Different stereoselective effects of (R)- and (S)-propafenone: clinical pharmacologic, electrophysiologic, and radioligand binding studies.
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 (R)- 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 x 10(-6) mol/L of both (R)- and (S)-propafenone resulted in significant changes (p less than 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.
Stoschitzky
K
K
Department of Medicine, Karl Franzens University, Graz, Austria.
Klein
W
W
Stark
G
G
Stark
U
U
Zernig
G
G
Graziadei
I
I
Lindner
W
W
D000284:Administration, Oral; D000328:Adult; D000818:Animals; D004311:Double-Blind Method; D004594:Electrophysiology; D005080:Exercise Test; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D020120:Iodocyanopindolol; D008297:Male; D010869:Pindolol / Q000031:analogs & derivatives; D011405:Propafenone / Q000008:administration & dosage / Q000494:pharmacology*; D011869:Radioligand Assay; D011897:Random Allocation; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013237:Stereoisomerism
D011943:Receptors, Adrenergic, beta; D011405:Propafenone; D020120:Iodocyanopindolol; D010869:Pindolol