Drici M D, Clément N
Department of Pharmacology, Pasteur University Hospital and University of Nice-Sophia Antipolis, Nice, France.
Drug Saf. 2001;24(8):575-85. doi: 10.2165/00002018-200124080-00002.
Drug-induced torsade de pointes is a rare life-threatening adverse drug reaction (ADR) which is strongly influenced by gender. Drugs that prolong cardiac repolarisation include antiarrhythmics, gastrokinetics, antipsychotics, antihistamines and antibacterials. Such drugs share the potential to block cardiac voltage-gated potassium channels, particularly the rapid component (I(Kr)) of the delayed rectifier potassium current (I(K)). By doing so, such drugs usually, but not always, prolong the QT interval. Even if the electrocardiographic signs are subdued, the underlying blockade of I(Kr) current may precipitate the occurrence of arrhythmia. Women are perceived to be more prone to ADRs than men. Such a propensity may result from gender-associated differences in drug exposure, in the number of drugs prescribed (polypharmacy), in drug pharmacology, as well as from possible differences in the way the adverse event is perceived. A prolonged QT interval on the electrocardiogram (time that elapses from the onset of the cardiac ventricular depolarisation to the completion of its repolarisation) is associated with the occurrence of torsade de pointes and related ventricular arrhythmias. The QT interval is influenced by heart rate, autonomic nervous system, electrolyte disturbances and above all, drugs that block potassium channels. Two-thirds of the cases of drug-induced torsade de pointes occur in women. Therefore, this adverse effect represents a perfect example of gender differences impairing women's health. Clinical and experimental studies show that female gender is associated with a longer corrected QT interval at baseline and a greater response to drugs that block I(Kr), both of which facilitate the emergence of arrhythmia. This results most likely from a specific regulation of ionic channel expression (potassium, calcium, etc) by sex steroids, even though nongenomic effects may play a role as well. Estrogens facilitate bradycardia-induced prolongation of the QT interval and the emergence of arrhythmia whereas androgens shorten the QT interval and blunt the QT response to drugs. Hence, underlying genetic defects of potassium channels that may be asymptomatic in normal conditions, may precipitate drug-induced arrhythmia in women more frequently than in men. Even in the presence of a drug that mildly blocks I(Kr) and seldom prolongs the QT interval, women are still more prone to drug-induced torsade de pointes, due to their reduced cardiac 'repolarisation reserve'. This is an important aspect of I(Kr) blockade to be aware of during the development of new drugs.
药物性尖端扭转型室速是一种罕见的、危及生命的药物不良反应（ADR），其受性别影响很大。延长心脏复极的药物包括抗心律失常药、胃肠动力药、抗精神病药、抗组胺药和抗菌药。这类药物都有可能阻断心脏电压门控钾通道，尤其是延迟整流钾电流（I(K)）的快速成分（I(Kr)）。通过这种方式，这类药物通常（但并非总是）会延长QT间期。即使心电图表现不明显，I(Kr)电流的潜在阻断也可能促使心律失常的发生。人们认为女性比男性更容易发生药物不良反应。这种倾向可能源于药物暴露、所开药物数量（多药联用）、药物药理学方面与性别相关的差异，以及对不良事件认知方式可能存在的差异。心电图上QT间期延长（从心室去极化开始到复极化完成所经过的时间）与尖端扭转型室速及相关室性心律失常的发生有关。QT间期受心率、自主神经系统、电解质紊乱影响，最重要的是受阻断钾通道的药物影响。三分之二的药物性尖端扭转型室速病例发生在女性身上。因此，这种不良反应是性别差异损害女性健康的一个典型例子。临床和实验研究表明，女性在基线时校正QT间期较长，对阻断I(Kr)的药物反应更大，这两者都有助于心律失常的发生。这很可能是由于性类固醇对离子通道表达（钾、钙等）的特定调节作用，尽管非基因组效应可能也起作用。雌激素会促进心动过缓引起的QT间期延长和心律失常的出现，而雄激素会缩短QT间期并减弱对药物的QT反应。因此，在正常情况下可能无症状的钾通道潜在遗传缺陷，在女性中比在男性中更频繁地引发药物性心律失常。即使存在轻度阻断I(Kr)且很少延长QT间期的药物，女性由于心脏“复极储备”降低，仍然更容易发生药物性尖端扭转型室速。这是新药研发过程中需要注意的I(Kr)阻断的一个重要方面。
