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

  • James A. Street

Student thesis: Doctoral ThesisDoctor of Philosophy

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.
Date of Award1979
Original languageEnglish

Keywords

  • properties
  • B-[Beta] adrenoceptor antagonists
  • partition coefficients
  • Drug distribution;
  • Noradrenaline uptake
  • pulmonary delivery

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