Psychotropic Drug Interactions
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Transcript of 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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