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

Propafenone is a class 1c antiarrhythmic agent with moderate β‐blocking activity as a result of a structural similarity to β‐adrenoceptor antagonists. In a randomized, double‐blind crossover exercise study, eight healthy volunteers were examined before and 2½ 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 (R)‐ and (S)‐propafenone ( p = 0.033). In β‐adrenoceptor–binding inhibition experiments with (S)‐( 125 I)iodocyanopindolol in a sarcolemmaenriched cardiac membrane preparation, the eudismic ratio of (S)‐ over (R)‐propafenone was 54. On the spontaneously beating Langendorff‐perfused guinea pig heart, 3 · 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 β‐blocking actions but equal effects on the sodium channel–dependent antiarrhythmic class 1 activity. More specific antiarrhythmic class 1 therapy with reduction of β‐blocking side effects may be attained with optically pure (R)‐propafenone hydrochloride instead of the currently used racemic mixture. Clinical Pharmacology and Therapeutics (1990) 47 , 740–746; doi: 10.1038/clpt.1990.102