Studies on the stereoisomers of β‐adrenoceptor antagonists in conscious A‐V blocked dogs

Abstract

1 Atrial and ventricular chronotropic effects of the individual stereoisomers of propranolol, pindolol, metoprolol and penbutolol were studied in conscious dogs with chronic atrio-ventricular (A-V) block. Ventricular P-adrenoceptor blocking activity was assessed for all drugs against isoprenaline under the same experimental conditions. 2 At low doses, the stereoisomers ofpropranolol and penbutolol decreased atrial rate, whereas those of pindolol and metoprolol produced an increase. At higher doses, all drugs increased atrial rate. All drugs decreased ventricular rate dose-dependently except (+ )-pindolol.3 Relative ventricular P-blocking potencies of the (-)-isomers of propranolol, pindolol, metoprolol and penbutolol were respectively 38, 21, >43 and 31 times higher than those of their corresponding (+ )-isomers. In addition, P-blocking potencies of (-)-and (+ )-pindolol were respectively 60 and 120 times higher, those of (-)-and (+ )-penbutolol 7 and 8 times higher and those of (-)-and (+)-metoprolol 4 and >4 times weaker than those of (-)-and (+ )-propranolol. 4 At comparable levels of ventricular P-adrenoceptor blockade, (-)-pindolol and (-)-metoprolol were more potent in producing ventricular bradycardia than their respective (+)-isomers, whereas (-)-and (+ )-propranolol and (-)-and (+ )-penbutolol were equiactive. In addition, regardless of which isomer was being studied, the order of ventricular bradycardiac potencies, at comparable levels of P-adrenoceptor blockade, was metoprolol > propranolol > penbutolol > pindolol. 5 These results show that antagonism of P-adrenoceptors in the ventricle is at least partly responsible for the ventricular bradycardiac effect produced by these drugs, but also that some other factor, apparently distinct from the membrane stabilizing activity, is involved, suggesting the existence of some other as yet unknown pharmacological property of the P-adrenoceptor blocking drugs, especially evident in metoprolol. Finally, these results demonstrate that the intrinsic sympathomimetic activity exhibited by some of these drugs attenuate their bradycardiac effect.

Influence of Metoprolol Dosage Release Formulation on the Pharmacokinetic Drug Interaction With Paroxetine

“…Metoprolol is supplied as a racemic mixture of S and R enantiomers. The S enantiomer is primarily responsible for beta‐receptor antagonism and is beta‐1 selective, whereas the R enantiomer has lower affinity and selectivity 1 , 2 . Metoprolol is primarily metabolized by the liver, with an estimated 65% of a dose O‐demethylated, 10% alpha‐hydroxylated, and 10% N‐dealkylated 3 .…”

“…The S enantiomer is primarily responsible for beta-receptor antagonism and is beta-1 selective, whereas the R enantiomer has lower affinity and selectivity. 1,2 Metoprolol is primarily metabolized by the liver, with an estimated 65% of a dose O-demethylated, 10% alpha-hydroxylated, and 10% N-dealkylated. 3 Cytochrome P-450 2D6 (CYP2D6) is responsible for alpha-hydroxylation and some O-demethylation of metoprolol with stereospecificity favoring metabolism of the R enantiomer.…”

Stereochemistry - Racemic Modification, Resolution, and Its Importance With Recently Used Optically Active Drugs.

“…Less interaction potential of S-metoprolol compared to R-isomer further makes it a sensible choice in patients taking CYP2D6 inhibitors or in patients with heart failure or hepatic insufficiency [37]. Relative ventricular P-blocking potencies of the (-)-isomers of metoprolol are >43 times higher than those of their corresponding (+)-isomers [38].…”