Antiepilepticdrugs

Dr.Hj.RikaYuliwulandari,PhD

Primary

Types of s

(focal)

Definisi Tujuan antiepilepticdrugs Classificationofantiepilepticdrugs Pharmacologyofantiepilepticdrugs

Definition Epilepsy:

Recurrentseizuredisorders Sudden Excessive Symptomsdependonthesiteofelectricaldischarge

Convulsionmotorcortex Visual,auditory,olfactoryhallucinations parietaloroccipitalcortex

Antiepilepticdrugs: Treat50%ofpatientwithconvulsion Tappering on tappering off Mekanisme:blok inisiasi lonjakan elektrik dari focalareaatau

mencegah penyebaran lonjakan elektrik abnormalke areaotak lainnya Goal:

Stopconvulsion Notharmfulforcerebralneurons Normalactivityposttreatment

Antiepileptic Drugs Classification

Golongan hidantoin Fenitoin (difenilhidantoin), mefenitoin, etotoin

Golongan barbiturat Fenobarbital, primidon

Golongan suksinimid Etosuksimid, metsuksimid, fensuksimid

Karbamazepin Golongan benzodiazepin

Diazepam, klonazepam, nitrazepam Asam valproat Antiepilepsi lain

Lamotrigin, gabapentin, Asetazolamid, vigabatrin,

PrincipleMechanismsofActionofAntiepilepticDrugs

DecreaseactivityofvoltagedependentNa+channels

DecreaseactivityofvoltagedependentCa+channels

AugmentGABA activity Decreaseglutamatereceptoractivity Drugtreatmentdeppends onthespecifictypeofseizure

ClinicalApplicationofAntiepilepticDrugs

Typesofepilepsy Drugs1 Drugs2

PARTIAL

Simple Phenitoin,CBZ Phenobarbital,Primidone

Complex Phenitoin,CBZ Primidone

GENERALIZED

TonicClonic(grandmal)

Phenytoin, CBZ Phenobarbital,Primidone,Valproic acid

Absence(Petitmal)

Ethosuximide Valproic acid,Clonazepam

Myoclonic Valproic acid,Clonazepam

Febrile Seizuresinchildren

Phenobarbital Primidone

Statusepilepticus

Phenitoin,Diazepam Phenobarbital

WhentoWithdrawAntiepilepticDrugs?

Normalneurologicalexamination NormalIQ NormalEEGpriortowithdrawal Seizure freefor25yrs orlonger NOjuvenilemyoclonicepilepsy

Phenytoin Hydantoin group

Phenytoin (Dephenylhydantoin) Mefenytoin Etotoin

Pharmacology: Nafluxinneurons stabilizesneuronalmembranesto

depolarization Ca influx Effect:Drowsiness,lethargywithouthypnosis Absorption:slow(i.m.isdepositedininjectionsitefor5days) Distributionisrapid Highconcentrationinbrain Mostlyboundtoplasmaalbumin T1/2:742hrs Proteinbinding:90%

Metabolism:hepatichydroxylationsystem Druginducedtoxicityiseasytooccur(needtightmonitoring!!!) Geneticvariationaffectthedrugmetabolisms Dose:200400mg(510mg/kgbw) Se:

GIproblems:nausea,vomiting Gingivalhyperplasiaandcoarseningoffacialfeaturesesp.inchildren Megaloblastic anemia Behavioralchanges:confusion,hallucination,drowsiness Inhibitinsulinsecretioncausinghyperglycemiaandglycosuria Pregnancy:teratogenic effect fetalhydantoin syndrome(cleftlip,cleft

palate,congenitalheartdisease,slowgrowthandmentaldeficiency) Indication:allpartialseizures,tonicclonic seizures,statusepilepticus

(noteffectiveforabsenceseizures) Druginteraction:

InhibitionofPhenytoin:Chloramphenicol,Dicumarol,Cimetidine,Sulfonamide,Isoniazid

IncreasePhenytoin metabolism:Carbamazepine,Teophylline,Phenobarbital Phenytoin induceP450system increasemetabolismofotherantiepileptics,

anticoagulants,oralcontraceptives,quinidine,Doxycycline,Cyclosporin,Mexiletine,Methadone,Levodopa

Carbamazepine Moa:blockingNachannel inhibitpropagationofabnormalimpulsesin

thebrain Pharmacology:

Absorption:slow Highlipidsolubility rapidlyenterthebrain EnhancehepaticP450system inchronicadministration,t1/2decrease Dose:4001200mg(Child:1030mg/kgbw) T1/2:824hrs Proteinbinding:75% Poonly Se:

Chronicuse:stupor,coma,respiratorydepression,drowsiness,vertigo,ataxia,blurredvision

GIproblem:nausea,vomiting Aplastic anemia,agranulocytosis,thrombocytopenia Potentiallyinducelivertoxicity(needfrequentliverfunctiontest!!!!)

Druginteraction: Allert:Carbamazepine andmostotherantiepilepticdrugsrequiredgradual

dosetitrationtofulldoseoverdaystoweeks,exceptPhenytoin

Phenobarbital Familyofbarbiturate:

Phenobarbital Primidone

Pharmacology: Moa:Potentiateinhibiton effectofGABA (gammaaminobutyric

acid)mediatedneurons Absorption:

Oral:wellabsorbed PotentinducerofP450 Almost75%isinactivatedinliver,therestisexcretedthroughkidney

Se: Sedation,ataxia,nystagmus,vertigo,acutepsychoticreactions Sensitiveindividual:nausea,vomiting,morbiliform rash Highdose:agitation,confusion Discontinuation:reboundseizures

Primidone

ResemblesPhenobarbital Orallywellabsorbed Poorproteinbinding

Valproic acid Moa:enhanceGABA actionatinhibitorysynapses Uses:mosteffectiveformyoclonic seizures Pharmacology:

Orallywellandrapidabsorbed Proteinbinding:90% 3%excretedunchanged,therestbecomeactivemetabolite MetabolizedinliverbyP450system Dose:7503000mg(child:1560mg/kgbw) T1/2:616hrs Se:

nausea,vomiting,sedation,ataxia,tremor Rashandalopeciainsomeindividuals Increasebleedingtimeduetothrombocytopeniaandinhibitionofplatelet

aggregation Druginteraction:

Inhibitsphenobarbital metabolismcausingincreasecirculatinglevelofthedrug

Ethosuximide FamilyofSuximide

Ethosuximide,Metsuximide,Fensuximide Pharmacology:

Moa:inhibitCachannelinneuronTcellofthalamus Wellabsorbedorally Proteinbinding:0% 25%excretedunchangedinurine 75%isinactivatedinliver DoesnotinduceP450system Dose:5001500mg(child:1530mg/kgbw) T:2060hrs Se:

stomachirritation,nausea,vomiting,drowsiness,lethargy,dixxiness,restlessness,agitation,anxiety,inabilitytoconcentrate

Sensitiveindividual:StevensJohnsonssyndrome,urticatia,leukopenia,aplastic anemia,thrombocytopenia

Diazepam

FamilyofBenzodiazepine Diazepam,Klonazepam,Nitrazepam

Pharmacology: Docofacutetreatmentinstatusepilepticus Dose:

520mgiv(slow) canberepeatedafter1520mnt Infant:0.5mg/kgbw perrectal,child

Otherantiepilepticdrugs Gabapentin:

AnalogofGABA Proteinbinding:0% Excretedunchangedinurine minimizedruginteraction Dose:9003600mg T1/2:57hrs Se:mildCNS

Lamotrigine: Moa:inhibitglutamateandaspartate release,blockssodiumchannels,

preventsrepetitivefiring Proteinbinding:55% Metabolizedinliver Dose:100600mg T1/2:1570hrs Se:mildCNSeffect,rash Druginteraction:

T1/2isinhibitedbyP450enzymeinducingdrug(CBZ,Phenytoin) TisIncreasedbyvalproic acid

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Patophysiology ofconvulsion