Antiseizure Drugs

The Pharmacokinetics of Antiseizure DrugsAntiseizure drugs are commonly used for long periods of timeIt is important to consider their pharmacokinetics for avoiding toxicity and drug interactionsAntiseizure drugs are well absorbed orally and have good bioavailability

The Pharmacokinetics of Antiseizure DrugsPhenytoin :The oral bioavailability is variableMetabolism : nonlinear elimination (zero-order) at moderate to high dose levelsThe drug binds extensively to plasma proteinInteraction : the metabolism inhibited by cimetidine, isoniazid and enhanced by inducer of liver metabolism (sulfonamide, valproic acid

The Pharmacokinetics of Antiseizure DrugsCarbamazepineCarbamazepine induces formation of liver drug-metabolizing enzymes increase metabolism of the drug itself, & may increase the clearance of many other anticonvulsantThe metabolism can be inhibited by propoxyphene, valproic acid

Valproic acidValproic acid inhibits the metabolism of phenytoin, phenobarbital, and lamotrigineHepatotoxic

The Pharmacokinetics of Antiseizure DrugsGabapentine & VigabatrinThese drugs eliminated by the kidney, largely in unchanged form

Lamotrigine & TopiramateLamotrigine is eliminated via hepatic glucoronidationTopiramates undergoes both hepatic metabolism and renal elimination of intact drug

Mechanism of action The general effect : suppress repetitive action potentials in epileptic foci in the brainThe mechanism of action of antiseizure drugs include :- sodium channel blockade- GABA-related Targets- Calcium channel blockade- enhancing K+ channel permeability- antagonist at some glutamate receptors

Mechanism of actionSodium Channel BlockadeBlock voltage-gate sodium channels in neuronal membranesExample : phenytoin, carbamazepine & lamotrigine at therapeutic concentration; phenobarbital and valproic acid at high dose

Mechanism of actionGABA-Related TargetsBenzodiazepine, barbiturat, tiagabine, gabapentin, vigabatrinBenzodiazepin facilitate the inhibitory effects of GABABarbiturat enhance the inhibitory actions of GABA but interact with different receptorVigabatrin inactivate GABA transaminase (an important enzyme in the termination of action of GABATiagabine inhibits GABA transporters in neurons & glia

Mechanism of actionCalcium Channel BlockadeExample : ethosuximide, valproic acid

Other Mechanism Enhancing K+ channel permeability (valproic acid)Antagonist at some glutamate receptors (phenobarbital, felbamate, topiramate)

Clinical UsesGeneralized Tonic-Clonic & Partial SeizuresValproic acid, carbamazepine, & fenitoin are DOC for generalized tonic-clonic seizure & partial seizurePhenobarbital is a primary drug in infantsAbsence SeizureEthosuximide and valproic acid are the preferred drugs because they cause minimal sedation

Clinical UsesMyoclonic seizure syndromesValproic acidClonazepam, but the high doses cause drowsinessStatus EpilepticusDiazepam & lorazepam i.v (effective in terminating attacks, providing short-term control)Phenytoin i.v (for prolong therapy, because it is less sedation)Phenobarbital has been used in status epilepticus, especially in children

Clinical UsesOther Clinical UsesBipolar disorder (valproic acid, carbamazepine, phenytoin, & gabapentinTrigeminal neuralgia (carbamazepine)Pain of neuropathic origin (gabapentin)Migraine (phenytoin)

ToxicityTeratogenicity (valproic acid, carbamazepin, phenytoin)Overdosage toxicity, include CNS depressants, respiratory depression(flumazenil may be used in benzodiazepine overdose)Fatal hepatotoxicity (valproic acid)Skin rashes & Stevens-Johnson syndrome (Lamotrigine)Aplastic anemia & acute hepatic failure (felbamate)Withdrawal