Ziprasidone and hypokalemia: a case of 2 predisposing factors for QTc prolongation without development of torsades de pointes.

Sir: Although concerns about sudden cardiac arrhythmia death associated with the use of an antipsychotic drug actually predate the description of torsades de pointes, it is this fatal arrhythmia and its electrocardiographic (ECG) predictor (corrected QT [QTc] interval prolongation) that have become of increasing concern related to the use of antipsychotic medications during recent years. The first case reports of patients dying from a fatal arrhythmia while taking an antipsychotic medication appeared in 1963, and 3 years later torsades de pointes was described. Although it would be some years before these 2 phenomena were linked, with similar cases mounting, the reality of antipsychotic medication–induced torsades de pointes has since become an entity that those prescribing these medications must guard against. Torsades de pointes is a term that refers to polymorphic ventricular tachycardia that occurs in the setting of an abnormally long QT interval. The most common cause of this arrhythmia is treatment with a drug that prolongs the QT interval. The QT interval is an ECG measurement that encompasses both depolarization and repolarization of the ventricle. Depolarization of the ventricle is primarily due to rapid influx of sodium ions through sodium channels, and its duration is represented electrocardiographically by the QRS interval. Repolarization, the duration of which is represented by the ST segment, involves sodium, potassium, and calcium channels. Although altering either of these components can yield arrhythmias, some antipsychotic medications prolong the QT interval through their effects on repolarization. More specifically, it is through a potassium channel that drug-induced QT prolongation is achieved. This potassium channel is the potassium rectifier channel (I Kr). Therefore, drugs that block the I Kr channel can induce QT prolongation and subsequent sudden cardiac death from torsades de pointes in otherwise healthy patients. Given this effect, QT intervals should be followed when patients are treated with medications that can significantly prolong the QT interval. Since the QT interval shortens with increasing heart rate, it is usually corrected for heart rate, and this corrected interval is known as the QTc interval. An absolute QTc interval greater than 500 msec, or an increase of 60 msec from baseline, is a surrogate marker for the ability of a drug to cause torsades de pointes. Although for many years the antipsychotic drug of most concern in this realm was thioridazine, in 1996 a new atypical antipsychotic, sertindole, was not registered in the United States because it prolonged the QTc interval and was associated with 12 sudden unexplained deaths in Europe. These concerns arose again when ziprasidone showed a modest effect on QTc interval during clinical trials. During these studies, patients treated with ziprasidone showed a QTc interval increase of 20.3 msec from baseline. Although this prolongation was somewhat less than that produced by thioridazine (35.6 msec), enough concern developed surrounding ziprasidone that it initially became common practice among many physicians to check baseline and periodic ECGs when employing ziprasidone therapy. While this practice has waned with time, concerns remain in the psychiatric community about ziprasidone’s QTc effects. As previously mentioned, QT-prolonging drugs are the most common cause of torsades de pointes; however, other factors such as congenital long QT syndromes and electrolyte abnormalities can also prolong the QT interval and induce torsades de pointes. Hypokalemia is the most notable of QT-prolonging electrolyte abnormalities. Even modest hypokalemia with potassium levels in the range of 2.8 to 3.5 mmol/L has been shown to prolong the QTc interval to 660 msec. Although hypokalemia has been shown as an independent variable to be a significant inducer of QTc prolongation and torsades de pointes, it also has been noted to trigger torsades de pointes in patients with other QTc prolongation issues. For example, hypokalemia was noted to trigger torsades de pointes in some groups of individuals with congenital long QT syndrome. Further, experimental models have shown that the pharmacologic blockade of I Kr by antiarrhythmics such as quinidine and dofetilide is increased proportionally with decreasing potassium concentrations. Given the above, it would be of both clinical concern and interest if a patient who was taking full-dose ziprasidone were to present with hypokalemia.