Drugs use in Epilepsy

Drugs use in EpilepsyDr. Pagan Pambudi, M.Si, Sp.SAdalah suatu gejala neurologik sepintasDapat berupa:MotorikSensorikPerilakuOtonomikYang disebabkan oleh aktivitas sekelompok neuron yang hipersinkron dan abnormalDefinisi Kejang epileptik

Aktivitas neuronNormal Brain activity recorded by EEG

Seizure activity

See the patientImbalans neuron eksitasi dan inhibisiChanelopathyAbnormal neuronal circuityPatofisologi KejangIdiopatikSimptomatikStrokeInfeksi SSPTumor SSPKelainan pembuluh darahTrauma kapitis dllKriptogenikPenyebab kejang

ekowr089Etiologi Epilepsi

Symptomatic or Cryptogenic (23%)Primary Idiopathic (77%)Sebagian besar epilepsi memiliki penyebab primer idiopatik. Dari penyebab simptomatik, yang paling umum adalah gangguan serebrovaskular, diikuti neoplasma SSP, malformasi kongenital bawaan, dan trauma. ekowr0810Etiologi Epilepsi102030405060IdiopathicVascularTumorTraumaTrauma lahirHerediterFrekuensi relatifUSIAPerkiraan frekuensi macam-macam etiologi epilepsi berdasarkan usiaEpilepsi idiopatik bisa ditemukan pada semua golongan umur dan memuncak pada usia dewasa muda (20-30 tahun). Epilepsi vaskular terutama pada lansia. Epilepsi herediter dan akibat trauma lahir biasanya muncul pada usia muda (terutama < 10 tahun).

Inhibitor kanal NatriumAgonis GABA AInhibitor kanal kalsiumMenghambat release vesikel neurotransmitterMerubah pH Mekanisme kerja obat antiepileptik

ekowr0812Cara Kerja OAEClass of Antiepileptic DrugsFirst GenerationSecond generationPhenytoinCarbamazepinBenzodiazepinBarbituratesEthosuximideAcetazolamidesACTHValproic AcidLevetiracetamOxcarbazepinZonisamideLamotrigineGabapentinTopiramateMOABlocks voltage-activated Na channelsThe Five Most Common Nystagmus, ataxia, slurred speech, decreased coordination

PhenytoinIdiosyncraticRash Rate. Approximately 5%Serious Rash Rate. Low, but Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.Hepatic Dysfunction Rate. UnknownHematologic Dysfunction Rate. UnknownOthersGingival hyperplasiaLymphadenopathySensory peripheral neuropathyOsteomalaciaNeonatal coagulation defects in newborns of mothers receiving phenytoinTeratogenesis. Category C

PhenytoinPHARMACOKINETICS AND DRUG INTERACTIONSMetabolism. Hepatic metabolismProtein Binding. High (90%)Half-life. Mean 22 hours: a wide range that depends on serum concentrationTime to steady state wide range that depends on serum concentration, may be up to 3 weeks

Phenytoin Phenytoin SE

PhenytoinInduced byInhibit byCarbamazepine alcohol (chronic)reserpine, and sucralfateAlcohol (acute intake), amiodarone, chloramphenicol, chlordiazepoxide, diazepam, dicumarol, disulfiram, estrogens, H2-antagonists, halothane, isoniazid, methylphenidate, phenothiazineMany drugs that are metabolized by hepatic enzymesOral contraceptiveInduceDosageLoadingOral loading dose is 1,000 mg in three divided doses given at 2-hour intervals.Intravenous loading dose for status epilepticus is 18 mg/kgMaintenace5-7 mg/kg BBGoal: 10-20 ug/mLPhenytoinMECHANISM OF ACTIONBlocks voltage-activated Na channelsReduces polysynaptic responsesBlocks post-tetanic potentiationDepresses thalamic potentialsDepresses bulbar and polysynaptic reflexes

CarbamazepinPHARMACOKINETICS AND DRUG INTERACTIONSMetabolism. >90% hepatic metabolismHalf-life. 10 to 25 hours after chronic dosingApparent Volume of Distribution. 0.8 to 1.9 L/kgProtein Binding. Moderate 67% to 81%Serum Concentration Range. 4 to 12 g/mLUnique Pharmacokinetic Property. Carbamazepine induces its own metabolism, necessitating a gradual increase in dose to avoid severe dose-related toxicity

CarbamazepinCarbamazepinMost common SEIdiosyncratics SETremorRashSedationAtaxiaNauseaDiplopiaWeight gain

ThrombocytopeniaNeutropeniaAplastic anemiaHepatic dysfunctionRashExfoliative dermatitisPancreatitis

Beware:CBZPHTOXCLTGSteven johnson syndrome

Dosage:Adults. 7 to 15 mg/kg/dayChildren. 10 to 40 mg/kg/dayAdjust every 3-4 weeks

CarbamazepineMECHANISM OF ACTIONBlocks voltage-activated Na channelsActivates calcium dependant potassium conductance

Valproic AcidPharmacokineticsMetabolism. Almost 100% metabolized by liverProtein Binding. High (approximately 90%)

Valproic AcidValproic AcidInduced byInhibitPhenytoinCBZPhenobarbital and primidone

Tricyclic antidepressantsCBZ (increase in CBZ-10,11-epoxide)LamotrigineEthosuximidePhenobarbital and primidonePhenytoin (also protein binding displaced)

FelbamateInhibit by does not interfere with oral contraceptivesSide effectNausea, somnolence, tremor, dizziness, astheniaHepatic DysfunctionHematologic Dysfunction Rate. Thrombocytopenia in up to 27%Dosage10 to 15 mg/kg/day, increase dosage by 5 to 10 mg/kg/week

Valproic AcidMechanism of ActionBlocks voltage-activated Na channelsBlocks release of glutamate and aspartate during repetitive firingInhibits high-amplitude calcium currents

LamotrigineMetabolism. Glucuronic acid conjugationProtein Binding. Low (44%)Drug InteractionsLamotrigine Induces Other Drugs. NoLamotrigine Inhibits Other Drugs. NoLamotrigine is Induced by Other DrugsPhenytoin, carbamazepine, primidone, phenobarbital, and estrogen-containing hormonal contraceptives (levels reduced by 40%)Lamotrigine is Inhibited by Other DrugsValproate inhibits lamotrigine (levels increased twofold)

Lamotrigine does not interfere with oral contraceptivesDosage as monotheraphyWeeks 1 and 2. 25 mg once a dayWeeks 3 and 4. 25 mg twice dailyWeeks 5 and 6. 50 mg twice dailyWeeks 7 and 8. 100 mg twice daily

Combination with other AED needs further adjustmen especially w/ valproic acid

LamotrigineSide Effect:Dizziness, headache, diplopia, ataxia, and nauseaRash (10%), headache

Lamotrigine MECHANISM OF ACTIONLevetiracetam binds to the synaptic vesicle protein SV2A

LevetiracetamPharmacokineticsLevetiracetam is not extensively metabolized in humans; activity is due to the parent compound.The major metabolic pathway is the enzymatic hydrolysis of acetamide group (not cytochrome P-450 dependent); metabolites have no known P.71pharmacologic activity and are renally excreted in the unchanged form.66% of parent compound is excreted unchanged in urine.Protein Binding. Low;