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Quantitative comparison of β1- and β2-adrenoceptor blockade by carvedilol in combination with PDE3 inhibition
Following the oral administration of the therapeutically used concentration of 25 mg carvedilol, peak plasma levels of 100 ng.ml-1 (246 nM) carvedilol have been measured in heart failure patients (Tenero et al. 2000). Since approximately 98% of carvedilol is bound to plasma protein (Martindale, 2002) the β-adrenoceptors would be expected to be in contact with approximately only 4.9 nM of plasma carvedilol. The concentrations of endogenous noradrenaline and adrenaline needed to surmount the carvedilol-induced blockade of β1- and β2-adrenoceptors can be estimated from the surmountable antagonism against noradrenaline and adrenaline respectively, and the corresponding dissociation equilibrium constants KB (Molenaar et al. 2006). From simple competitive inhibition, the concentration-ratio (CR) of a catecholamine in the presence and absence of carvedilol can be calculated from CR = 1 + ([carvedilol] × KB-1). Using KB values of carvedilol of 0.95 nM for the β1-adrenoceptor and 0.074 nM for the β2-adrenoceptor (Molenaar et al. 2006), 4.9 nM carvedilol would produce CR values of 6.2 and 67 for β1- and β2-adrenoceptors respectively. Therefore, due to the β2-adrenoceptor-selective affinity of carvedilol, endogenous adrenaline would hardly be expected to cause cardiostimulation through β2-adrenoceptors in carvedilol-treated patients treated with a PDE3 inhibitor, despite the 10-35-fold potentiation of the adrenaline effects.
The estimates of blocking potency from plasma concentrations of carvedilol may actually not represent the concentration of carvedilol at the β1- and β2-adrenoceptors because carvedilol still causes substantial β-adrenoceptor blockade at plasma levels below the carvedilol detection level of 1 ng.ml-1(Kindermann et al. 2004). It is likely that under these conditions carvedilol stored in cardiac tissues is slowly released and diffuses across the cardiomyocytes thereby causing some occupancy of β1-adrenoceptors and greater occupancy of β2-adrenoceptors due to its higher affinity for the latter receptors (Molenaar et al. 2006). The cardiac capture and storage of carvedilol is supported by evidence demonstrating that the cardiac concentrations of active S-enantiomer of carvedilol exceed the plasma concentrations by 7-fold (Stahl et al. 1993). Our ex-vivo experiments, demonstrating consistently greater persisting blockade of β2- than β1-adrenoceptors in atrial and ventricular tissues from heart failure patients treated with carvedilol (Molenaar et al. 2006 confirmed in this work), are consistent with these mechanisms.
References
Kindermann M, Maack C, Schaller S, Finkler N, Schmidt KI, Läer S,Wuttke H, Schäfers H-J, Böhm M(2004). Carvedilol but not metoprolol reduces β-adrenergic responsiveness after complete elimination from plasma in vivo. Circulation 109: 3182-3190.
Martindale (2002). The Complete Drug Reference. Hardcover, Pharmaceutical Press 33rd Edition, Editor Sean C. Sweetman.
Molenaar P, Christ T, Ravens U, Kaumann AJ (2006). Carvedilol blocks β2- more than β1-adrenoceptors in human heart. Cardiovasc Res69:128-139.
Stahl E, Mutschler E, Baumgartner U, Spahn-Langguth H (1993). Carvedilol stereopharmacokinetics in rats: affinities to blood constituents and tissues. Arch Pharm 326: 529-533.
Tenero D, Boike S, Boyle D, Ilson B, Fesniak HF, Brozena S,Jorkasky D (2000). Steady-state pharmacokinetics of carvedilol and its enantiomers in patients with congestive heart failure. J Clin Pharmacol 40: 844-853.