Studies on the Properties of Some B-[Beta] Adrenoceptor Antagonists

Abstract

A study has been made of some aspects of the physicochemical, pharmacological and pharmacokinetic properties of a number of clinically-used S-adrenoceptor antagonists. The drugs used were propranolol, oxprenolol, metoprolol, acebutolol, practolol and atenolol; the former two compounds being non-selective in their action on B-adrenoceptors, whilst the remaining four drugs were cardioselective agents. The apparent octanol/buffer partition coefficients of the 8-adrenoceptor antagonists were measured under physiological conditions with respect to temperature, pH, ionic strength and solute concentration. Observed lipophilicity followed the order propranolol > oxprenolol > metoprolol > acebutolol > practolol > atenolol. Apparent partition coefficients were found to be significantly lowered by temperature reduction. In drug distribution studies all six compounds were detected in rat brain 5 minutes after systemic administration, and CNS penetration at this time appeared to correspond to lipophilicity. Drug distribution within the brain was found to be uniform. The central uptake of atenolol, but not propranolol, appeared to be facilitated during chronic administration. These findings are discussed with reference to the hypothesis that the antihypertensive effects of ®-blockers may be centrally-mediated. Propranolol, oxprenolol and metoprolol were found to be effective inhibitors of noradrenaline Uptake, in synaptosomal (P2) fractions from rat brain, but were less potent than desipramine and cocaine. The uptake inhibition was characterised by a depression of both Km and Vmax, and the effect was thought to be related to the membrane stabilizing properties of these 8-blockers. In further experiments, propranolol was incorporated into (P2) fractions to a greater extent than noradrenaline, but this accumulation did not appear to be via the Uptake, mechanism. Pulmonary concentration of several 8-adrenoceptor antagonists was observed in vivo and in vitro. The lung uptake of propranolol and oxprenolol exceeded that of the cardioselective agents, and appeared to involve both carrier-mediated and diffusional transport. Uptake was found to be reversible, and was inhibited by other basic lipophilic amines. Pulmonary metabolism of 8-blockers was minimal.

Divisions: College of Health & Life Sciences
Additional Information: Copyright © JA Street, 1979. JA Street asserts their moral right to be identified as the author of this thesis. This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without appropriate permission or acknowledgement. If you have discovered material in Aston Publications Explorer which is unlawful e.g. breaches copyright, (either yours or that of a third party) or any other law, including but not limited to those relating to patent, trademark, confidentiality, data protection, obscenity, defamation, libel, then please read our Takedown Policy and contact the service immediately
Institution: Aston University
Uncontrolled Keywords: properties,B-[Beta] adrenoceptor antagonists,partition coefficients,Drug distribution;,Noradrenaline uptake,pulmonary delivery
Last Modified: 22 Aug 2024 14:40
Date Deposited: 01 Feb 2011 09:07
Completed Date: 1979
Authors: Street, James A.

Export / Share Citation


Statistics

Additional statistics for this record