ABSTRACTEncainide, a class IC antiarrhythmic agent, has been associated with proarrhythmic responses of ventricular tachycardia and fibrillation requiring defibrillation in patients. We examined the short-term effects of intravenous encainide and its two major metabolites, O-demethyl-encainide (ODE) and 3-methoxy-ODE (MODE), on the energy requirements for successful defibrillation in 25 pentobarbital-anesthetized, open-chest dogs. Truncated exponential (60% tilt) defibrillation shocks were administered through right atrial spring and left ventricular epicardial patch electrodes identical to those used in man with the automatic implantable defibrillator. At baseline multiple shocks of varying energy were applied to construct curves of percent successful defibrillation as a function of energy (DF curves) for each animal. Encainide, ODE, or MODE was then infused in loading and maintenance doses to achieve QRS widening of 20% to 50%. Saline was administered to animals serving as controls. Determination of the DF curve was repeated, after which the infusion was discontinued. After 1 hr washout period, an additional DF curve was constructed. The data were analyzed by logistic regression,and the energies required for 50% successful defibrillation (E50) were compared. No significant differences existed between the four groups in body or heart weight, extent of QRS widening, or baseline E50 values. After administration of encainide and ODE, the E50 increased by 129 ± 43%(p < .001) and 76 + 34% (p < .005), respectively. Return of E50 toward baseline was observed after the washout periods in both groups (p < .025), demonstrating the reversibility of the drugs' effects. No significant increase in E50 was observed after administration of MODE, and the results were not statistically different from those in the control group. We conclude that both encainide and ODE greatly increase the energy required for successful defibrillation, while MODE does not exert a significant effect. Also, their effect on defibrillation cannot be predicted by plasma drug concentration, extent of QRS widening, or increase in ventricular refractoriness.