan Tasman,wiley essentials of psuchiatry,2006
Richard A Harvey, Pamela C. Champe (2006) Lippincott’s Illustrated Reviews: Pharmacology: 3rd Edition. Lippincott Williams & Wilkins
contd• New Oxford Textbook of Psychiatry vol.1
by M.G. Gelder, Juan J. Lopez-Ibor Jr, Nancy C. Andreasen
• Dr. Brunton, Parker, and Lazo: Goodman Gillman’s The Pharmacological Basis of Therapeutics, 10th edition. McGraw Hills
• B.J.Sadock”s,V.A.Sadock”s,Kaplan & sadock”s synopsis of psychiatry,10th edition
• Psychopharmacology treatment of psychiatric disorders,(late) jambur anant,2007,jaypee publisher
• Wikipedia• Googleimages.com