Comparative actions of phenytoin and other anticonvulsant drugs on potassium- and veratridine-stimulated calcium uptake in synaptosomes.

The actions of phenytoin and several anticonvulsants drugs on veratridine-stimulated (Na-dependent) and K-stimulated (Na-independent) Ca uptake were studied in isolated nerve terminals (synaptosomes) from rat cerebral cortex. Phenytoin inhibits both veratridine- and K-induced Ca uptake but is more potent against veratridine. Inhibition of veratridine-stimulated Ca uptake by phenytoin appears to be a competitive relationship, whereas the interaction between K and phenytoin is noncompetitive. Hydroxyphenyl-phenylhydantoin, mephenytoin and ethylphenylhydantoin have actions similar to phenytoin but all are substantially less potent. Carbamazepine, phenobarbital, diazepam and lidocaine also inhibit veratridine- and K-stimulated Ca uptake, but ethosuximide and valproic acid are ineffective. Only carbamazepine and lidocaine have a relatively selective action against veratridine which is similar to phenytoin, and only these three drugs are active at concentrations which approximate their clinically effective anticonvulsant blood levels. The results of this study, in conjunction with reported data, suggest that phenytoin inhibits Na and Ca conductances in nervous tissue by separate and probably independent mechanisms. The present data also lead to the hypothesis that inhibition of Na uptake (perhaps associated with inhibition of Ca uptake) in nervous tissues is a mechanism of action responsible for some of the selective antiepileptic effects and/or analgesic effects of phenytoin, carbamazepine and lidocaine.