Metabolism In liver It is a potent inducer

• Metabolism: – In liver – It is a potent inducer of liver enzymes – So induces its own metabolism & metabolism of many other drugs causing various drug interactions e. g. with other antiepileptics • Excretion: – In urine as metabolites

BARBITURATES • Phenobarbitone: Oldest available antiepileptic. • Mephobarbitone: Similar to phenobarbitone but may have lesser adverse effects • Primidone: – Uses & ADRs similar to phenobarbitone

– Acts partly by converting into phenobarbitone but the mechanism is similar to phenytoin – May be more effective than phenobarbitone but less than phenytoin and carbamazepine • All Barbiturates are contraindicated in Porphyrias

Phenobarbitone • Mechanism: – GABA mediated neuronal inhibition – Blocks Na+ channels & Ca++ channels at higher concentrations • Clinical Use: Broad spectrum antiepileptic – Partial seizures – Generalized tonic clonic seizures But being a sedative drug, is only preferred in infants.

Carboxylic acids • Valproate: – Available as both valproic acid and its sodium salt, sodium valproate • Divalproex: – It is a 1: 1 co-ordination complex of valproic acid & sodium valproate – Its absorption is slow causing lesser side-effects – Preferred by most patients

Valproate • Mechanism: – GABA levels in brain by inhibiting its degradation b GABA transaminase enzyme – Na+ channels – Ca++ channels (T-type) • Clinical Use: Broad spectrum antiepileptic – Generalized tonic clonic seizures: DOC – Partial seizures

– Absence seizures – Atonic seizures: DOC – Myoclonic seizures: DOC – Infantile spasms – Non-epileptic uses: Mood stabilizer & Migraine prophylaxis

Valproate • Absorption: – Good; Food delays absorption – Can be given after meals to toxicity • Distribution: – Highly plasma protein bound – It occurs in highly ionized form

• Metabolism: – In liver • Excretion: – In urine with a half life of 9 -18 hours – At high concentration follows zero order kinetics

Valproate: Adverse Effects omiting lopecia: Hair loss iver toxicity: Can be prevented by Carnitine ancreatitis: So, Contraindicated in alcoholics ashes edema taxia eratogenicity* (e. g. Spina bifida) and Tremors nzyme inhibition: Metabolism of Phenobarb. & Phenytoin

Newer Antiepileptics • Gabapentin: GABA effect by ing its release • Vigabatrin: GABA-ergic transmission either by acting as GABA agonist or by ing GABA transaminase enzyme It is reserved for use in resistant epilepsy

• Tiagabine: GABA effect by ing its reuptake • Lamotrigine: Blocks Na+ & Ca 2+ channels • Topiramate: Blocks Na+ & Ca 2+ channels and GABA effect; Can cause weight loss

• Zonisamide: Blocks Na+ & Ca 2+ channels and GABA effect • Felbamate: Blocks glutamate NMDA receptors; May produce fatal aplastic anemia & severe hepatitis; So reserved for resistant epilepsies like Lennox Gestaut Syndrome

• Levetiracetam: Under development; Mechanism unknown No enzyme induction/ inhibition; Minimal interactions

Ethosuximide • Mechanism: – Main action: Blocks Ca++ channels (T-type) – Other actions: Na+K+ATPase, Cerebral metabolism & GABA aminotransferase • Clinical Use: Only in Absence seizures (Petit Mal): DOC

• Pharmacokinetics: – Completely absorbed & then distributes uniformly except in fat – Not plasma protein bound – Metabolized in liver & then excreted in urine with a half-life of 40 hours

• Adverse effects: – Very safe drug – Gastric irritation is common – Other adverse effects much less e. g. fatigue, headache, hiccups, rashes & blood dyscrasias • Drug interaction: Valproate s ethosuximide metabolism

Benzodiazepines �Diazepam: I. V. or rectal administration is highly effective in status epilepticus Oral administration for long term epilepsy control is not very effective because of rapid development of tolerance �Lorazepam: DOC in status epilepticus because of more efficacy & longer duration of action than Diazepam

�Clonazepam: Is highly effective in absence seizures Also useful in myoclonic seizures & infantile spasms �Nitrazepam: Used as an alternative to Clonazepam �Clorazepate: Used as an adjuvant in complex partial seizures �Clobazam: Useful in a variety of seizure types. Lesser sedation

Acetazolamide • It is a diuretic • Inhibits carbonic anhydrase enzyme Neuronal excitation • Useful as an adjuvant to antiepileptics in all types of seizures • But its usefulness is limited to only few weeks because of rapid development of tolerance