Phenytoin: mechanisms of its anticonvulsant action

Phenytoin is a major anticonvulsant drug that is very effective in controlling a wide variety of seizure disorders while impairing neurological function little, if at all. Early work suggested the hypothesis that the drug's effects were due to a selective block of high-frequency neuronal activity. This theory is reevaluated in the light of accumulated observations on the effects of phenytoin in many neuronal and synaptic preparations. Most of these observations can be explained by a use- and frequency-dependent suppression of the sodium action potential by phenytoin, with a consequent filtering out of sustained high-frequency neuronal discharges and synaptic activity. The molecular mechanism for this is a voltage-dependent blockade of membrane sodium channels responsible for the action potential. Through this action, phenytoin obstructs the positive feedback that underlies the development of maximal seizure activity, while normal brain activity, proceeding at lower neuronal firing rates, is spared its depressant action. Other mechanisms of action that may contribute to the drug's efficacy and selectivity are also discussed.