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.