Anticonvulsive and convulsive effects of lidocaine: comparison with those of phenytoin, and implications for mechanism of action concepts.

The anticonvulsive action of lidocaine was tested in mice against a series of convulsants, and its profile of action compared with that of phenytoin. Both agents antagonized seizures induced by ouabain or glutamate (injected i.c.b.), effects attributable to reduction of the sodium conductance of neuronal membranes. Lidocaine and phenytoin were relatively ineffective against convulsants that act on synaptic chloride channels via the GABA-ionophore receptor complex. At higher dose levels, both lidocaine and phenytoin are excitatory within limited ranges. Lidocaine-induced seizures were potentiated by phenytoin, and antagonized by chlordiazepoxide, phenobarbital, valproate, trimethadione and muscimol, but not by ethosuximide. This profile of action is similar to that of bicuculline, suggesting that lidocaine may bind to the GABA recognition site and to another site in the GABA-ionophore receptor complex. Phenytoin-induced excitation was antagonized by chlordiazepoxide, less effectively by phenobarbital or trimethadione, only minimally by valproate, and not by trimethadione or muscimol. Phenytoin is known to bind to picrotoxin and benzodiazepine receptor sites; these findings suggest that it may be excitatory at one or both of these sites.