Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan.
Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan.
J Pharmacol Sci. 2024 Oct;156(2):134-141. doi: 10.1016/j.jphs.2024.07.011. Epub 2024 Jul 31.
Risperidone is a second-generation antipsychotic for treating schizophrenia and bipolar disorder. It can potently inhibit I, but is classified into conditional risk for torsade de pointes (TdP) by CredibleMeds®. Our previous studies using chronic atrioventricular block dogs showed that risperidone alone did not induce TdP, and that dl-sotalol (β-adrenoceptor blockade plus I inhibition) induced TdP three times more frequently than d-sotalol (I inhibition alone). Since risperidone can block α-adrenoceptor and decrease blood pressure, the resulting reflex-mediated increase of sympathetic tone on β-adrenoceptor might protect the heart from its I inhibition-associated TdP. To validate this hypothesis, risperidone was administered to chronic atrioventricular block dogs after β-adrenoceptor blocker atenolol infusion with monitoring J-T and T-T, which are proarrhythmic surrogate markers of "substrate" and "trigger" toward TdP, respectively. Atenolol alone induced TdP in 1 out of 5 dogs; moreover, an additional infusion of risperidone induced TdP in 3 out of 4 dogs. Risperidone prolonged QT interval, J-T and T-T in animals that induced TdP. These findings indicate that β-adrenoceptor blockade can diminish repolarization reserve to augment risperidone's torsadogenic potential, thus advising caution when using β-adrenoceptor blockers in patients with I inhibition-linked labile repolarization.
利培酮是一种用于治疗精神分裂症和双相情感障碍的第二代抗精神病药物。它可以强效抑制 I，但被 CredibleMeds® 归类为尖端扭转型室性心动过速（TdP）的条件风险药物。我们之前使用慢性房室传导阻滞犬的研究表明，利培酮单独使用不会引起 TdP，而 dl-索他洛尔（β-肾上腺素受体阻断加 I 抑制）引起 TdP 的频率比 d-索他洛尔（单独 I 抑制）高 3 倍。由于利培酮可以阻断 α-肾上腺素受体并降低血压，因此由此产生的反射性增加β-肾上腺素受体上的交感神经张力可能会保护心脏免受其 I 抑制相关 TdP 的影响。为了验证这一假设，在慢性房室传导阻滞犬中，在 β-肾上腺素受体阻滞剂阿替洛尔输注后给予利培酮，并监测 J-T 和 T-T，它们分别是 TdP 的“基质”和“触发”的心律失常替代标志物。阿替洛尔单独使用时，有 1 只犬发生 TdP；此外，额外输注利培酮可使 4 只犬中的 3 只发生 TdP。利培酮延长了 QT 间期、J-T 和 T-T 在诱发 TdP 的动物中。这些发现表明，β-肾上腺素受体阻断可以减少复极储备，从而增加利培酮的致扭转型，因此在具有 I 抑制相关不稳定复极的患者中使用β-肾上腺素受体阻滞剂时应谨慎。
