title: Severe Proarrhythmic Potential of the Antiemetic Agents Ondansetron and Domperidone.
abstract: The potential of ondansetron and domperidone, both clinically established antiemetic agents, to increase the QT-interval has been described in several case reports. Therefore, the aim of the present study was to investigate whether these drugs may provoke polymorphic ventricular tachycardia in a sensitive experimental model of drug-induced proarrhythmia. In 10 female rabbits, ondansetron (1, 5 and 10 µM, n = 10) or domperidone (0.5, 1 and 2 µM, n = 8) was infused after obtaining baseline data. Eight endo- and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG reproduced the clinically observed QT-prolongation (ondansetron: 1 µM:+17 ms, 5 µM:+41 ms, 10 µM:+78 ms, p < 0.01; domperidone: 0.5 µM:+57 ms, 1 µM:+79 ms, 2 µM:+99 ms, p < 0.01). This was accompanied by a significant increase in action potential duration at 90% of repolarization. Administration of both agents also increased dispersion of repolarization (ondansetron: 1 µM:+12 ms, 5 µM:+17 ms; 10 µM:+18 ms, p < 0.05; domperidone: 0.5 µM:+19 ms, 1 µM:+27 ms; 2 µM:+23 ms p < 0.05). Lowering of potassium concentration in bradycardic AV-blocked hearts provoked early afterdepolarizations (EADs) in 9 of 10 ondansetron-treated hearts and induced polymorphic ventricular tachycardia (VT) resembling torsade de pointes in 7 of 10 ondansetron-treated hearts (86 episodes). Under the influence of domperidone, EAD and polymorphic VT occurred in 7 of 8 hearts (131 episodes). In the present study, both ondansetron and domperidone demonstrated a severe proarrhythmic potential. A significant prolongation of cardiac repolarization as well as a marked increase in spatial dispersion of repolarization represents the underlying electrophysiologic mechanisms. These results imply that application of ondansetron should be handled carefully. For regular administration, ECG monitoring should be mandatory.
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany. gerrit.frommeyer@ukmuenster.de.
authors.forename: Gerrit
authors.initials: G
authors.lastname: Frommeyer
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Fischer
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Ellermann
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Lange
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors.forename: Dirk G
authors.initials: DG
authors.lastname: Dechering
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Kochhäuser
authors.affiliation: Clinic of Exotic Pets, Reptiles, Exotic and Feral Birds, University of Hanover, Hanover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Fehr
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Eckardt
mesh_terms: D000818:Animals; D000932:Antiemetics / Q000633:toxicity*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology*; D004294:Domperidone / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D017294:Ondansetron / Q000633:toxicity*; D011817:Rabbits; D012720:Severity of Illness Index
chemical_list: D000932:Antiemetics; D017294:Ondansetron; D004294:Domperidone
keywords: Dispersion of repolarization; Domperidone; Ondansetron; Polymorphic ventricular tachycardia; QT-prolongation; Sudden cardiac death