Current frontline antiepileptic drugs tend to fall into several cellular mechanistic categories, and these categories often correlate with the clinical spectrum of action of the various antiepileptic drugs. Many antiepileptic drugs effective in control of partial and generalized tonic-clonic seizures are use- and voltage-dependent blockers of sodium channels. This mechanism selectively dampens pathologic activation of sodium channels, without interacting with normal sodium channel function. Examples include phenytoin, carbamazepine, valproic acid, and lamotrigine. Many antiepileptic drugs effective in control of generalized absence seizures block low threshold calcium currents. Low threshold calcium channels are present in high densities in thalamic neurons, and these channels trigger regenerative bursts that drive normal and pathologic thalamocortical rhythms, including the spike wave discharges of absence seizures. Examples include ethosuximide, trimethadione, and methsuximide. Several antiepileptic drugs that have varying clinical actions interact with the γ-aminobutyric acid (GABA)ergic system. Diazepam and clonazepam selectively augment function of a subset of GABA A receptors, and these drugs are broad-spectrum antiepileptic drugs. In contrast, barbiturates augment function of all types of GABAA receptors, and are ineffective in control of generalized absence seizures, but effective in control of many other seizure types. Tiagabine and vigabatrin enhance cerebrospinal levels of GABA by interfering with reuptake and degradation of GABA, respectively. These antiepileptic drugs are effective in partial seizures. Lamotrigine is effective against both partial and generalized seizures, including generalized absence seizures. Its sole documented cellular mechanism of action is sodium channel block, a mechanism shared by phenytoin and carbamazepine. These drugs are ineffective against absence seizures. Consequently, unless there are unique aspects to the sodium channel block by lamotrigine, it seems unlikely that this mechanism alone could explain its broad clinical efficacy. Therefore, lamotrigine may have as yet uncharacterized cellular actions, which could combine with its sodium channel blocking actions, to account for its broad clinical efficacy. (J Child Neurol 1997;12(Suppl 1):S2-S9).
Modified kinetics and selectivity of sodium channels in frog skeletal muscle fibers treated with aconitine.
