Proarrhythmic potential of metoclopramide in a sensitive whole‐heart model

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.

A fatal case of repeated ventricular fibrillation due to torsade de pointes following repeated administration of metoclopramide

“…QT prolongation caused by metoclopramide has been reported in some studies. 7 , 8 , 9 A recent study stated that supratherapeutic doses of metoclopramide might lead to QT and action potential prolongation by inhibiting the human ether‐a‐go‐go‐related gene and sodium channels, resulting in the development of ventricular arrhythmias. 8 Moreover, 80% of metoclopramide is excreted in the urine, and impaired renal function prolongs its half‐life.…”

“… 7 , 8 , 9 A recent study stated that supratherapeutic doses of metoclopramide might lead to QT and action potential prolongation by inhibiting the human ether‐a‐go‐go‐related gene and sodium channels, resulting in the development of ventricular arrhythmias. 8 Moreover, 80% of metoclopramide is excreted in the urine, and impaired renal function prolongs its half‐life. 1 Therefore, we hypothesized that QT prolongation due to metoclopramide occurred due to the administration of multiple doses in a patient with impaired renal dysfunction.…”

D2 dopamine receptor‐mediated mechanisms of dopaminergic system modulation in in vivo and in vitro experimental models of migraine

“…Afterwards, the preparations were fixed in a humid incubator at 37°C after being placed in caps filled with vaseline. Then, the preparations were treated with ACSF (control) or apomorphine (10 μM, Himeno et al, 2011), metoclopramide (10 μM, Wolfes et al, 2021), haloperidol (10 μM, Romeo et al, 2021) and ondansetron (10 μM, Hur et al, 2014) or their combinations, respectively; 250 μL of incubation medium was collected for each treatment at 10 min intervals and was mixed with 20 μL of aprotinin to prevent the degradation of CGRP. The aliquots were stored at −20°C until CGRP measurement.…”