Psychotropic Drug Interactions

8/12/2019 Psychotropic Drug Interactions

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DRUG INTERACTIONS

OFPSYCHOTROPICS

By

Dr: ATIF FARRAG

SUPERVISOR

Dr: SALWA RABAE


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Doctors pour drugs of which they

know little, to cure diseases of

which they know less, into patients

of whom they know nothing.1

VoltaireThe true pol

the ski l l fu l c

remedies.2

- Sir Will iam


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What is Meant by a Drug-Drug Interactio

victim

magntude

nature

duration

A perpetrator

alters

Adding a co-presc

To a given dose


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Altered nature : ssri+mao inhibitor serotonin syn Altered magnitude : victim drug dose is either less or

effective than expected when given alone Altered duration of action : effect of a victim drug dos

became shorter or longer than expected

Why PSYCHIATRIC DDIs ?

No of pts receiving psychotropics in the last 2 d

No of psychiatric pts receiving complex drug reis exceeding those non psychiatric pts

Use of antidepressants exceeds antihypertensives in USA

One out of 10 Americans over 6ys receive an antidepre

whom received another psychotropic


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How do DDIs Present and How Impo rtant are T

A multitude of seriousside effects : suddendeath,fits,NMS,cardiacarrhythmia and

malignant hypertension

Symptoms mimiking

hence leading tomisdiagnosis of a newdisease

Poor tolerability: pt issensitive to side effects

Apparant

worsening of adisease condition

Lake of is resistan

beneficia

Withdr

symptseekin


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or


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A pharmacokinetic drug interaction o

when a drug alters the absorption,

distribution,metabolism or excretion of another dru

Pharmacodynamic interactionsoccu

two drugs act on interrelated receptoresulting

in either additive or antagonistic effect

.


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The Cytochrome P450 isoenzymes (CYPs)areof haemoprotein enzymes found on the membrane

endoplasmic reticulum. They are responsible for ca

metabolism of large number of endogenous and excompounds. CYPs are also calledpolysubstrate as

isoenzyme can have multiple substrates.[These enz

responsible for biotransformation of drugs.

P-glycoprotein is efflux pump or transporter present

capillary endothelial cells, intestinal mucosal, renal

cells, hepatic canalicular cells etc and are respons

extrusion or efflux of drugs thereby enhancing drug
http://www.indianjmedsci.org/article.asp?issn=0019-5359;year=2007;volume=61;issue=2;spage=102;epage=116;aulast=Kalrahttp://www.indianjmedsci.org/article.asp?issn=0019-5359;year=2007;volume=61;issue=2;spage=102;epage=116;aulast=Kalra


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Factors influencing drug metabolis Age : young pt metabolizes faster than olderGender: men faster than women

Smokers: faster metabolizer of clozapine andthan non-smokersCo-morbid liver cirrhosis and congestive hea

decreases rate of drug metabolismCYP450 enzymes are polymorphic with ethnic

differences :10% of caucasians are poor metaCYP2D6 isozymes, 20% of Japanese are poormetabolizers at CYP 2C19

Some persons are known as ultrarapid metab

while others are poor metabolizers


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Absorption

Desirable interference :activated charcoal

giving to pts with TCAoverdose

Phenothiazine &suinactivated by anttaken within 2 hs

Anticholinergics raises gastric ph causingdestruction of enteric coated drugs

Delay gastric empting leading to delaiedabsorption

Thyroxin is rendered inactive if given with iromsulphate


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distribution

Most of psychotropics are protein bound except lithium

&gabapentin

Side effects appear when a drug displaces another froprotein eg.BZ displaces phynatoin from its protein bind

Elimination

Increase in urine ph more alkaline increases clearan

lithium decrease clearance of amphetamine NSAIDs &COX2 inhibitors causes decrease in PGE tha

lithium clearance


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Metabolic

pharmacokinetic

interactions


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Inducers of CYP Enzymes

2C19

Carbamazepine

2C9

Phenobarbital

3A4

Phenytoin

Carbamazepine

Phenobarbital

Corticosteroids

2D6 Carbamazepine

Phenobarbital

Phenytoin

Rifampin


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CYP 450

INDUCINGDRUG

Synthesis of more enzymesDelayed degradation of old

ones

Asubstrate

Rapid biotof substrate

Shorten tDecreased

of substrateDevelopme

pharmacotolerance

Enzyme inductionThe onset and durat ion of induc t ion depends bo th on ththe drug and half l i fe of CYP enzyme, which ranges from

days Usually i t takes 4-14 days for peak in duc t ion and o

w ithd rawing ind ucer the CYP returns to their origin al le

weeks


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inducersphenobarbitone t long Onset of

induction 2-3weeks

40 folds increasein enzyme

Refampicin onlytakes 4 days to

start induction

alcohol

Increases CYP1E2 by 2 folds

Induces itselfhence

pharmacokinetic

tolerance

Polycyclic

hydroc

In cig

Strong ind1A2 to whclozapine

substrate Importan

smokers liponex w

stopCBZ, phenytoin

Potent inducers ofTCA

Sodium valproate and lamotrigine both are s


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Sodium valproate and lamotrigine both are scompeting for gluconidation in liver concomiboth together leads to rise in level of lamotiginblood

Other competitors of s.valproate include : lora,oxazepam and olanzapine Enzyme inhibitioneffect of increasing the levels of the substrate metabolised by the inhibited enzyme.

Enzyme inhibition begins to occur with the firsthe inhibitor and is maximal when the inhibitosteady state, which is usually after four to sevelives.


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Inhibitors of CYP Enzymes

1A2 Fluvoxamine

2C19

Fluoxetine

Fluvoxamine

Paroxetine

Topiramate

2C9

Fluvoxamine

Paroxetine

2D6

Chlorpheniramine

Cimetidine

Sertraline

Fluoxetine Haloperidol

Methadone

Paroxetine


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Mood stabilizers


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Carbamazepine


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pCYP 3A4

Acetazolamide &cimetidine

rapid &toxic levels Fluvouxamine,fluo

xetine,ketoconazole,deltazime&eryth

romycine

Aheteroind

decreaseown bloolevel

Potentinducer oTCA,SSRI,

ethadoneoxine,oeen


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S.ValproateHigh protein- bound

Displaced by asprin leadingto rise in plasma levels

Displaces warfarin a lesprotein-bound drug leato bleeding tendency

Being inhibitor of CYP 3A4INCREASED blood levels ofclomipramine,quetiapine,lamotrigine and phenobarbitone


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Benzodiazepinesdo not induce m icrosomal enzymes and frequent ly p recip i ta te pharmacokinet ic interact ions with any o th

Most benzodiazepines are metabo l ised by CYP3A4, wh ich is inh i

erythrom yc in, several SSRIs and ketocon azole.I t is theoret ical ly

poss ib le that co-adm inist rat ion of these drugs wi l l resul t in high

levels of benzodiazepines.

Pharmacod ynam ic interact ions (usual ly increased sedat ion) can

Benzodiazepin es are assoc iated w ith an important interact ion wi


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Interaction of

antidepressants


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f luvo xam ine is a po tent inhibi to r of CYP1A2

wh ich can result in inc reased theophyl l in e serum levels, and f lu o

potent inh ibi tor of CYP2D6 which c an result in inc reased seizure

clozapine.


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If the pat ient is also takin g w arfar in, suggest ci talopramprobab

interact ion potent ial

Mirtazapinehas a small effect o n INR.


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Antipsychoticinteractions

Clozapine


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ClozapineHalf life 12 h needs 5 half lives to reach steady st

Metabolized byCYP 1A2Inhibited byfavarin &

grape fruit in bigamounts rising levels ofliponex

Induced bysmoking

cigarettes

CYP 2D6

Inhibited byfluoxetine,paroxetineand large dose of

serteraline ieading to

rising level of clozapine

C Inhibi

erythretoco

Inducgluco

,phynarbito

rifamp

Phamacodynamically: lowers seuizer threshold havoid combining with wellbutrin and largactil

OLANZAPINE t 30h t d t t ithi k


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t = 30hs steady state within a week Metabolized by: CYP 1A2 ,CYP 2D6 and glucoronizati Serum level not related to drug drug interaction but if

smoker is given olanzapine he needs 20 mg daily to a

therapuetic effect whereas older female nonsmoker omg to achieve it

Serum level deminished by smoking

RESPERIDONE t =20hs once daily doses, steady state is reached w Metabolized by CYP 2D6 to 9-hydroxyl resperidone w

equipotent to parent compound and its serum level is

times of resperidone

Because of equipotency of resperidone and metabol

inhibitors had no effect on effective doses


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Psychotropic Drug Interactions

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