Drug-induced block of cardiac HERG potassium channels and development of torsade de pointes arrhythmias: the case of antipsychotics

Abstract

The prolongation of the cardiac repolarization process, a result of the blocking of the Human Ether-ago-go Related Gene potassium channel, is an undesired accessory property shared by many pharmacological classes of non-cardiovascular drugs. Often the delayed cardiac repolarization process can be identified by a prolongation of the QT interval of the electrocardiograph. In these conditions, premature action potentials can trigger a dangerous polymorphic ventricular tachyarrhythmia, known as torsade de pointes, which occasionally can result in lethal ventricular fibrillation. In this work, brief descriptions of the electrophysiological basis of torsade de pointes and of the several pharmacological classes of torsadogenic drugs are given. Attention is focused on antipsychotics, with a deeper overview on the experimental and clinical reports about their torsadogenic properties. The cardiac action potentialCardiac action potentials are generated by trans-membrane movements of ion species, flowing principally through specific channels. In a typical human cardiac action potential ( Figure 1A), five different phases can be recognized. Phase 0 is a rapid depolarization process resulting from a massive inward flow of Na þ (current I Na ). The following phase 1 is linked to the inactivation of the I Na current and to a weak and transient repolarization due to an outward flow of K þ (current I to ). Phase 2 reflects an almost iso-electric plateau generated by the simultaneous activation of a depolarizing inward Ca þþ current, a repolarizing outward rapidly activated K þ current (current I Kr ) and a repolarizing outward slowly activated K þ current (current I Ks ). Phase 3 reflects the complete membrane repolarization due to many K þ currents (mainly I Ks and I Kr ), which leads the cell to the recovery of resting membrane potential. Finally, phase 4 is the resting period, ensured by inward rectifier K þ currents (I K1 ), before a new following cardiac cycle. The QT intervalA typical electrocardiograph (ECG) tracing of a human cardiac cycle ( Figure 1B) starts with a P wave (80-110 ms) representing the atrial depolarization. The following iso-electric time (about 100 ms) reflects the propagation of the depolarization through the atrio-ventricular node to the ventricular conduction system. The QRS complex (<120 ms) represents the whole ventricular depolarization, followed by an isoelectric time (about 120 ms) starting from the J point. Finally, the T wave (230-300 ms) represents the final ventricular repolarization and the end of the cycle. Among the various ECG parameters that are useful in analysing the cardiac functions, the QT interval is the most usual one for estimating the ventricular repolarization process. Drug-induced torsade de pointesMany drugs belonging to different pharmacological classes (Table 1) can trigger lifethreatening polymorphic ventricular tachyarrhythmias, such as torsade de pointes. In particular, many non-cardiovascular drugs in common clinical use cause the prolongation

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“…Yet, cardiovascular events may occur more frequently when quetiapine is prescribed compared to the majority of other second‐generation antipsychotics 19‐21 . Molecular biological experiences and several case report evaluations strongly indicate a higher risk of QTprolongation when quetiapine is combined with other QT‐prolonging drugs, 22,23 for example methadone 24 …”

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