DRUG INTERACTIONS OF PSYCHOTROPICS

By Dr: ATIF FARRAG SUPERVISOR Dr: SALWA RABAE

Doctors pour drugs of which they know little, to cure diseases of which they know less, into patients of whom they know nothing.1 Voltaire
The true polypharmacy is the skillful combination of remedies.2 - Sir William Osler

What is Meant by a Drug-Drug Interaction?

A perpetrator Adding a co-prescribed drug

alters

nature

magntude

duration

victim

To a given dose of another drug

 Altered nature : ssri+mao inhibitor serotonin syndrome Altered magnitude : victim drug dose is either less or more effective than expected when given alone Altered duration of action : effect of a victim drug dose is either became shorter or longer than expected

Why PSYCHIATRIC DDIs ?

Use of antidepressants exceeds antihypertensives in USA since 2005 One out of 10 Americans over 6ys receive an antidepressant ,38% of whom received another psychotropic

No of pts receiving psychotropics in the last 2 decades No of psychiatric pts receiving complex drug regimens is exceeding those non psychiatric pts

How do DDIs Present and How Important are They?

A multitude of serious side effects : sudden death,fits,NMS,cardiac arrhythmia and malignant hypertension

Poor tolerability: pt is
sensitive to side effects

Lake of efficacy : pt
is resistant to a beneficial drug

Symptoms mimiking hence leading to misdiagnosis of a new disease

Apparant worsening of a disease condition

Withdrawal symptoms or drug seeking behavior

or

A pharmacokinetic drug interaction occurs when a drug alters the absorption, distribution, metabolism or excretion of another drug. . Pharmacodynamic interactions occur when two drugs act on interrelated receptor sites resulting in either additive or antagonistic effects.

 The Cytochrome P450 isoenzymes (CYPs) are superfamily

of haemoprotein enzymes found on the membrane of endoplasmic reticulum. They are responsible for catalyzing the metabolism of large number of endogenous and exogenous compounds. CYPs are also called polysubstrate as one isoenzyme can have multiple substrates.[ These enzymes are responsible for biotransformation of drugs. P-glycoprotein is efflux pump or transporter present in brain capillary endothelial cells, intestinal mucosal, renal and tubular cells, hepatic canalicular cells etc and are responsible for extrusion or efflux of drugs thereby enhancing drug elimination

 Age : young pt metabolizes faster than older Gender: men faster than women Smokers: faster metabolizer of clozapine and olanzapine than non-smokers Co-morbid liver cirrhosis and congestive heart failure decreases rate of drug metabolism CYP450 enzymes are polymorphic with ethnic differences :10% of caucasians are poor metabolizers at CYP2D6 isozymes, 20% of Japanese are poor metabolizers at CYP 2C19 Some persons are known as ultrarapid metabolizers while others are poor metabolizers

Factors influencing drug metabolism

Absorption
Desirable interference : activated charcoal giving to pts with TCA overdose

Phenothiazine &sulpride inactivated by antiacids taken within 2 hs

Anticholinergics raises gastric ph causing destruction of enteric coated drugs Delay gastric empting leading to delaied absorption Thyroxin is rendered inactive if given with irom sulphate

distribution
Most of psychotropics are protein bound except lithium &gabapentin Side effects appear when a drug displaces another from a plasma protein eg.BZ displaces phynatoin from its protein binding

Elimination
Increase in urine ph more alkaline increases clearance of lithium decrease clearance of amphetamine NSAIDs &COX2 inhibitors causes decrease in PGE that reduces lithium clearance

Metabolic pharmacokinetic interactions

Inducers of CYP Enzymes

2C19 Carbamazepine 2C9 Phenobarbital 3A4 Phenytoin Carbamazepine Phenobarbital Corticosteroids

2D6

Carbamazepine Phenobarbital Phenytoin Rifampin

CYP 450

Synthesis of more enzymes Delayed degradation of old ones

INDUCING DRUG

A substrate

Rapid biotransformation of substrate Shorten t Decreased serum level of substrate Development of pharmacokinetic tolerance

Enzyme induction
The onset and duration of induction depends both on the kinetics of the drug and half life of CYP enzyme, which ranges from 1-6 days Usually it takes 4-14 days for peak induction and on withdrawing inducer the CYP returns to their original level in 1-3 weeks

inducers
phenobarbitone t long Onset of induction 2-3 weeks 40 folds increase in enzyme Refampicin only takes 4 days to start induction alcohol

Polycyclic aromatic hydrocarbon In cigarettes

Strong inducer of CYP 1A2 to whom clozapine is a substrate Important in chronic smokers treated with liponex who wants to stop

Increases CYP 1E2 by 2 folds Induces itself hence pharmacokinetic tolerance CBZ, phenytoin Potent inducers of TCA

 Sodium valproate and lamotrigine both are substrate competing for gluconidation in liver concomitant use of both together leads to rise in level of lamotigine in blood Other competitors of s.valproate include : lorazepam ,oxazepam and olanzapine Enzyme inhibition has the effect of increasing the levels of the substrate that is metabolised by the inhibited enzyme. Enzyme inhibition begins to occur with the first dose of the inhibitor and is maximal when the inhibitor reaches steady state, which is usually after four to seven halflives.

Inhibitors of CYP Enzymes

1A2

Fluvoxamine Fluoxetine Fluvoxamine Paroxetine Topiramate Fluvoxamine Paroxetine

2D6

2C19

2C9

Chlorpheniramine Cimetidine Sertraline Fluoxetine Haloperidol Methadone Paroxetine

Substrates of CYP Enzymes

1A2

2D6

Amitriptyline Desipramine Acetaminophen Barbiturates Topiramate Warfarin Phenytoin Naproxen

2C19

2C9

Codeine Tramadol Meperidine Propoxyphene Oxycodone Hydrocodone Nortriptyline

Doxepin

Mood stabilizers

Carbamazepine CYP 3A4 A heteroinducer decrease its own blood level Potent inducer of TCA,SSRI,BZ,m ethadone,thyr oxine,oestrog en

Acetazolamide & cimetidine rapid &toxic levels Fluvouxamine,fluo xetine,ketoconazo le,deltazime&eryth romycine

Carbamazepine Pharmacodynamic interactions also occur.

The anticonvulsant activity of carbamazepine is reduced by drugs that lower the seizure threshold (e.g. antipsychotics and antidepressants), the potential for carbamazepine to cause neutropenia may be increased by other drugs that have the potential to depress the bone marrow (e.g. clozapine), the risk of hyponatraemia may be increased by other drugs that have the potential to deplete sodium (e.g. diuretics) Neurotoxicity has been reported when carbamazepine is used in combination with lithium. This is rare.

S.Valproate High protein- bound

Displaced by asprin leading to rise in plasma levels Displaces warfarin a less protein-bound drug leading to bleeding tendency

Being inhibitor of CYP 3A4

INCREASED blood levels of clomipramine,quetiapine,lam otrigine and phenobarbitone

Benzodiazepines do not induce microsomal enzymes and so do not

frequently precipitate pharmacokinetic interactions with any other drugs. Most benzodiazepines are metabolised by CYP3A4, which is inhibited by erythromycin, several SSRIs and ketoconazole. It is theoretically possible that co-administration of these drugs will result in higher serum levels of benzodiazepines. Pharmacodynamic interactions (usually increased sedation) can occur. Benzodiazepines are associated with an important interaction with methadone

Interaction of antidepressants

fluvoxamine is a potent inhibitor of CYP1A2 which can result in increased theophylline serum levels, and fluoxetine is a potent inhibitor of CYP2D6 which can result in increased seizure risk with clozapine.

 If the patient is also taking warfarin, suggest citalopram probably lowest interaction potential Mirtazapine has a small effect on INR.

Antipsychotic

interactions

Half life 12 h needs 5 half lives to reach steady state Metabolized by CYP 3A4 CYP 1A2 CYP 2D6
Inhibited by favarin & grape fruit in big amounts rising levels of liponex Induced by smoking cigarettes Inhibited by fluoxetine,paroxetine and large dose of serteraline ieading to rising level of clozapine

Clozapine

Inhibited by erythromycin and etoconazole Induced by glucocorticoids,CBZ ,phynatoins,phenob arbitones and rifampicin

Phamacodynamically: lowers seuizer threshold hence avoid combining with wellbutrin and largactil

OLANZAPINE

t = 30hs steady state within a week Metabolized by: CYP 1A2 ,CYP 2D6 and glucoronization Serum level not related to drug drug interaction but if a youg male smoker is given olanzapine he needs 20 mg daily to achieve a therapuetic effect whereas older female nonsmoker only need 5 mg to achieve it Serum level deminished by smoking

RESPERIDONE

t =20hs once daily doses, steady state is reached within a week Metabolized by CYP 2D6 to 9-hydroxyl resperidone which is equipotent to parent compound and its serum level is several times of resperidone Because of equipotency of resperidone and metabolite enzyme inhibitors had no effect on effective doses

QUETIAPINE AND ZEPRASIDONE

t = 6-7 hs bid dosing steady state 1-2 days Rising serum level with use of erythromycin and ketoconazole which are inhibitors of CYP 3A4 with resultant hypotension and sedation Lowering of serum level with use of carbamazepine,phynatoin ,phenbabiton rifampicine and glucocorticoids which are inducers with expected lost effectiveness Zerprasidon should be taken with full stomach if not even once steady state is lost Quetiapine is better for demented elderly with behavoural symptoms as it is devoid of anticholinergic effect counteracting anticholinestrases for dementia not to use zyprtxa nor liponex

aripeprazole