Extent of beta 1- and beta 2-receptor occupancy in plasma assesses the antagonist activity of metoprolol, pindolol, and propranolol in the elderly.
We estimated antagonist activity of metoprolol, pindolol, and propranolol in elderly cardiovascular patients by determining the extent to which the drugs occupied rabbit lung beta 1- and rat reticulocyte beta 2-adrenoceptors in plasma samples during drug treatment. The randomized, double-blind, crossover study was carried out by administering twice daily 100 mg metoprolol, 5 mg pindolol, and 80 mg propranolol for 7 days to 20 hypertensive subjects with a mean age of about 70 years. A 2-week interval was kept between administration of the different regimens. Receptor occupancy was measured at 1 hour before and 2 hours after administration of the last dose of each regimen by adding rabbit lung beta 1- and rat reticulocyte beta 2-receptors to plasma samples and by labeling the receptors with a radiolabeled beta-antagonist, (-)-[3H]CGP-12177. The results and conclusions were the following: (a) The extent to which metoprolol, pindolol, and propranolol occupied rabbit lung beta 1- and rat reticulocyte beta 2-adrenoceptors in plasma samples estimated accurately the intensity of beta-receptor antagonism in the patients who did not tolerate physiological and pharmacological tests measuring the degree of beta 1- and beta 2-adrenoceptor blockade. (b) The mean beta 1- and beta 2-receptor occupancy of pindolol and propranolol varied between 76% and 99% during the treatments. The mean beta 1-receptor occupancy of the metoprolol regimen varied between 54% and 92%, and its beta 2-receptor occupancy varied between 6% and 38%. Thus the antagonist activity of the metoprolol regimen differed significantly from that of the other regimens (ANOVA for repeated measures, p < 0.05 and 0.001, for the beta 1- and beta 2-occupancy, respectively). (c) The extent of beta 1- and beta 2-receptor occupancy in plasma samples was in conformity with the literature on the intensity, selectivity, and duration of beta-blockade after similar drug doses. (d) The data on the receptor occupancy of beta-blocking drugs in plasma samples appear to be valuable in analyzing their effects, and it may be a method for optimizing drug therapy for aged cardiovascular patients.
Kaila
T
T
Department of Clinical Pharmacology, University of Turku, Finland.
Iisalo
E
E
Lehtonen
A
A
Saarimaa
H
H
D000319:Adrenergic beta-Antagonists / Q000097:blood / Q000494:pharmacology*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000188:drug therapy; D007700:Kinetics; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008790:Metoprolol / Q000097:blood / Q000494:pharmacology; D008875:Middle Aged; D010869:Pindolol / Q000097:blood / Q000494:pharmacology; D011433:Propranolol / Q000097:blood / Q000494:pharmacology; D011817:Rabbits; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D012156:Reticulocytes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
D000319:Adrenergic beta-Antagonists; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D011433:Propranolol; D010869:Pindolol; D008790:Metoprolol