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

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Abstract

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

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Authors and Affiliations

  1. Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, 113, Tokyo, Japan

    Yasuhiko Yamada, Kyoko Matsuyama, Kiyomi Ito, Yasufumi Sawada & Tatsuji Iga

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  1. Yasuhiko Yamada
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  2. Kyoko Matsuyama
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  3. Kiyomi Ito
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  4. Yasufumi Sawada
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  5. Tatsuji Iga
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Yamada, Y., Matsuyama, K., Ito, K. et al. Risk assessment of adverse pulmonary effects induced by adrenaline β-receptor antagonists and rational drug dosage regimen based on receptor occupancy. Journal of Pharmacokinetics and Biopharmaceutics 23, 463–478 (1995). https://doi.org/10.1007/BF02353469

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