Differential effects of O-demethyl encainide on induced and spontaneous arrhythmias in the conscious dog

Abstract

Encainide is highly effective in suppressing most nonsustained ventricular arrhythmias, but there is evidence that the drug is less effective and may worsen some arrhythmias, particularly in patients with sustained ventricular tachycardia. In most patients it is likely that the major antiarrhythmic effects of encainide are mediated through a potent metabolite, O-demethyl encainide. The effects of infusions of saline solution or O-demethyl encainide on spontaneous ventricular ectopic activity and ventricular fibrillation (VF) threshold were compared in 25 dogs with a mottled myocardial infarct produced by transient coronary occlusion. Plasma levels of the metabolite above 100 ng/ml suppressed (> 92%) the spontaneous ventricular ectopic activity that occurred 48 hours after MI, whereas saline solution had no effect. In 15 dogs treated with O-demethyl encainide, the VF threshold decreased an average of 23%, from a baseline level of 23 ± 8 mA to 18 ± 9 mA (p < 0.05). There was a concentration-dependent fall in VF threshold with plasma concentrations of O-demethyl encainide above 150 ng/ml. In 2 dogs with very high plasma concentrations of the metabolite (> 1,000 ng/ml), VF was induced by right ventricular pacing alone (S 1S 1 300 ms). No change in VF threshold was observed in the 8 dogs treated with saline solution, and in each of these dogs VF could be terminated by the countershock protocol. However, in 7 of the 17 dogs treated with O-demethyl encainide, VF could not be terminated by the countershock protocol. These 7 dogs, which died from VF, had higher O-demethyl encainide levels (314 ng/ml or above) than the other 10 dogs. It is concluded that O-demethyl encainide is effective in suppressing spontaneous ventricular ectopic activity in this model of myocardial infarction, but at plasma levels higher than 150 ng/ml, the agent lowers the VF threshold and at higher levels impedes defibrillation.