PHARMACODYNAMIC INTERACTION BETWEEN PHENYTOIN AND SODIUM VALPROATE CHANGES SEIZURE THRESHOLDS AND PATTERN

1 In this study we used cortical stimulation to assess the effects of phenytoin (PHT), sodium valproate (VPA), and their interaction on tota l motor seizure and on the constituent elements of the seizure. 2 PHT (40 mg kg(-1)) was administered as an intravenous bolus infusion to an imals receiving either a continuous infusion of VPA or saline. VPA pla sma concentration was maintained at levels that produced no detectable anticonvulsant effect. 3 Analysis of ictal components (eyes closure, jerk, gasp, forelimb, clonus, and hindlimb tonus) and their durations revealed both qualitative and quantitative differences in drug effects . 4 The anticonvulsant effect is represented by the increase in the du ration of the stimulation required to reach a given seizure threshold. PHT significantly increased the duration of the stimulation and of th e motor seizure. This increase was greatly enhanced by VPA. In additio n, ictal component analysis revealed that the combination of PHT and V PA causes the reduction of a specific seizure component (JERK). 5 Neit her the free fraction of PHT nor the biophase equilibration kinetics c hanges in the presence of VPA. It is concluded that the synergism may be due to a pharmacodynamic rather than a pharmacokinetic interaction.