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The effects of chronic dosing on the β1 and β2-adrenoceptor antagonism of betaxolol and atenolol

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Summary

Six normal subjects were given once daily treatment for 15 days with placebo (PL), betaxolol 10 mg (B10), 40 mg (B40); atenolol 100 mg (A100); and nadolol 40 mg (N40). Measurements of β1-adrenoceptorblockade (reduction of exercise heart rate) and of β2-adrenoceptor-blockade (attenuation of isoprenaline induced finger tremor) were made after the first, eighth and fifteenth doses of each drug.

Plasma concentrations showed dose related increases between 10 mg and 40 mg doses of betaxolol, and there was significant drug accumulation at steady state compared with after single dosing. The reduction in exercise heart rate (EHR) with B10 was less in comparison with all other treatments.

There were no significant differences in effects between single and chronic-dosing for any of the treatments (% reduction EHR compared with placebo, on days 1 and 15): B10 (18.2, 19.0), B40 (28.6, 26.5); A100 (22.7, 23.1); N40 (26.6, 23.8). Dose-ratios for attenuation of isoprenaline-induced finger tremor (IT100) were significantly greater with B40 compared with B10 or A100 (no dose-ratio for finger tremor could be calculated for N40).

There were no differences between single and chronic-dosing (IT100 dose-ratios on days 1 and 15): B10 (3.0, 2.5), B40 (4.4, 5.3); A100 (3.0, 3.0). The attenuation of isoprenaline-induced chronotropic response (IH25) by N40 was significantly greater in comparison with all other treatments. IH25 dose-ratios (on days 1 and 15) were as follows: B10 (2.8, 3.6), B40 (5.1, 5.8); A100 (3.6, 3.6); N40 (19.0, 17.4).

Thus, despite drug accumulation after chronic-dosing, there was no evidence of any increase in either β1 or β2-adrenoceptor antagonism at steady-state in comparison with after single-dosing. The apparent dissociation between plasma concentration and β-adrenoceptor antagonism after chronic-dosing my be a consequence of β-adrenoceptor up-regulation, resulting in partial attenuation of β-blockade.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee, Scotland, UK

    B. J. Lipworth, N. A. Irvine & D. G. McDevitt

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  1. B. J. Lipworth
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  2. N. A. Irvine
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  3. D. G. McDevitt
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Lipworth, B.J., Irvine, N.A. & McDevitt, D.G. The effects of chronic dosing on the β1 and β2-adrenoceptor antagonism of betaxolol and atenolol. Eur J Clin Pharmacol 40, 467–471 (1991). https://doi.org/10.1007/BF00315224

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