Comparative antiarrhythmic actions of encainide and its major metabolites.
The local anesthetic, antiarrhythmic, and acute toxicologic properties of the O-demethyl (ODE), 3-methoxy-O-demethyl (MODE) and N-demethyl (NDE) analogs of encainide (E) were compared with those of parent drug in several models. In the mouse chloroform-induced fibrillation model, the order of antiarrhythmic potency was ODE greater than E greater than MODE greater than NDE. The acute LD50 values for ODE, E, MODE and NDE in mice were 22.6, 38.1, 43.6 and 81.1 mg/kg, i.p. Based upon the toxic/therapeutic ratio in mice, ODE appeared to have the greatest margin of safety and MODE the least; E and NDE were intermediate. In dogs with ouabain-induced tachyarrhythmias, the converting doses of encainide, ODE, MODE and NDE were 0.67, 0.15, 0.39 and 1.1 mg/kg, i.v., respectively. The ODE and MODE metabolites thus appear to be more potent on a mg basis, but both have shorter durations of action than the parent compound. Antiarrhythmic activity in this model was best reflected by plasma drug level (Cp) rather than dose of drug administered. Antiarrhythmic onset Cp associated with encainide (244 ng/ml), ODE (77 ng/ml), MODE (164 ng/ml) and NDE (851 ng/ml) have been identified in this anesthetized dog model. In conscious dogs previously subjected to Harris two-stage coronary artery ligation, the minimal effective doses of encainide were 0.5 mg/kg i.v. and 1 mg/kg orally. For ODE and MODE the minimal effective doses were 0.25 and 0.19 mg/kg injected i.v., respectively, and 0.5 and 0.38 mg/kg given orally. By both routes, encainide had the shortest onset, longest duration and most consistent profile of sustained antiarrhythmic effects. Antiarrhythmic activity did not correlate with local anesthetic potency of either encainide or its metabolites. The data are consistent with the hypothesis that the metabolites of encainide may contribute to and/or be responsible, at least in part, for the persistent antiarrhythmic actions observed clinically following chronic administration of the parent drug in patients.
D000779:Anesthetics, Local; D000813:Anilides / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001711:Biotransformation; D002725:Chloroform / Q000633:toxicity; D004285:Dogs; D016700:Encainide; D005260:Female; D006168:Guinea Pigs; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010042:Ouabain / Q000633:toxicity; D012882:Skin Tests; D013610:Tachycardia / Q000139:chemically induced; D014693:Ventricular Fibrillation / Q000139:chemically induced / Q000517:prevention & control
D000779:Anesthetics, Local; D000813:Anilides; D000889:Anti-Arrhythmia Agents; D010042:Ouabain; D002725:Chloroform; D016700:Encainide