Altered β-Adrenergic Sensitivity and Protein Binding to 1-Propranolol in the Elderly

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Abstract
The elderly are reported to be less sensitive to the .beta.-blocking effects of propranolol. However, age-related changes in the stereoselective pharmacokinetics or protein binding of propranolol enantiomers could have confounded the results of previous studies because only l-propranolol contributes significantly to the .beta.-blocking effects of the racemate. To avoid these confound variables, we studied 10 young (mean 28 years) and 10 elderly (mean 64 years) subjects, and determined the cardiac .beta.-receptor sensitivity in terms of unbound, active 1-propranolol. The doses of isoproterenol required to increase heart rate (HR) by 25 beats/min were determined before and during a continuous infusion of propranolol. The serum concentration of 1-propranolol was determined enantioselective high-performance liquid chromatography (HPLC), and the unbound fraction was determined by equilibrium dialysis. The apparent in vivo receptor dissociation constant for unbound 1-propranolol increased from 0.066 .+-. 0.047 ng/ml in the young to 0.218 .+-. 0.264 ng/ml in the older group (p < 0.05). The unbound fraction was decreased in the older subjects (0.141 .+-. 0.023 vs. 0.121 .+-. 0.025, p < 0.05) because of an increase in .alpha.1-acid glycoprotein concentration (55 .+-. 11 mg/dl vs. 72 .+-. 19 mg/dl, p < 0.05). Advancing age was associated with a decreased sensitivity to isoproterenol (rs = 0.76, P < 0.05) and to unbound l-propranolol (rs = 0.45, p < 0.05). We conclude that the older subjects have (a) decreased sensitivity to the .beta.-blocking effects of 1-propranolol and to the agonist effects of isoproterenol, and (b) a lower unbound fraction of 1-propranolol.