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ANTI EPILEPTIC DRUGS EPILEPSY: A chronic disorder characterized by recurrent seizure SEIZURE: Is a violent involuntary spasmodic contraction of skeletal muscle EPIDEMIOLOGY: 1% worlds population & 57/1000 AETIOLOGY • in children-idiopathic • in young- hypoxia, birth asphyxia, intracranial trauma during birth, metabolic disturbances, infection • In adult- head injury, alcohol abuse, cerebrovascular disease • DIAGNOSIS: EEG( electroencephalo gram) MRI(magnetic resonance imaging) CT scan brain mapping ACTIVATION OF EXCITATORY NEURO TRANSMITTOR TISSUE DAMAGE PATHOPHYSIOLOGY IDIOPATHIC & HERIDITORY INHIBITION OF INHIBITORY NEURO TRANSMITTOR SEIZURE CLASSIFICATION MECHANISM OF ANCTIONS • a) enhancement of GABAnergic transmission • b) diminution of excitatory transmission • c) modification of ionic conductance 1ST LINE TREATMENT 2ND LINE TREATMENT SIMPLE PARTIAL SEIZURE CARBAMAZEPINE VIGABATRIN ,ZONISAMIDE COMPLEX PARTIAL SEIZURE PHENYTOIN CLOBAZAM TONIC CLONIC VALPROATE VIGABATRIN TONIC CARBAMAZEPINE CLOBAZAM CLONIC PHENYTOIN, LAMOTRIGINE PHENOBARBITAL ABSENCE ETHOSUXIMIDE ,VALPROATE CLONAZEPAM, LAMOTRIGINE ACETAZOLAMIDE ATONIC CLONAZEPAM ,CLOBAZEPAM LAMOTRIGINE ,CARBAMAZEPINE PHENYTOIN ,ACETAZOLAMIDE MYOCLONIC VALPROATE, CLONAZEPAM PHENOBARBITAL, ACETAZOLAMIDE TOPIRAMATE SEIZURE TYPE PARTIAL SEIZURE GENERALISEDSEIZURES Cyclic ureides: Phenytoin, fosphenytoin MECHANISM OF ACTION • Blocks high-frequency firing of neurons through action on voltage-gated (VG) Na+channels, decreases synaptic release of glutamate PHARMACO KINETICS • Absorption is formulation dependent,highly bound to plasma proteins • no active metabolites ,Dose dependent elimination, ,t1/2 12-36h • fosphenytoin is for IV, IM routes Toxicity: Diplopia, ataxia,, hirsutism, neuropathy Interactions: isoniazid, felbamate, oxcarbazepine, topiramate, fluoxetine, fluconazole, digoxin, quinidine, cyclosporine, steroids, oral contraceptives,. Phenobarbital • Mechanism of action: • Enhances phasic GABAa receptor responses ,Reduces excitatory synaptic responses • Pharmaco kinetics: • Nearly complete absorption, not significantly bound to plasma Proteins,peak concentrations in 4 h, no active metabolites,t1/2 varies from 75 to 125h • Toxicity: Sedation, cognitive issues, ataxia, hyperactivity • Interactions:Valproate,carbamazepine,felbamate,phenytoin,cyclosporine, felodipine,,nifedipine, nimodipine, steroids,theophylline, verapamil, Ethosuximide • Mechanism of action: Reduces low threshold Ca2+ currents (Ttype) • Pharmacokinetics: Well absorbed orally, with peak levels in 3-7 h, not proteinbound completely metabolized to inactive compounds ,t1/2 typically 40 h • Toxicity: Nausea, headache, dizziness,hyperactivity • Interactions: Valproate,phenobarbital, phenytoin, carbamazepine,rifampicin Tricyclics: Carbamazepine • Mechanism of action: Blocks high- frequencyfiring of neurons through action on VG Na+ channels decreases synaptic release of glutamate • pharmacokinetics: Well absorbed orally, with peak levels in 6 to 8 h • no significant protein binding • metabolized in part to active 10-11-epoxide • t1/2 of parent ranges from 8to 12 h in treated patients to 36 h in normal subjects • Toxicity: Nausea,, headache • Interactions: valproate, fluoxetine, verapamil, macrolide antibiotics, isoniazid. Benzodiazepines : Diazepam &LORAZEPAM • MECHANISM OF ACTION: Potentiates GABAA responses • PHARMACO KINETICS: • Well absorbed orally • rectal administration gives peakconcentration in ~1 h with 90% bioavailability • IV for status epilepticus,highly protein-bound • extensively metabolized to several active metabolites, t1/2 ~2 d • Toxicity: Sedation Clonazepam • MECHANISM OF ACTION: As for diazepam • PHARMACO KINETICS: • >80% bioavailability • Extensively metabolized but no active metabolites • t1/2 20-50 h • Toxicity: Similar to diazepam GABA derivatives :Gabapentin • MECHANISM OF ACTION: Decreases excitatory transmission by acting on VG Ca2+ channels presynaptically • PHARMACO KINETICS: • Bioavailability 50%, decreasing with increasing doses ,not bound to plasma proteins • not metabolized,t1/2 6-8 h • Toxicity: Somnolence, dizziness, ataxia Pregabalin • MECHANISM OF ACTION: As for gabapentin • PHARMACO KINETICS: • Well absorbed orally ,not bound to plasma proteins • not metabolized,t1/2 6-7 h • Toxicity: Somnolence, dizziness, ataxia Vigabatrin • MECHANISM OF ACTION: • Irreversibly inhibits GABA-trans aminase • PHARMACO KINETICS: • 70% bioavailable ,not bound to plasma proteins • not metabolized,t1/2 5-7 h • Toxicity: Drowsiness, dizziness, psychosis visual field loss Miscellaneous: Valproate • MECHANISM OF ACTION: Blocks high-frequency firing of neurons, modifies amino acid metabolism • PHARMACO KINETICS: • Well absorbed from several formulations • highly bound to plasma proteins • Extensively metabolized, t1/2 9-16 h • Toxicity: Nausea, tremor, weight gain, hair loss, teratogenic, hepatotoxic • Interactions: felbamate, rifampin, ethosuximide, primidone Lamotrigine • MECHANISM OF ACTION: Prolongs inactivation of VG-Na+ channels,acts presynaptically on VG-Ca2+ channels,decreasing glutamate release • PHARMACO KINETICS: • Well absorbed orally • no significant protein binding • extensively metabolized, but no active metabolites • t1/2 25-35 h • Toxicity: Dizziness, headache, diplopia, rash • Interactions: Valproate, oxcarbazepine, primidone, succinimides, topiramate Levetiracetam • MECHANISM OF ACTION: Action on synaptic protein SV2A • PHARMACO KINETICS: • Well absorbed orally • not bound to plasma proteins • metabolized to 3 inactive metabolites • t1/2 6-11 h • Toxicity: Nervousness, dizziness, depression, • Interactions:,primidone Tiagabine • MECHANISM OF ACTION: Blocks GABA reuptake in forebrain by selective blockade of GAT-1 • PHARMACO KINETICS: • Well absorbed • highly bound to plasma proteins • extensively metabolized, but no active metabolites • t1/2 4-8 h • Toxicity: Nervousness, dizziness, depression, seizures • Interactions: Phenobarbital, phenytoin, carbamazepine, primidone Topiramate MECHANISM OF ACTION: Multiple actions onsynaptic function, probably via actions on phosphorylation PHARMACO KINETICS: Well absorbed, not bound to plasma proteins extensively metabolized, but 40% excreted unchanged in the urine no active metabolites t1/2 20 h, but decreases with concomitant drugs Toxicity: confusion Interactions: Phenytoin, carbamazepine, oral contraceptives,, lithium Zonisamide • MECHANISM OF ACTION: Blocks high-frequency firing via action on VG Na+ channels • PHARMACO KINETICS: • Approximately 70% bioavailable orally • minimally bound to plasma proteins • >50% metabolized, t1/2 50-70 h • Toxicity: Drowsiness,, confusion. Lacosamide • MECHANISM OF ACTION: • Enhances slow inactivation of Na+ channels • Blocks effect of neurotrophins (via CRMP-2) • PHARMACO KINETICS: • Well absorbed ,minimal protein binding • one major nonactive metabolite ,t1/2 12-14 h • Toxicity: Dizziness, headache, nausea small increase in PR interval RETIGABINE • MECHANISM OF ACTION: Enhances k+ channel opening • PHARMACOKINETICS: Readily absorbed,Requires 3-times daily dosing • TOXICITY : dizziness, confusion, blurred vision RUFINAMIDE • MECHANISM OF ACTION: Prolongs inactivation of VG Na+ channels • PHARMACOKINETICS: • Well absorbed orally,Peak concentration in 4-6h • t1/2 6-10h,Minimal plasma protein binding • No active metabolites ,Excreted in urine • TOXICITY: vomiting ,diarrhea • INTERACTIONS: not metabolized by CYP 450 Enzymes REFERENCES • Basic and clinical pharmacology- katzung, RogerJ.Porter,MD ,& Brain S. Meldrum,MB, PhD 11th edition • RANG & DALE’S Pharmacology 7th edition • CLINICAL PHARMACOLOGY BY Rooger & Walker • Conceptual pharmacology by D. jagadeesh Prasad • Goodman & Gilman