Analysis of Clinical Efficacy and Adverse Effects of β-Blocking Agents Used Clinically for Chronic Heart Failure

• Published in: Biological and Pharmaceutical Bulletin 2017-06, Vol.40 (6), p.837-843
• Main Authors: Risa Takayanagi, Kaori Fujito, Koji Kimura, Yasuhiko Yamada
• Format: Article
• Language: Japanese
• ISSN: 0918-6158

Clinical efficacy and adverse effects of the β-blocking agents, carvedilol, bisoprolol, and metoprolol were analyzed theoretically, and then compared quantitatively, for the purpose of determining their proper use for chronic heart failure. Initially, we evaluated occupancy binding to the β1 and β2 receptors (Φssβ1 and Φssβ2) by these drugs. Thereafter, we examined the relationship between Φssβ1 values and left ventricular ejection fraction (LVEF) increase rate to determine efficacy. The result showed that the efficacy with carvedilol could be attained with a lower Φssβ1 value than the others. Therefore, we constructed a model under the assumption that β-blocking agents exert both indirect action of LVEF increase through the β1 receptor and direct action on ryanodine receptor 2. Using the model, it was suggested that these drugs have no differences in regard to the efficacy, while it was clarified theoretically that only carvedilol produces an effect that directly involves ryanodine receptor 2 at clinical doses. We also investigated decreases in heart rate and forced expiratory volume in 1s as adverse effects of β-blocking agents using a ternary complex model. It was indicated that carvedilol is less likely to induce a heart rate decrease. Meanwhile, it was also suggested that the risk of an asthmatic attack was higher for carvedilol at clinical doses. Our results are considered useful for selection of a proper β-blocking agent and its administration at a reasonable dose for successful heart failure therapy.