Sala Michela, Coppa Fabio, Cappucciati Corrado, Brambilla Paolo, d'Allio Giorgio, Caverzasi Edgardo, Barale Francesco, De Ferrari Gaetano M
Department of Physiology and Pharmacological Sciences, University of Pavia, School of Medicine, Italy.
Curr Opin Investig Drugs. 2006 Mar;7(3):256-63.
The cardiovascular side effects of older antidepressants, such as tricyclic antidepressants, are well established and are known to be linked to their capacity to inhibit cardiac and vascular ion channels. Newer compounds, such as selective serotonin reuptake inhibitors, mirtazapine and venlafaxine, have been reported to have a more benign cardiovascular profile, although they also share antagonistic properties with regard to voltage-dependent ion channels in different tissues. The electrophysiological effects that antidepressants exert on ion channels may affect the cardiac action potential (AP), lengthening both depolarization and repolarization phases, widening the QRS complex, prolonging the QT interval or causing Brugada-like electrocardiogram patterns. Lengthening of the depolarization phase can slow conduction through the His-Purkinje system and myocardium, while slowing repolarization can lead to early after depolarizations and Torsade de Pointes (TdP). In this review, we discuss data from experimental animal models regarding the effects of antidepressants on the cardiac AP, as well as antidepressant-induced QT prolongation in humans and sudden death in patients treated with antidepressants. It appears that although various experimental studies may lead to an understanding of the mechanisms involved in the modulation of cardiac electrical activity, there are significant discrepancies between in vitro data describing the action of antidepressants on the AP, data from clinical trials on QT prolongation by antidepressants and risk of TdP. The role of genetic polymorphisms of potassium-channel-encoding genes in determining the individual risk of cardiac arrhythmias and the limits of QT use as a marker of risk are discussed. Extensive pharmacokinetic and pharmacodynamic studies are required to determine the doses and plasma ranges of each drug that are associated with the greatest risk of arrhythmic complications.
较老的抗抑郁药，如三环类抗抑郁药的心血管副作用已得到充分证实，并且已知与其抑制心脏和血管离子通道的能力有关。据报道，较新的化合物，如选择性5-羟色胺再摄取抑制剂、米氮平和文拉法辛，具有更良性的心血管特征，尽管它们在不同组织中对电压依赖性离子通道也具有拮抗特性。抗抑郁药对离子通道产生的电生理效应可能会影响心脏动作电位（AP），延长去极化和复极化阶段，增宽QRS波群，延长QT间期或导致类Brugada心电图模式。去极化阶段的延长会减慢通过希氏-浦肯野系统和心肌的传导，而复极化减慢会导致早期后去极化和尖端扭转型室速（TdP）。在本综述中，我们讨论了来自实验动物模型的关于抗抑郁药对心脏AP影响的数据，以及抗抑郁药在人类中引起的QT间期延长和接受抗抑郁药治疗患者的猝死情况。似乎尽管各种实验研究可能有助于理解参与调节心脏电活动的机制，但在描述抗抑郁药对AP作用的体外数据、关于抗抑郁药导致QT间期延长的临床试验数据以及TdP风险之间存在显著差异。还讨论了钾通道编码基因的遗传多态性在确定个体心律失常风险中的作用以及QT作为风险标志物的局限性。需要进行广泛的药代动力学和药效学研究，以确定每种药物与心律失常并发症最大风险相关的剂量和血浆浓度范围。
