ABSTRACT
BACKGROUND: Metoclopramide (MCP) is a dopamine D2 -receptor antagonist, mainly used to treat post-operative or chemotherapy-induced nausea. While it is very effective in the cure of gastric symptoms, MCP can cause severe neurologic side effects. Furthermore, there is growing evidence for severe arrhythmic side effects resulting from inhibitory effects on cardiac sodium and potassium channels. METHODS AND RESULTS: Thirteen hearts of New Zealand white rabbits were retrogradely perfused, and electrophysiology studies were performed to obtain action potential duration (APD90 ) and effective refractory period (ERP). After generating baseline data, the hearts were perfused with increasing concentrations of metoclopramide (MCP 10 µM, MCP 50 µM, MCP 100 µM) and the standardized protocol was repeated for each concentration. Perfusion with MCP resulted in a significant prolongation of APD90 and QT interval. In parallel, the incidence of ventricular tachycardias was significantly increased by high doses of MCP. CONCLUSION: This is the first experimental study that investigated the effect of increasing doses of metoclopramide on a sensitive whole-heart model of proarrhythmia. MCP led to a significant increase in action potential duration and QT interval; meanwhile, the number of ventricular tachycardias was significantly increased.
Subject(s)
Action Potentials/drug effects , Dopamine D2 Receptor Antagonists/adverse effects , Heart/drug effects , Metoclopramide/adverse effects , Metoclopramide/pharmacology , Animals , Cardiac Electrophysiology , Disease Models, Animal , Female , Postoperative Nausea and Vomiting/drug therapy , Rabbits , Refractory Period, Electrophysiological/drug effects , Tachycardia, VentricularABSTRACT
Several case reports suggest QT prolongation leading to ventricular arrhythmias with fatal outcome after intoxication with the µ-opioid receptor agonist and anti-diarrheal agent loperamide. The number of cases of loperamide misuse are growing due to its potential stimulating effects. Loperamide intoxications can be treated by naloxone. However, previous reports described a further QT prolongation associated with naloxone administration. Therefore, the aim of this study was to investigate the effects of loperamide and naloxone on the cardiac electrophysiology in a sensitive whole-heart model. Twenty-six hearts of New Zealand White rabbits were retrogradely perfused in a modified Langendorff apparatus. Monophasic action potentials were recorded by endo- and epicardially positioned catheters. Hearts were stimulated at different cycle lengths, thereby obtaining action potential duration at 90% of repolarization (APD90) and QT intervals. Programmed ventricular stimulation was used to assess ventricular vulnerability. Fourteen hearts were perfused with ascending concentrations of loperamide (0.2 µM, 0.35 µM, and 0.5 µM) after obtaining baseline data. Another 12 hearts were treated with naloxone (0.1 µM, 0.5 µM, 2 µM). Loperamide led to a significant increase in QT interval, APD90, and ventricular tachycardia (VT) episodes. In contrast, naloxone led to a decrease in QT interval and APD90. Accordingly, the number of VT episodes was unaltered. To the best of our knowledge, this is the first experimental study that investigated the effects of loperamide and naloxone in a whole-heart model. Loperamide led to a significant increase in action potential duration and QT interval. Simultaneously, the number of ventricular tachycardias was significantly increased. In contrast, naloxone led to a shortening of the action potential duration without altering arrhythmia susceptibility.
Subject(s)
Analgesics, Opioid/toxicity , Antidiarrheals/toxicity , Heart/drug effects , Loperamide/toxicity , Naloxone/toxicity , Narcotic Antagonists/toxicity , Tachycardia, Ventricular/chemically induced , Action Potentials/drug effects , Animals , Cardiac Pacing, Artificial , Cardiotoxicity , Female , Heart/physiopathology , Heart Rate/drug effects , Isolated Heart Preparation , Rabbits , Tachycardia, Ventricular/physiopathology , Time FactorsABSTRACT
Recent results from data mining analyses and reports of adverse drug events suggest a QT-prolonging drug-drug interaction resulting from the combination of distinct proton pump inhibitors and cephalosporins. Therefore, this study aimed at investigating the effect of the suspected QT-prolonging combinations of lansoprazole + ceftriaxone and esomeprazole + cefazolin, respectively. 26 hearts of New Zealand White rabbits were retrogradely perfused and paced at different cycle lengths. After generating baseline data, the hearts were assigned to two groups: In group 1, hearts were treated with 5 µM lansoprazole. Thereafter, 200 µM ceftriaxone was infused additionally. Group 2 was perfused with 10 µM esomeprazole followed by 250 µM cefazolin. In group 1, lansoprazole did not significantly alter QT intervals and APD90. Additional treatment with ceftriaxone significantly shortened QT interval, APD90 and slightly reduced dispersion of repolarization compared to sole lansoprazole infusion. In group 2, esomeprazole led to a significant shortening of the QT interval without altering APD90 or dispersion. Additional treatment with the antibiotic cefazolin further shortened QT interval, APD90 and reduced the dispersion of repolarization. Incidence of ventricular arrhythmias was not significantly altered in both groups. This is the first experimental whole-heart study that investigated the impact of a concomitant treatment with proton pump inhibitors and cephalosporins. In contrast to previous reports, the combination of both agents did not cause QT prolongation but instead shortened QT interval and action potential duration. As a consequence, no triggered activity occurred in the presence of a stable dispersion of repolarization.
