Calderone V, Cavero I
Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Sezione di Farmacologia, Università degli Studi, Pisa, Italy.
Minerva Med. 2002 Jun;93(3):181-97.
The electrocardiogram shows a sequence of cardiac electrical events generated by individual electrical currents generated mainly by sodium (Na+), potassium (K+) and calcium (Ca++) ions transiting via specialized transport pathways, such as ion channels, inserted in the membranes of excitable cardiac cells. Na+ and Ca++, entering the cells, are messengers of activating, inward, depolarizing currents (INa, ICa), generating the QRS wave of the electrocardiogram, whereas K+, leaving the cells, carries outward repolarizing currents (e.g. Ito, IKr, IKs and IK1), generating the T wave of the electrocardiogram, which drives the cell to a rest condition. Therefore, a significantly prolonged repolarization process results in a prolonged QT interval which can initiate ectopic cardiac beats that may evolve into a potentially lethal ventricular tachyarrhythmia, called torsades de pointes. This implies that the measurement of QT interval, appropriately corrected (QTc) for heart rate values by applying available algorithms, is a current tool of diagnostic investigation to reveal abnormalities of the cardiac repolarisation process. Numerous non cardiovascular drugs in general clinical use (psychotropics, prokinetics, antimalarials, antibiotics, antihistamines, etc.) can prolong QT interval, often by a mechanism not necessary for their therapeutic effects, which is a reduction of the potassium current IKr conveyed by the HERG channel. The torsadogenic potential of these drugs can be facilitated by factors (female gender, bradycardia, electrolyte imbalances, cardiac diseases, simultaneous use of multiple drugs prolonging QT interval, etc.) known to have the propensity to reduce the redundant cardiac repolarization reserve, characterizing the healthy myocardium. Presently, drug candidates are routinely subjected to preclinical and clinical examination for cardiac safety, a property required by health authorities for any new medicine before allowing marketing authorization. Finally, before prescribing a medicinal product prolonging QT interval, a physician should carefully evaluate not only the disease he wants to treat but also the availability of equally effective, alternative drugs. The golden rule, to which such a prescription has always to abide, requires that the beneficial effects expected from a therapy should for each treated patient outweigh any possible adverse consequence, particularly when the latter one could be of lethal nature.
心电图显示一系列心脏电活动，这些电活动由主要由钠（Na+）、钾（K+）和钙（Ca++）离子通过专门的转运途径（如插入可兴奋心脏细胞膜中的离子通道）产生的单个电流所引发。进入细胞的Na+和Ca++是激活内向去极化电流（INa、ICa）的信使，产生心电图的QRS波，而离开细胞的K+携带外向复极化电流（如Ito、IKr、IKs和IK1），产生心电图的T波，使细胞恢复到静息状态。因此，显著延长的复极化过程会导致QT间期延长，这可能引发异位心脏搏动，进而可能演变成潜在致命的室性快速心律失常，即尖端扭转型室速。这意味着通过应用可用算法对心率值进行适当校正（QTc）来测量QT间期，是目前用于揭示心脏复极化过程异常的诊断研究工具。一般临床使用的许多非心血管药物（精神药物、促动力药、抗疟药、抗生素、抗组胺药等）可延长QT间期，通常通过与其治疗效果无关的机制，即减少HERG通道传导的钾电流IKr。这些药物的致尖端扭转型室速潜力可因一些因素（女性、心动过缓、电解质失衡、心脏病、同时使用多种延长QT间期的药物等）而加剧，这些因素已知有降低健康心肌所具有的冗余心脏复极化储备的倾向。目前，候选药物在临床前和临床阶段都会常规接受心脏安全性检查，这是卫生当局在批准任何新药上市前要求具备的一项特性。最后，在开具延长QT间期的药品处方前，医生不仅应仔细评估其想要治疗的疾病，还应评估是否有同等有效的替代药物。此类处方始终必须遵循的黄金法则是，对于每位接受治疗的患者，治疗预期的有益效果应超过任何可能的不良后果，尤其是当后者可能具有致命性质时。
