Mexiletine's antifibrillatory actions are limited by the occurrence of convulsions in conscious animals.

The antiarrhythmic actions of the racemate and enantiomers of mexiletine were studied in conscious and anaesthetised rats. Racemate or enantiomers, at 20 mg/kg i.v., had little effect on ischaemia-induced ventricular fibrillation in conscious or anaesthetised rats. In conscious rats 20 mg/kg caused convulsions in 78-89% of rats when the plasma concentration of racemate was 20 +/- 2 microM. In anaesthetized animals a higher dose (40 mg/kg) of racemate could be given; this completely prevented ischaemia-induced fibrillation when the plasma concentration was 26 +/- 2 microM. Racemate and enantiomers accumulated in the heart and brain of conscious animals to give tissue: plasma ratios of 7.5 and 23, respectively. With electrical stimulation, both racemate and enantiomers dose dependently (4-32 mg/kg) increased threshold currents for induction of ventricular fibrillation, increased refractory period and minimally changed the ECG; findings expected with a Class Ib antiarrhythmic. The above studies failed to show major differences between racemate or enantiomers except for consistently lower (20-30%) plasma concentrations of R(-) at all dose levels. In conclusion, mexiletine prevented ischaemia-induced ventricular fibrillation in anaesthetised animals but only when given at doses producing convulsions in conscious animals.