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Cardiovascular adverse effects of metoclopramide:Review of literatureMartha M Rumore

ABSTRACTIntroduction: Articles pertaining to reports andclinical or pharmacological research forcardiovascular adverse effects ofmetoclopramide were identified via a search ofMEDLINE (1966­February 2012), SCOPUS, andGoogle Scholar. Objective: To review thereports in literature of patients receivingmetoclopramide who sufferred from cardiacarrest, bradycardia, total heart block, acutehypotension, supraventricular tachycardia,circulatory collapse, QT prolongation, Torsadede Pointes, ST depression, and congestive heartfailure. Discussion: In most cases the reactionsoccurred immediately after administration ofmetoclopramide, were associated with normaldoses administered via intravenous or centrallines, and resolved. Rechallenge occurred inseveral cases. The likelihood of these eventsoccurring and the mechanism by whichmetoclopramide affects the cardiovascularsystem is unclear, however, it has been shown tohave a direct effect on the heart, blockpresynaptic autoreceptors and enhancecatecholamine release, enhance cholinergic

neurotransmission and cause 5­HT3 receptorblockade and 5­HT4 receptor antagonism.Conclusion: Due to cardiovascular risksassociated with the use of IV metoclopramide,recommendations are to monitor patients andreport these events.Keywords: Metoclopramide, Cardiovascular,Adverse drug reactions, Case reports, Cardiac

*********Rumore MM. Cardiovascular adverse effects ofmetoclopramide: Review of literature. InternationalJournal of Case Reports and Images 2012;3(5):1–10.

*********doi:10.5348/ijcri­2012­05­116­RA­1

INTRODUCTIONMetoclopramide (1,4­amino­5­chloro­2 methoxy­N­(2­diethyl­aminoethyl) benzamide), a dopaminergicantagonist structurally related to procainamide, is aneffective agent in treating and preventing vomiting andis useful in esophageal reflux disease, gastroparesis,dyspepsia and other gastrointestinal disorders. Itpromotes gastric emptying prior to anesthesia andreduces post­operative vomiting, possibly by blockingthe chemoreceptor trigger zone for vomiting [1].Although metoclopramide has been available fordecades, its side effect profile continues to evolve. In2009, the Food and Drug Administration (FDA)required a Black Box warning regarding the increasedrisk of tardive dyskinesia when metoclopramide is usedat high doses or over long periods of time. Today, over1,000 lawsuits claiming tardive dyskinesia frommetoclopramide are pending in New Jersey courts alone[2]. Reports of cardiovascular adverse effects frommetoclopramide first appeared in the literature in 1974,

REVIEW ARTICLE OPEN ACCESS

Martha M Rumore1

Affi l iations: 1Assistant Director, Pharmacy Clinical &Educational Services, Cohen Children’s Medical Center,North Shore-LIJ, New Hyde Park, N.Y. and AdjunctProfessor, Pharmacy & Health Outcomes, Touro Collegeof Pharmacy, New York, N.Y.Corresponding Author: Dr. Martha M Rumore, CohenChildren’s Medical Center, 420 Lakevil le Road, NewHyde Park, NY - 11 040. Attn: Pharmacy Dept. , Ph: (51 6)470-8643; Email : mrumore@nshs.edu

Received: 20 August 2011Accepted: 1 0 February 201 2Published: 31 May 201 2

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when Shaklai et al. noted cardiac arrhythmias,specifically multifocal preventricular contractions(PVCs) which resolved within one hour and reoccurredupon rechallenge [3]. Since then, a number of casereports have appeared in literature.

OBJECTIVEThe aim of this study is to review all available reportsand patient series of metoclopramide inducedcardiovascular (CV) adverse effects and providerecommendations for clinicians.

DISCUSSIONMetoclopramide is a benzamide derivative havingvarious physiologic effects with side effects occurring in10­20% of patients [4]. The most common side effectsinclude drowsiness, GI disturbances, extrapyramidalreactions and increased lactation [5]. Metoclopramidehas long been considered to lack significant CV effects.However, conflicting literature for CV effects ofmetoclopramide has appeared and will be discussed. Inlarge doses in patients with heart disease,metoclopramide had no marked influence onhemodynamic parameters [6]. In animal studies,metoclopramide had a negligible effect on bloodpressure (BP) responses to acetylcholine, adrenaline,histamine and noradrenaline [7]. The drug has beenfound to block the hypotensive action of dopamine.Cardiac conduction is unaffected by metoclopramide,but in animal studies large doses preventedexperimentally­induced cardiac arrhythmias andproduced a slight blood pressure decrease [1]. Carefulconsideration should be given to examine the risks andbenefits of using metoclopramide for preoperativeprophylaxis of nausea and vomiting.Study Method: To identify pertinent literature,including but not limited to case reports describing CVadverse reactions from use of metoclopramide, weconducted a search using MEDLINE (1966­ to February2012), SCOPUS and Google Scholar engine using thesearch terms: adverse effects, metoclopramide, cardiac,cardiovascular, cardiac arrest, sinus arrest, bradycardia,tachycardia, arrhythmia, QT prolongation, Torsade dePointes, hypotension and a combination of text andMeSH terms. Bibliographies of identified articles weresubsequently reviewed for additional citations.Review of Cases in the Literature: Cases ofsinus or cardiac arrest [8–15], bradycardia followed bytotal heart block [14, 16–18], acute hypotension[19–24], and circulatory collapse [24] have beenreported with metoclopramide. The duration of thecardiac arrest reported in the cases is mostly between15–30 sec, but on one occasion it lasted two min [11].Several cases describe extreme bradycardia [9, 10,12, 14, 16]. Others have reported cardiac arrhythmiassuch as QT prolongation [25–27], Torsade de Pointes[13, 26, 28, 29], supraventricular tachycardia (SVT) [28,

30–32] and ST depression [28, 30]. Cases of congestiveheart failure have occurred following chronicmetoclopramide at doses of 40 mg/day [31]. In patientswith heart failure, metoclopramide at doses of 10 mgthree times a day blunted the natriuretic response tosaline load [34]. The authors concluded thatmetoclopramide should be used with caution in heartfailure patients and those with volume overload. SingleIV doses of 10 mg decreased diastolic BP in women withpregnancy­induced hypertension and increased plasmaaldosterone in every subject [35]. However, the increasein plasma aldosterone was greater in women withpregnancy­induced hypertension than in normalpregnant women (p < 0.05). Congestive heart failure ismost likely due to a different mechanism of action asdopaminergic inhibition is thought to result in increasesin plasma aldosterone, thereby producing sodiumretention [30]. The summary of key cases retrieved ispresented in table 1.A number of cardiovascular adverse effects are listedin the metoclopramide prescribing information,including AV block, bradycardia, heart failure,hypertension/hypotension, SVT but not circulatorycollapse, cardiac arrest, Torsade de Pointes, QTprolongation, and ST depression [36].Rechallenge with metoclopramide occurred in anumber of cases. Lau et al. reported two separateepisodes of circulatory collapse following IVmetoclopramide [24]. Bentsen et al. reported fiverepeated episodes of cardiac arrest following fiveseparate metoclopramide injections over 48 hours [11].Unusual drug reactions may arise as a result of multiplefactors. Suggested underlying predisposing orcontributory factors for development of cardiac adverseeffects with metoclopamide include previouscardiovascular disease, atrial fibrillation [8],autonomous dysfunction [15], hyperbilirubinemia [11],halothane anesthesia [19, 21], and pericardial drainagetube [16]. However, in other cases there has been noclear association with any risk factors. For example,cardiac arrest following metoclopramide has beenreported in patients without known cardiac disease [13].Risk Factors: Neither age nor dose appears to becontributory factors for cardiovascular adverse reactionsfrom metoclopramide. While the patients in most of thecases were elderly, cardiac arrest, for example, followingmetoclopramide has occurred in middle­agedindividuals as well [11]. However, no case reports inpediatric patients were found. Rose et al. observed thatrapidly administered IV metoclopramide at 0.25 mg/kghad no effect on either heart rate or BP in 45 childrenbetween the ages of 2–16 years old prior to electivesurgery [37]. However, in adult patients, Blanco et al.observed that IV metoclopramide decreased BP in bothnormotensive and hypertensive adults with greaterdecreases in the later [38]. Other studies have alsodemonstrated vascular hyperreactivity during coldpresser test (CPT) with metoclopramide at doses of 7.5mcg/kg/min during a 30 minute period in bothnormotensive and hypertensive patients [39].Metoclopramide significantly decreased BP but did not

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Table 1. Published case reports of M­associated cardiac adverse drug events.

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Abbraviations: M­metoclopramide

alter heart rate (HR). The authors attributed this effectto an α­adrenergic blocking effect but not to anantidopaminergic effect. In labetalol pre­treatedhypertensive patients, HR increased about 11.5 beats perminute during CPT. BP increased from a mean of 157/97mmHg to 193/123 mmHg (+36.8/+25.7 mmHg) [40].The BP response was blocked by bromocriptine, aknown D2­dopaminergic agonist. Moreover, thecardiovascular adverse effects do not appear to be adose­related effect they occurred after single dosesranging from 2.5–10 mg IV [13, 15, 16].The route of administration may be a causativefactor. In all cases, metoclopramide was given IV eitherperipherally or via a central venous line. The rate ofinjection may also be causative. In a number of cases,metoclopramide was administered over seconds, not

over 1–2 minutes [20]. In one study in a series of 16patients, doses of 10 mg IV produced average decreasesin systolic and diastolic BP of 22% and 20%,respectively, occurring on average 44 seconds afteradministration over a 10 second period [21]. Theprescribing information specifically cautions that IVadministration should be slow over 1–2 minutes.However, the reason stated in the package insert forslow injection is avoidance of “a transient but intensefeeling of anxiety and restlessness, followed bydrowsiness”, and not to avoid rapid decreases in BP orcardiovascular adverse effects [36].Potential Mechanisms Involved:Metoclopramide has potent central anti­dopaminergicand peripheral cholinergic effects [1–41]. Themechanism(s) by which metoclopramide causes

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cardiovascular adverse effects such as cardiac arrest isnot known but may be multifactorial involving: 1) adirect effect on the heart; 2) blockade of presynapticautoreceptors and enhanced catecholamine release [14,42]; 3) other actions caused by enhancement ofcholinergic neurotransmission [5]; or 4) 5­hydroxytryptamine (5­HT3) receptor blockade or 5­HT4 receptor agonism [43].Support for a mechanism involving a direct effect ofmetoclopramide on the heart may be found in thestructural similarity of metoclopramide withprocainamide. Metoclopramide differs fromprocainamide by only a 2,5 aryl substitution [5].Procainamide prolongs AV conduction and mayproduce tachycardia. Moreover, procainamide can alsocause peripheral vasodilation. Procainamide andcholinergic stimulation, in general, have long beenknown to cause sinus arrest [14].The effects of metoclopramide may be due to either adirect cardiac effect (i.e. myocardial depression) orvasodilation. However, the BP lowering effects ofmetoclopramide are unlikely to be due to adopaminergic mechanism but may be caused byarteriolar vasodilation. Doses of 40 mg dailymetoclopramide reduced HR and antagonized BPincreases induced by treadmill exercise in normotensivesubjects [44].The first potential mechanism, a direct effect is likelyto appear immediately after injection and may possiblybe linked to sodium channel blocking antiarrhythmiceffects. In four cases of cardiac arrest, the heart stoppedwithin 30 seconds [9–11, 16]. However, in one casesinus arrest and bradycardia occurred 10­15 minutesafter IV administration, which suggests a differentmechanism [45].With regard to the possible blockade of presynapticautoreceptors by metoclopramide, it is known thatmetoclopramide enhances catecholamine release inpatients with pheochromocytoma and “essential”hypertension [46, 47]. This results in a severe pressorreaction with increased BP and decreased HR and isbelieved to be, at least in part, mediated by vasopressinrelease [41]. Metoclopramide is known to have astriking influence on vasopressin secretion [48]. Thiseffect is believed to be mediated by cholinergicstimulation. Vasopressin produces constriction ofcoronary arteries (thereby reducing oxygen delivery)and increases myocardial oxygen demand by increasingafterload on the heart. It also increases peripheralvascular resistance, which in turn, increases BP. In thepast, the drug was actually used to treat orthostatichypotension and vascular headaches because of itsvasoconstrictive effects [48]. Metoclopramide 20 mg IVinduces increased vasopressin levels in healthy patientsand type 2 diabetics [49]. In one study in hypertensivepatients, intraveneously administered metoclopramidewas shown to release catecholamines [41]. One case ofcardiac arrest occurred following discontinuation ofdopamine. The long­standing influence of dopamine onthe number and function of cardiac beta 1 receptors orthe dopamine effect of release of norepinephrine in

cardiac sympathetic nerve terminals and inducedrelease of circulating catecholamines were postulated aspossible contributory factors. Alternatively,metoclopramide releases acetylcholine from cholinergicnerve terminals inducing peripheral vasodilation [43].Studies have shown that acetylcholine levels areincreased after metoclopramide administration [51, 52].Additionally, in vitro metoclopramide inhibitedacetylcholine to prevent its degradation [53].Metoclopramide increases release of acetylcholine in theCNS possibly causing cholinergic­inducedbradyarrhythmias. It is possible that the effect on theheart may be the result of changes in cholinergic tonemimicking vagal stimulation [29].In animal studies, metoclopramide blocks cardiacdopamine receptors in rats and high doses in catsproduces transient hypotensive effects [54, 55]. In otheranimal studies, doses of 10 mg/kg produced bradycardia[45, 54]. In dogs, doses of 10 mg/kg decreased systolicand diastolic blood pressure, left ventricular systolicpressure, and total peripheral resistance [57].In humans, quinidine­like antiarrhythmic effectshave been observed [55, 56]. Bozzi et al. observed thatmetoclopramide as a 20 mg bolus followed by 20 mg IVat a rate of 1 mg/min had no significant effect on sinusnode conduction but did increase atrial and AV nodalrefractory periods [58].A potential fourth mechanism for CV effects ofmetoclopramide is 5­HT3 receptor blockade or 5­HT4receptor agonism. In addition to its dopamine D2receptor antagonist effects, metoclopramide is a mixed5­HT3 receptor antagonist and 5­HT4 receptor agonist.Metoclopramide’s peripheral action to increase loweresophageal tone and gastric emptying occurs via 5HT4receptor stimulation, whereas the antiemetic effects maybe attributed to 5HT3 receptor blockade [59, 60]. 5­HT3receptor blockage could influence serotonin (Bezold­Jarish reflex) causing bradycardia and hypotension [61].Metoclopramide has also been shown to antagonizeserotonin­induced bradycardia [62]. Lau attributedcirculatory collapse from metoclopramide to excessiveserotonin autoinhibition [24].5­HT4 receptors are also located in the heart and thevasculature where they exert a positive chronotropiceffect and tachycardia by an action on the atrium. 5­HT4receptor agonists are well known to exert their sideeffects mainly on the lower urinary tract and the CVsystem. Metoclopramide is structurally related tocisapride, both being gastric prokinetic substitutedbenzamides. Cisapride was known to trigger tachycardiaand SVT through stimulation of 5­HT4 atrial receptors.The cardiotoxic potential of cisapride was mainly due toQT prolongation and development of Torsades dePointes. This effect was deemed especially problematicin patients concomitantly treated with drugs known toinhibit the CYP3A4 isoenzyme [63, 64]. As recently asfive years ago, a new metabolic pathway formetoclopramide involving the CYP2D6 isoenzyme wasidentified [65]. In 100 healthy subjects, 10 mg ofmetoclopramide prolonged the QT interval from 13.2±1to 19±1 m sec [27]. Elimination of metoclopramide takes

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place through hepatic metabolism involving CYP2D6.Metoclopramide elimination is likely to be slowed inpoor metabolizers of CYP2D6 or those taking inhibitorsof this isoform such as omeprazole [64]. It has beensuggested that a toxic metabolite of metoclopramidemay be linked to the tardive dyskinesia from this agent[66]. Whether or not the CV adverse effects frommetoclopramide can also be linked to the CYPisoenzymes is unknown. However, since the CV adverseeffects in most cases occurred immediately, a metaboliceffect is deemed unlikely to have been causative.Future Research: It is unlikely that furtherresearch will be undertaken as metoclopramide isavailable generically and there are over 10manufacturers listed in the Orange Book. In summary,metoclopramide may occasionally causebradyarrhythmias progressing to cardiac arrest,paroxysmal SVT, hypotension, circulatory collapse, QTprolongation, Torsade de Pointes, heart block, andhypotension in patients without evidence of underlyingfunctional or structural cardiac abnormalities.

CONCLUSIONCardiovascular CV adverse effects ofmetoclopramide are rare but some can be fatal. It wouldappear to be prudent to monitor patients receivingmetoclopramide IV immediately after injection for CVadverse effects. Due to the possibility of CV risksassociated with metoclopramide, it is important forclinicians to take at least some of the steps outlined intable 2. We believe it is also appropriate to warn againstrapid IV injection, especially via the central venousroute. Postmarketing surveillance has helped to identifyrare side effects of drugs after they are on the market,but the occurrence of CV adverse effects such asbradycardia and cardiac arrest from metoclopramidewhich may be ascribed to an underlying disease, areprobably underreported. Further, in view of the numberof cases reported, we recommend additional CV adverseeffects be included in the “Adverse Reactions” section ofthe Prescribing Information for metoclopramide.Rarely, poorly understood side effects occur with manyhighly effective drugs. This review should prompt acritical re­evaluation of the risk/benefit ofmetoclopramide and consideration of therapeutic

Table 2: Recommendations for clinicians.• Recognize factors such as underlying cardiacabnormalities, or familial long QT interval• Perform baseline and periodic ECGs• Avoid concomitant use with other QT prolonging drugs• Monitor serum concentrations of magnesium andpotassium in critically ill patients• Report any CV ADRs to FDA MedWatch• Administer IV metoclopramide slowly over at least twominutes

alternatives, in concert with a search for underlyingpredisposing factors or mechanisms of action involved.*********

Author ContributionsMartha M Rumore – Conception and design,Acquisition of data, Analysis and interpretation of data,Drafting the article, Critical Review of the Article, Finalapproval of the version to be publishedGuarantorThe corresponding author is the guarantor ofsubmission.Conflict of InterestAuthors declare no conflict of interest.Copyright© Martha M Rumore 2012; This article is distributedunder the terms of Creative Commons attribution 3.0License which permits unrestricted use, distributionand reproduction in any means provided the originalauthors and original publisher are properly credited.(Please see www.ijcasereportsandimages.com/copyright­policy.php for more information.)

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ECGs ­ Electrocardiogram; CV ­ Cardiovascular; ADRs ­Adverse drug reactions; FDA ­ Food and drug administration

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