In epilepsy certain neurons and/or groups of neurons become hyperexcitable and begin firing bursts of action potentials that propagate in a synchronous manner to other brain structures (and in the case of generalized seizures, to practically all areas of the brain). These may be the result of abnormalities in neuronal membrane stability or in the connections among neurons. It is known that the epileptic bursts consist of sodium-dependent action potentials and a calcium-dependent depolarizing potential.
Recent drug development studies have centered on the capacity of known antiepileptic drugs (AEDs) to interact with ion channels, and it is now established that several agents appear to be exerting their effects primarily by inhibiting ion channels. Modulation of neuronal sodium channels decreases cellular excitability and the propagation of nerve impulses. Inhibition of sodium channels appears to be a major component of the mechanism of action of several anticonvulsant drugs.
Much interest is also centered on the role of calcium channels in neuronal activity, since the depolarization associated with burst firing is mediated by the activation of calcium channels. At therapeutically relevant concentrations, the antiabsence drug ethosuximide appears to exert its effect by inhibiting the T-type calcium channels. A portion of valproic acid's activity may also be attributable to this effect.
Disinhibition may play an important role in the generation of epileptic seizures, since a reduction of GABAergic inhibition is necessary to produce the synchronous burst discharges in groups of cells. Compounds that antagonize the activity of GABA (picro-toxinin, penicillin C, bicuculline) are CNS convulsants, while agents that facilitate GABA's inhibition have an-ticonvulsant activity. Several anticonvulsant drugs act to facilitate the actions of GABA.
Excitatory neurotransmitters also may be involved in the appearance of epilepsy, since the bursting activity typically seen during epileptic discharges may be due in part to the action of glutamate acting on N-methyl-d-aspartate (NMDA) receptor channels to produce depolarization. It is likely that a major part of the anticon-vulsant activity of felbamate involves blockade of the NMDA receptor. Table 32.2 summarizes the most likely mechanism of action associated with available anticon-vulsant drugs.
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