Risk assessment of adverse pulmonary effects induced by adrenaline beta-receptor antagonists and rational drug dosage regimen based on receptor occupancy.

To clarify the beta-1 selectivity of beta-adrenergic receptor blocking agents (beta-blocking agents) after typical oral doses, the relationships between the effects on exercise heart rate or FEV1 and beta-1 or beta-2 receptor occupancies (phi 1, phi 2) of seven beta-blocking agents, acebutolol, atenolol, metoprolol, oxprenolol, timolol, propranolol, and pindolol were analyzed retrospectively. Nonlinear relationships between the pharmacologic effect and phi 1 and between the pulmonary adverse effect and phi 2 were obtained. Based on these findings, a new index of cardiovascular selectivity is proposed, given by the ratio of beta-1 receptor occupancy to beta-2 receptor occupancy (phi 1/phi 2). Using this new index, there was a little difference in beta-1 selectivity between acebutolol and pindolol (3.1:1.0), in contrast to a marked difference in beta-1 selectivity (320:1) as a conventional index between these two drugs. This finding indicates that even beta-1 selective drugs must be administered carefully to patients with pulmonary disease. Furthermore, the relationship between the pharmacologic or pulmonary effects and phi 1 or phi 2 has been analyzed quantitatively with a ternary complex model and used to develop rational dosage regimens for beta-1 selective beta-blocking agents, such as atenolol, to obtain the desired pharmacologic effects with minimum adverse pulmonary effects.