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

Drug Interaction: Drug Effects in the Body

Differing Metabolic Pathways

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

P (permeability) -Glycoprotein

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

Protein Binding of AtypicalAntipsychotics

2005 Physicians’Desk Reference

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

contd

Iso enzymes

>200 P450 enzymes in nature at least 40 enzymes in humans

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

Inhibitors and Inducers of 2C9

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

SSRI”s

SSRI”s

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.

contd

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 Interactions of Herbal Medicines

contd

contd

Drug interactions with grape fruit

Psychostimulants interactions

MPH = MethylphenidateAMP= amphetamine

MPH = MethylphenidateDEX= Dextroamphetamine

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

THANK YOU