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Pimozide (Orap®) Prolongs Cardiac Repolarization by Blocking the Rapid Component of the Delayed Rectifier Potassium Current in Native Cardiac MyocytesInstitut de cardiologie de Quebec, Hôpital Laval et Facultés de, Universiti Laval, Sainte-Foy, Quebec, Canada; Institut de cardiologie de Quebec, Pharmnacie et de, Universiti Laval, Sainte-Foy, Quebec, Canada; Centre de Recherche, Hôpital du Sacré-Cawur de Montréal, Departement de Pharmacologie, Faculte de, Montréal, Quebec, Canada
Centre de Recherche, Hôpital du Sacré-Cawur de Montréal, Departement de Pharmacologie, Faculte de, Montréal, Quebec, Canada; Centre de Recherche, Medecine et Faculte de, Montréal, Quebec, Canada
Centre de Recherche, Hôpital du Sacré-Cawur de Montréal, Departement de Pharmacologie, Faculte de, Montréal, Quebec, Canada;; Institut de cardiologie de Quebec, Médecine, Universiti Laval, Sainte-Foy, Quebec, Canada
Centre de Recherche, Hôpital du Sacré-Cawur de Montréal, Departement de Pharmacologie, Faculte de, Montréal, Quebec, Canada; Centre de Recherche, Medecine et Faculte de, Montréal, Quebec, Canada
Centre de Recherche, Pharmacie, Université de Montréal, Montréal, Quebec, Canada
Institut de cardiologie de Quebec, Hôpital Laval et Facultés de, Universiti Laval, Sainte-Foy, Quebec, Canada; Centre de Recherche, Hôpital du Sacré-Cawur de Montréal, Departement de Pharmacologie, Faculte de, Montréal, Quebec, Canada; Centre de Recherche, Pharmacie, Université de Montréal, Montréal, Quebec, Canada Background: Several cases of QT prolongation and ventricular tachyarrhythmia have been reported with pimozide, a potent neuroleptic useful in the management of motor and phonic tics associated with Tourette syndrome. To further elucidate the mechanism underlying these clinical observations, the effects of pimozide on monophasic action potential duration (MAPD9O) and on potassium currents involved in the repolarization of native isolated ventricular myocytes were examined. Methods and Results: Studies were undertaken in eight isolated guinea pig hearts that demonstrated reverse rate-dependent prolongation of cardiac repolarization by pimozide 100 nmol/L. Action potential duration increased 24% from baseline 115 ± 2 to 142 ± 4 msec with pimozide 100 nmol/L during pacing at 250 msec cycle length, while a 10% increase from 97 ± 2 to 107 ± 3 msec was seen with pacing at a cycle length of 150 msec. Experiments in native isolated ventricular myocytes (n = 20) demonstrated concentration-dependent block of the rapid component (I,) of the delayed rectifier potassium current: tail current was decreased by 50% at 15 nmol/L. Conclusions: Pimozide possesses cardiac electrophysiological effects similar to those of class III antiarrhythmic drugs. These effects are concentration-dependent and observed at recommended dosages of the drug. Since pimozide is strongly metabolized by CYP3A4, special care should be taken to avoid potential pharmacokinetic interactions leading to high plasma levels of pimozide and proarrhythmia.
Key Words: pimozide • potassium currents • repolarization • cardiac arrhythmia
Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 6, No. 3,
255-260 (2001) This article has been cited by other articles:
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