Sertindole: cardiac electrophysiological profile

QT interval prolongation is the ECG correlate of prolongation of the cardiac action potential (AP). Abnormal or excessive QT interval prolongation may be associated with an increased risk of ventricular tachycardia. This association appears increasingly evident in congenital long QT syndrome and with certain classes of cardiovascular and non-cardiovascular therapeutics. Almost all drugs causing QT interval prolongation inhibit the rapid component of the delayed rectifier potassium current (I Kr ), an ion channel involved in the termination of the myocardial AP. Inhibition of I Kr leads to AP and QT interval prolongation. Drugs, which do not encounter a sufficient electrophysiological counterbalance to the inhibitory effect on I Kr , may thus impose a risk of ventricular tachyarrhythmia. Some non-cardiac drugs, including the antipsychotic sertindole, have inhibitory effects on I Kr but, in contrast to the drugs that are known to cause tachyarrhythmia, sertindole possesses an important electrophysiological counterbalancing profile. Sertindole inhibits f 1 -adrenoceptors and blocks both sodium and calcium channels. The balanced electrophysiological profile of sertindole may well explain the low proarrhythmic potential observed in animal proarrhythmia models against positive comparators. It also supports the lack of increased cardiac mortality observed in clinical trials with sertindole and in large epidemiological studies.