Cardiotoxic Antiemetics Metoclopramide and Domperidone Block Cardiac Voltage-Gated Na+ Channels

Stoetzer, Carsten; Voelker, Marc; Doll, Thorben; Heineke, Joerg; Wegner, Florian; Leffler, Andreas

doi:10.1213/ane.0000000000001673

Cited by 13 publications

(8 citation statements)

References 33 publications

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“…On the other hand, after the one-week therapy, there were clinically related changes in the ECG of two patients of the metoclopramide group, particularly prolongation of QT intervals. In similarity to the findings of the current study, other studies and case reports have reported cardiotoxic effects caused by metoclopramide especially with higher doses and with long-term use [44,45].…”

Section: Safetysupporting

confidence: 92%

The efficacy and safety of itopride in feeding intolerance of critically ill patients receiving enteral nutrition: a randomized, double-blind study

et al. 2021

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Background Enteral feeding intolerance (EFI) is a frequent problem in the Intensive care unit (ICU) and is associated with poor clinical outcomes leading to worse prognosis in terms of mortality and ICU stay. Nowadays, prokinetic drugs are the mainstay of therapy in EFI. However, available prokinetics have uncertain efficacy and safety profiles. Itopride, is a prokinetic agent which is different and unique from the available prokinetics because of its dual mode of action as well as its tolerability and safety. The current study compared the efficacy and safety of Itopride against metoclopramide for EFI in critically ill patients. Moreover, it tested the utility and applicability of ultrasonography to measure gastric residual volume (GRV) in this population. Methods This randomized, double-blind study included 76 EFI patients who were randomly assigned to either Itopride or metoclopramide group. The primary outcome was to measure GRV by ultrasonography. Secondary outcomes included the percentage ratio of enteral feed volume, energy and protein received by patients over 7 days of treatment, ICU length of stay, safety parameters and occurrence of infectious complications or vomiting. Results Thirty-five patients of each group completed the study. At day 7, itopride significantly decreased GRV compared with metoclopramide group (p = 0.001). Moreover, there was a significant increase in the ratios of received enteral nutrition feed volume, calories, and protein after the one-week therapy in the itopride group more than the metoclopramide group (p = 0.001), (p = 0.002), (p = 0.01), respectively and there were no differences in any secondary outcomes or adverse events between the two groups. Conclusion In critically ill patients with EFI, itopride was well tolerated with superior efficacy to metoclopramide. In addition, we demonstrated that ultrasonography is a simple, non-invasive, inexpensive, and undemanding method for GRV measurements and can offer reliable assessments in the gastric emptying modality. Trial registration The trial was registered in ClinicalTrials.gov (NCT03698292). Date: October 5, 2018

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Section: Safetysupporting

confidence: 92%

The efficacy and safety of itopride in feeding intolerance of critically ill patients receiving enteral nutrition: a randomized, double-blind study

et al. 2021

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“…A meta-analysis by Trelle et al 13 showed that most NSAIDs administered chronically increased morbidity and mortality in patients with cardiovascular disease. Clinically relevant cardiotoxicity is associated with the anti-emetics domperidone and metoclopramide due to their rather potent and local anaesthetic-like inhibition of cardiac sodium channels, leading to cardiovascular side effects such as malignant arrhythmias 14 . Inhibition of the hERG (human Ether-a-go-go Related Gene) channel by clozapine also results in clinically overt cardiotoxicity 15 , 16 …”

Section: Drug-induced Arrhythmiasmentioning

confidence: 99%

Definition of hidden drug cardiotoxicity: paradigm change in cardiac safety testing and its clinical implications

Ferdinándy

Baczkó

Bencsik³

et al. 2018

European Heart Journal

100

101

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Unexpected cardiac adverse effects are the leading causes of discontinuation of clinical trials and withdrawal of drugs from the market. Since the original observations in the mid-90s, it has been well established that cardiovascular risk factors and comorbidities (such as ageing, hyperlipidaemia, and diabetes) and their medications (e.g. nitrate tolerance, adenosine triphosphate-dependent potassium inhibitor antidiabetic drugs, statins, etc.) may interfere with cardiac ischaemic tolerance and endogenous cardioprotective signalling pathways. Indeed drugs may exert unwanted effects on the diseased and treated heart that is hidden in the healthy myocardium. Hidden cardiotoxic effects may be due to (i) drug-induced enhancement of deleterious signalling due to ischaemia/reperfusion injury and/or the presence of risk factors and/or (ii) inhibition of cardioprotective survival signalling pathways, both of which may lead to ischaemia-related cell death and/or pro-arrhythmic effects. This led to a novel concept of 'hidden cardiotoxicity', defined as cardiotoxity of a drug that manifests only in the diseased heart with e.g. ischaemia/reperfusion injury and/or in the presence of its major comorbidities. Little is known on the mechanism of hidden cardiotoxocity, moreover, hidden cardiotoxicity cannot be revealed by the routinely used non-clinical cardiac safety testing methods on healthy animals or tissues. Therefore, here, we emphasize the need for development of novel cardiac safety testing platform involving combined experimental models of cardiac diseases (especially myocardial ischaemia/reperfusion and ischaemic conditioning) in the presence and absence of major cardiovascular comorbidities and/or cotreatments.

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“…The cardiotoxic effects of metoclopramide and domperidone were investigated in neonatal rat cardiomyocytes. Cardiotoxicity was deemed to be due to potent local anesthetic-like inhibition of cardiac Na channels 94 and inhibition of hERG channel activity, which inhibits the rapid component of the cardiac delayed rectifier K (+) current. 88 , 95 Recently, a meta-analysis of observational studies reported a 70% increase in the risk of cardiac arrhythmia and sudden cardiac death with domperidone use.…”

Section: Drug–drug Interactionsmentioning

confidence: 99%

Diabetic gastroparesis: current challenges and future prospects

Avalos¹,

Sarosiek²,

Loganathan³

et al. 2018

CEG

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Diabetic gastroparesis (DMGP) is a condition of delayed gastric emptying after gastric outlet obstruction has been excluded. Symptoms of nausea, vomiting, early satiety, bloating, and abdominal pain are associated with DMGP. Uncontrolled symptoms can lead to overall poor quality of life and financial burdens on the healthcare system. A combination of antiemetics and prokinetics is used in symptom control; metoclopramide is the main prokinetic available for clinical use and is the only U.S. Food and Drug Administration-approved agent in the United States. However, a black box warning in 2009 reporting its association with tardive dyskinesia and recommending caution in chronically using this agent beyond 3 months has decreased its role in clinical practice. There is an unmet need for new prokinetics with good efficacy and safety profiles. Currently, there are several new drugs with different mechanisms of action in the pipeline that are under investigation and show promising preliminary results. Surgically combining gastric electrical stimulation with pyloroplasty is considered “gold” standard. Advances in therapeutic endoscopic intervention with gastric per-oral endoscopic pyloromyotomy have also been shown to improve gastric emptying and gastroparesis (GP) symptoms. In this review, we will comment on the challenges encountered when managing patients with DMGP and provide an update on advances in drug development and endoscopic and surgical interventions.

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Cardiotoxic Antiemetics Metoclopramide and Domperidone Block Cardiac Voltage-Gated Na+ Channels

Cited by 13 publications

References 33 publications

The efficacy and safety of itopride in feeding intolerance of critically ill patients receiving enteral nutrition: a randomized, double-blind study

The efficacy and safety of itopride in feeding intolerance of critically ill patients receiving enteral nutrition: a randomized, double-blind study

Definition of hidden drug cardiotoxicity: paradigm change in cardiac safety testing and its clinical implications

Diabetic gastroparesis: current challenges and future prospects

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