Olanzapine prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current

Abstract

Prolongation of the QT interval has been observed during treatment with olanzapine, a thienobenzodiazepine antipsychotic agent. Our objectives were 1) to characterize the effects of olanzapine on cardiac repolarization and 2) to evaluate effects of olanzapine on the major time-dependent outward potassium current involved in cardiac repolarization, namely IKr (IKr: rapid component of the delayed rectifier potassium current).

Isolated, buffer-perfused guinea pig hearts (n = 40) were stimulated at different pacing cycle lengths (150—250 msec) and exposed to olanzapine at concentrations ranging from 1 to 100 µM. Olanzapine increased monophasic action potential duration measured at 90% repolarization (MAPD90) in a concentration-dependent manner by 6.7 ± 0.7 msec at 3 µM but by 26.0 ± 4.3 msec at 100 µM (250 msec cycle length). Increase in MAPD₉₀ was also reverse frequency dependent; 30 µM olanzapine increased MAPD90 by 28.0 ± 6.2 msec at a pacing cycle length of 250 msec but by only 18.9 ± 2.2 msec at a pacing cycle length of 150 msec. Experiments in HERG-transfected (HERG: human ether-a-gogo-related gene) HEK293 cells (n = 36) demonstrated concentration-dependent block of the rapid component (IKr) of the delayed rectifier potassium current: tail current was decreased 50% at olanzapine 3.8 µM.

Olanzapine possesses direct cardiac electrophysiological effects similar to those of class III anti-arrhythmic drugs. These effects were observed at concentrations that can be measured in patients under conditions of impaired drug elimination such as renal or hepatic insufficiency, during co-administration of other CYP1A2 substrates/inhibitors or after drug overdose. These results offer a new potential explanation for QT prolonging effects observed during olanzapine treatment in patients.

Keywords

antipsychotics drug-induced long QT syndrome potassium channel torsades de pointes arrhythmia

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References

Bran S. , Murray W.A. , Hirsch I.B. , Palmer J.P. (1995) Long QT syndrome during high-dose cisapride . Arch Intern Med 155: 765—768

Broadhurst P. , Nathan A.W. (1993) Cardiac arrest in a young woman with the long QT syndrome and concomitant astemizole ingestion . Br Heart J 70: 469—470

Callaghan J.T. , Bergstrom R.F. , Ptak L.R. , Beasley C.M. (1999) Olanzapine. Pharmacokinetic and pharmacodynamic profile . Clin Pharmacokinet 37: 177—193

Chakrabarti J K. , Hotten T.M. , Tupper D.E. (1993) 2-Methyl-thieno-benzodiazepine. United States Patent 5,229,382, Issued July 20, 1993. United States. pp. 229, 285

Cohen L.G. , Fatalo A. , Thompson B.T. , Di Centes Bergeron G. , Flood J.G. , Poupolo P.R. (1999) Olanzapine overdose with serum concentrations . Ann Emerg Med 34: 275—278

Dineen S. , Withrow K. , Voronovitch L. , Munshi F. , Nawbary M.W. , Lippmann S. (2003) QTc prolongation and high-dose olanzapine . Psychosomatics 44: 174—175

Dobrusin M. , Lokshin P. , Belmaker R.H. (1999) Acute olanzapine overdose . Hum Psychopharmacol 14: 355—356

Drici M.D. , Wang W.X. , Liu X.K. , Woosley R.L. , Flockhart D.A. (1998) Prolongation of QT interval in isolated feline hearts by antipsychotic drugs . J Clin Psychopharmacol 18: 477—481

Drolet B. , Khalifa M. , Daleau P. , Hamelin B.A. , Turgeon J. (1998) Block of the rapid component of the delayed rectifier potassium current by the prokinetic agent cisapride underlies drug-related lengthening of the QT interval . Circulation 97: 204—210

10.

Drolet B. , Yang T. , Daleau P. , Roden D.M. , Turgeon J. (2003) Risperidone prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current . J Cardiovasc Pharmacol 41: 934—937

11.

Drolet B. , Rousseau G. , Daleau P. , Cardinal R. , Simard C. , Turgeon J. (2001) Pimozide (Orap) prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current in native cardiac myocytes . J Cardiovasc Pharmacol Ther 6: 255—260

12.

Drolet B. , Zhang S. , Deschenes D. , Rail J. , Nadeau S. , Zhou Z. , January C.T. , Turgeon J. (1999) Droperidol lengthens cardiac repolarization due to block of the rapid component of the delayed rectifier potassium current . J Cardiovasc Electrophysiol 10: 1597—1604

13.

Gomez J.C. , Sacristan J.A. , Hernandez J. , Breier A. , Ruiz Carrasco P. , Anton Saiz C. , Fontova Carbonell E. (2000) The safety of olanzapine compared with other antipsychotic drugs: results of an observational prospective study in patients with schizophrenia (EFESO Study). Pharmacoepidemiologic Study of Olanzapine in Schizophrenia . J Clin Psychiatry 61: 335—343

14.

Gurovich I. , Vempaty A. , Lippmann S. (2003) QTc prolongation: chlorpromazine and high-dosage olanzapine . Can J Psychiatry 48: 348

15.

Hassaballa H.A. , Balk R.A. (2003) Torsade de pointes associated with the administration of intravenous haloperidol: a review of the literature and practical guidelines for use. Expert Opin Drug Saf 2: 543—547

16.

Koh K.K. , Rim M.S. , Yoon J. , Kim S.S. (1994) Torsade de pointes induced by terfenadine in a patient with long QT syndrome . J Electrocardiol 27: 343—346

17.

Kongsamut S. , Kang J. , Chen X.L. , Roehr J. , Rampe D. (2002) A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs . Eur J Pharmacol 450: 37—41

18.

Nattel S. , Ranger S. , Talajic M. , Lemery R. , Roy D. ( 1990) Erythromycin-induced long QT syndrome: concordance with quinidine and underlying cellular electrophysiologic mechanism . Am J Med 89: 235—238

19.

Nemeroff C.B. (1997) Dosing the antipsychotic medication olanzapine . J Clin Psychiatry 58 (suppl. 10): 45—49

20.

Pettignano R. , Chambliss C.R. , Darsey E. , Heard M. , Clark R. (1996) Cisapride-induced dysrhythmia in a pediatric patient receiving extra-corporeal life support . Crit Care Med 24: 1268—1271

21.

Redfern W.S. , Carlsson L. , Davis A.S. , Lynch W.G. , MacKenzie I. , Palethorpe S. , Siegl P.K. , Strang I. , Sullivan A.T. , Wallis R. , Camm A.J. , Hammond T.G. (2003) Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development . Cardiovasc Res 58: 32—45

22.

Ring B.J. , Catlow J. , Lindsay T.J. , Gillespie T. , Roskos L.K. , Cerimele B.J. , Swanson S.P. , Hamman M.A. , Wrighton S.A. (1996) Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine . J Pharmacol Exp Ther 276: 658—666

23.

Roden D.M. (2004) Drug-induced prolongation of the QT interval . N Engl J Med 350: 1013—1022

24.

Su K.P. , Lane H.Y. , Chuang C.L. , Chen K.P. , Shen W.W. (2004) Olanzapine-induced QTc prolongation in a patient with Wolff-Parkinson-White syndrome . Schizophr Res 66: 191—192

25.

Zimmermann M. , Duruz H. , Guinand O. , Broccard O. , Levy P. , Lacatis D. , Bloch A. (1992) Torsades de pointes after treatment with terfenadine and ketoconazole . Eur Heart J 13: 1002—1003