Mechanisms of anticonvulsant drug action

The actions of clinically used anticonvulsant drugs on sustained high frequency repetitive firing of action potentials and on responses to gamma aminobutyric acid (GABA) have been determined using mouse neurons in cell culture, and a classification of anticonvulsant drug actions has been developed based on these cellular actions. Actions of the anticonvulsant drugs were accepted as clinically relevant only if they occurred at concentrations achieved in cerebrospinal fluid or in plasma unbound to plasma proteins. Based on their cellular mechanisms of actions, drugs have been divided into 3 categories: (1) Phenytoin, carbamazepine and valproic acid limited sustained high frequency repetitive firing but did not alter GABA responses. (2) Phenobarbital and the benzodiazepines, clonazepam, diazepam and nitrazepam, augmented postsynaptic GABA responses. These drugs limited sustained high frequency repetitive firing only at concentrations above the therapeutic range in ambulatory patients, but equal to concentrations achieved in the acute treatment of status epilepticus. (3) Ethosuximide failed to reduce sustained high frequency repetitive firing or enhance GABA responses even at supertherapeutic concentrations. Limitation of sustained high frequency repetitive firing by anticonvulsant drugs correlated well with efficacy against generalized tonic-clonic seizures in man and against maximal electroshock seizures in experimental animals. Enhancement of postsynaptic GABA responses correlated with efficacy against generalized absence seizures in man and against pentylenetetrazol seizures in animals. Ethosuximide, however, did not alter GABA responses or sustained high frequency repetitive firing suggesting that its action against generalized absence seizures in man and pentylenetetrazol seizures in experimental animals occurs by an additional, as yet unknown, mechanism.