Altered beta-adrenergic sensitivity and protein binding to 1-propranolol in the elderly.
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 1-propranolol contributes significantly to the beta-blocking effects of the racemate. To avoid these confounding 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 by 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 less than 0.05). The unbound fraction was decreased in the older subjects (0.141 +/- 0.023 vs. 0.121 +/- 0.025, p less than 0.05) because of an increase in alpha 1-acid glycoprotein concentration (55 +/- 11 mg/dl vs. 72 +/- 19 mg/dl, p less than 0.05). Advancing age was associated with a decreased sensitivity to isoproterenol (rs = 0.76, p less than 0.05) and to unbound 1-propranolol (rs = 0.45, p less than 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.
Department of Clinical Pharmacy, University of Tennessee, Memphis 38163.
D M
DM
Tenero
M B
MB
Bottorff
B S
BS
Burlew
J B
JB
Williams
R L
RL
Lalonde
D000328:Adult; D000367:Age Factors; D000368:Aged; D001798:Blood Proteins / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009961:Orosomucoid / Q000032:analysis; D011433:Propranolol / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011943:Receptors, Adrenergic, beta / Q000032:analysis / Q000187:drug effects*; D013237:Stereoisomerism
D001798:Blood Proteins; D009961:Orosomucoid; D011943:Receptors, Adrenergic, beta; D011433:Propranolol; D007545:Isoproterenol