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Thursday, November 19, 2009

Mechanism of action of antiepileptic drugs

enhancement of GABA action
inhibition of sodium channel function
inhibition of calcium channel function
Newer drugs act by other mechanisms, yet to be elucidated.
Drugs that block glutamate receptors are effective in animal models but are not yet developred for clinical use.
Tonic clonic seizures:
carbamazepine (preferred because of low incidence of side-effects), phenytoin, valproate
use of a single drug is preferred when possible to avoid pharmacokinetic interactions
newer agents (not yet fully assessed) include vigabatrin, lamotrigine, felbamate, gabapentin.
Partial (focal) seizures: carbamazepine, valproate; clonazepam or phenytoin are alternatives.
Absence seizures (petit mal): ethosuximide or valproate
valproate is used when absence seizures coexist with tonic-clonic seizures, since most other drugs used for tonic-clonic seizures can worsen absence seizures.
Myoclonic seizures: diazepam intravenously or (in absence of accessible veins) rectally.
Neuropathic pain, e.g. carbamazepine, gabapentin (see Ch. 40).
To stabilise mood (as an alternative to lithium), e.g. carbamazepine, valproate

Valproate:
chemically unrelated to other antiepileptic drugs
mechanism of action not clear; weak inhibition of GABA transaminase; some effect on sodium channels
related few unwanted effects: baldness, teratogenicity, liver damage (rare, but serious).
Phenytoin:
acts mainly by use-dependent block of sodium channels
effective in many forms of epilepsy, but not absence seizures
metabolism shows saturation kinetics; therefore, plasma concentration can vary widely and monitoring is needed
drug interactions are common
main unwanted effects are confusion, gum hyperplasia, skin rashes, anaemia, teratogenesis
widely used in treatment of epilepsy; also used as antidysrhythmic agent

Carbamazepine:
derivative of tricyclic antidepressants
similar profile of that of phenytoin, but with fewer unwanted effects
effective in most forms of epilepsy (except absence seizures); particularly effective in psychomotor epilepsy; also useful in trigenimal neuralgia
strong enzyme-inducing agent; therefore, many drug interactions
low incidence of unwanted effects; principally sedation, ataxia, mental disturbances, water retention.

Other drugs include:
phenobarbital: highly sedative
various benzodiazepines (e.g. clonazepam); diazepam used in treating status epilepticus.

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