Pharmacological studies on propafenone and its main metabolite 5-hydroxypropafenone

Abstract

1. The new antiarrhythmic drug propafenone and its main human metabolite 5-hydroxypropafenone were investigated for antiarrhythmic, local anaesthetic, Ca++-antagonistic and β-adrenoceptor blocking effects as well as for their activity on the central nervous system. 2. In isolated organs (guinea-pig atria, rat aortic strips) 5-hydroxypropafenone had a smaller effect on the maximum following frequency, a greater negative inotropic effect, a greater Ca++-antagonistic effect and a very distinctly weaker β-adrenoceptor blocking effect than propafenone. 3. Consistent with its antiarrhythmic potency in vitro, intracutaneous 5-hydroxypropafenone had a smaller local anaesthetic effect in the guinea pig wheal. 4. In contrast to these findings 5-hydroxypropafenone showed a stronger antiarrhythmic potency in vivo (rat and dog, as demonstrated on aconitine and infarction arrhythmias. In addition, in His bundle studies 5-hydroxypropafenone caused a more marked prolongation of the conduction time in atria, AV-node and His-Purkinje system. In vivo the β-adrenoceptor blocking effect of 5-hydroxypropafenone (isoprenaline tachycardia, rat) was smaller than that of propafenone. 5. The difference between the in vitro and in vivo potency of 5-hydroxypropafenone may be explained by differences in pharmacokinetics, e.g. by a smaller distribution volume compared to propafenone. 6. CNS effects were investigated due to local anaesthetic properties of the substances tested. As an indicator of CNS activity, anticonvulsant effects, detectably beneath convulsion-inducing doses, were determined in rats (max. electroshock seizures). The results show low CNS activity of propafenone which is even lower for the metabolite but which is distinctly higher for lidocaine and - related to the antiarrhythmic potency - for flecainide, too. Studies on CNS side effects with simultaneous EEG and ECG recording in rabbits revealed that overdoses of propafenone and 5-hydroxypropafenone manifest themselves as ECG changes (2nd degree AV block; extrasystoles) while neurotoxic effects (EEG seizure patterns, visible clonism) may occur only after further drug administration. By contrast, toxic CNS symptoms following lidocaine overdosage are not preceded by marked ECG changes.