title: In vitro receptor occupancy allows to establish equieffective doses of beta-blockers with different pharmacodynamic profiles in man. Investigations with propranolol and bufuralol.
abstract: The aim of the present study was to establish equieffective doses of propranolol (PROP) and bufuralol (BUF) in man. Both drugs compete for radioligand binding of 3H-CGP 12177 at beta-adrenoceptors of rat reticulocytes with Ki-values of 6.7 (PROP) and 19.6 (BUF) ng/plasma in the mean. In contrast to PROP, which is a pure antagonist, BUF shows partial agonism with an intrinsic activity around 5% (relative to isoprenaline) in vitro. After i.v. injection of cumulative doses of both drugs to 10 healthy volunteers, drug present in plasma occupies beta-adrenoceptors in vitro in a dose-dependent manner up to 80%. In man the full beta-adrenoceptor agonist isoprenaline (8 micrograms/min for 3 min) induces an increase in heart rate by 73%, an increase in stroke volume by 47%, a decrease in total peripheral resistance by 63% and a shortening of the preejection period by 70%. PROP exerts effects in man in the opposite direction of isoprenaline (at resting state), whereas BUF does not influence heart rate and stroke volume to a significant extent. Only the preejection period and total peripheral resistance are influenced in analogy to the isoprenaline effects. A direct comparison of the effects of PROP and BUF at 50% in vitro receptor occupancy by the respective plasma samples shows the clear-cut qualitative differences between the pharmacodynamics of both drugs in man as expected from the comparison of the full agonist isoprenaline and the antagonist propranolol. It is concluded that only on the basis of the respective receptor occupancy one may delineate pharmacodynamic differences of different drugs of the same class in man.
mesh_terms: D000328:Adult; D001667:Binding, Competitive; D004983:Ethanolamines / Q000008:administration & dosage* / Q000097:blood; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D011433:Propranolol / Q000008:administration & dosage* / Q000097:blood; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D012156:Reticulocytes / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D004983:Ethanolamines; D011943:Receptors, Adrenergic, beta; C010831:bufuralol; D011433:Propranolol