Different stereoselective effects of (R)- and (S)-propafenone: Clinical pharmacologic, electrophysiologic, and radioligand binding studies

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Abstract
Propafenone is a class 1c antiarrhythmic agent with moderate .beta.-blocking activity as a result of a structural similarity to .beta.-adrenoceptor antagonists. In a randomized, double-blind crossover exercise study, eight healthy volunteers were examined before and 2 1/2 hours after oral administration of 300 mg (R,S)-, 150 mg (R)-, and 150 mg (S)-propafenone hydrochloride. The mean rate pressure product was significantly reduced by (R,S)-propafenone hydrochloride (-5.2%; p = 0.045) and half-dosed (S)-propafenone hydrochloride (-5.9%; p = 0.013), whereas the (R)-enantiomer caused no significant changes. There was a significant difference between the effects of (R0- and (S)-propafenone (p = 0.033). In .beta.-adrenoceptor-binding inhibition experiments with (S)-(125I)iodocyanopindolol in a sarcolemma-enriched cardiac membrane preparation, the eudismic ratio of (S)- over (R)-propafenone was 54. On the spontaneously beating Langendorff-perfused guinea pig heart, 3 .cntdot. 10-6 mol/L of both (R)- and (S)-propafenone resulted in significant changes (p < 0.01) on His bundle conduction (+79% .+-. 27% and +69% .+-. 9%), as well as comparable decreases in the maximal rate of pacing with 1:1 conduction of the atrial (-54% .+-. 10% and -57% .+-. 8%) and ventricular myocardium (-42% .+-. 6% and -43% .+-. 6%), indicating equal effects in sodium channel-dependent antiarrhythmic class 1 activity. Thus (R)- and (S)-propafenone exert different .beta.-blocking actions but equal effects on the sodium channel-dependent antiarrhythmic class 1 activity. More specific antiarrhythmic class 1 therapy with reduction of .beta.-blocking side effects may be attained with optically pure (R)-propafenone hydrochloride instead of the currently used racemic mixture.

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