Antiepileptic drug actions

Abstract

Antiepileptic drugs (AEDs) vary in their efficacy against generalized tonic-clonic, myoclonic, and absence seizures, suggesting different mechanisms of action. Phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) reduced the ability of mouse central neurons to sustain high-frequency repetitive firing of action potentials (SRF) at therapeutic free serum concentrations. Phenobarbital (PB) and the benzodiazepines (BZDs), diazepam (DZP), clonazepam (CZP), and lorazepam (LZP), also reduced SRF, but only at supratherapeutic free serum concentrations achieved in treatment of generalized tonic-clonic status epilepticus. These AEDs interact with sodium channels to slow the rate of recovery of the channels from inactivation. The BZDs and PB enhanced gamma-aminobutyric acid (GABA) responses evoked on mouse central neurons by binding to two different sites on the GABAA receptor channel. BZDs increased the frequency of GABA receptor channel openings. In contrast, barbiturates increased the open duration of these channels. VPA enhanced brain GABA concentration and may enhance release of GABA from nerve terminals. Ethosuximide (ESM) reduced a small transient calcium current which has been shown to be involved in slow rhythmic firing of certain neurons. Reduction of SRF, enhancement of GABA-ergic inhibition, and reduction of calcium current may be, in part, the bases for AED action against generalized tonic-clonic, myoclonic, and absence seizures, respectively.