Canadian Journal of Cardiology

Loperamide Cardiac Toxicity: Pathophysiology, Presentation, and Management

Published:April 14, 2022DOI:


      Loperamide is a nonprescription medication commonly used to treat diarrhea. Although it is an opioid, it is very poorly absorbed and well tolerated, with no systemic toxicity at standard doses. In recent years, however, loperamide has been ingested in very large quantities, sometimes with concomitant medications intended to enhance absorption and/or passage across the blood-brain barrier. Most people who misuse loperamide do so for its euphoric effects or to treat symptoms of opioid withdrawal. In addition to the risks of central opioid toxicity, this practice can result in potentially fatal cardiac dysrhythmias, because very high concentrations of loperamide alter the cardiac action potential. Patients will often present with recurrent, unexplained syncope accompanied with marked electrocardiographic abnormalities including QT-interval prolongation, widening of the QRS complex, and dysrhythmias such as torsades de pointes. Treatment involves early identification and discontinuation of loperamide, reversal of central opioid effects if present, and interventions aimed at addressing any cardiac conduction abnormalities. In addition, if there is an underlying opioid use disorder, efforts should be made to refer to specialised addictions care and initiate opioid agonist therapy when appropriate. We review the pharmacology of loperamide and the clinical presentation, pathophysiology, and suggested management of loperamide cardiac toxicity.


      Le lopéramide est un médicament en vente libre couramment utilisé pour traiter la diarrhée. Bien qu'il s'agisse d'un opioïde, il est très peu absorbé et bien toléré, sans toxicité systémique aux doses standard. Ces dernières années, cependant, le lopéramide a été ingéré en très grandes quantités, parfois concomitamment avec des médicaments destinés à améliorer l'absorption et/ou le passage de la barrière hémato-encéphalique. La plupart des personnes qui abusent du lopéramide le font pour ses effets euphorisants ou pour traiter les symptômes du sevrage des opioïdes. Outre les risques de toxicité centrale des opioïdes, cette pratique peut entraîner des dysrythmies cardiaques potentiellement mortelles, car de très fortes concentrations de lopéramide modifient le potentiel d'action cardiaque. Les patients présentent souvent des syncopes récurrentes et inexpliquées, accompagnées d'anomalies électrocardiographiques marquées, notamment un allongement de l'intervalle QT, un élargissement du complexe QRS et des troubles du rythme tels que des torsades de pointes. Le traitement implique l'identification précoce et l'arrêt du lopéramide, l'inversion des effets centraux des opioïdes s'ils sont présents, et des interventions visant à traiter toute anomalie de la conduction cardiaque. En outre, s'il existe un déséquilibre sous-jacent de la consommation d'opioïdes, il faut s'efforcer d'orienter le patient vers des soins spécialisés en toxicomanie et instaurer un traitement par agoniste opioïde le cas échéant. Nous passons en revue la pharmacologie du lopéramide ainsi que le tableau clinique, la pathophysiologie et la prise en charge suggérée de la toxicité cardiaque du lopéramide.
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        • van Nueten J.M.
        • Helsen L.
        • Michiels M.
        • et al.
        Distribution of loperamide in the intestinal wall.
        Biochem Pharamcol. 1979; 28: 1433-1434
        • Galligan J.J.
        • Sternini C.
        Insights into the role of opioid receptors in the GI tract: experimental evidence and therapeutic relevance.
        Handb Exp Pharmacol. 2017; 239: 363-378
        • Epple H.J.
        • Fromm M.
        • Riecken E.O.
        • et al.
        Antisecretory effect of loperamide in colon epithelial cells by inhibition of basolateral K+ conductance.
        Scand J Gastroenterol. 2001; 36: 731-737
        • Reynolds I.J.
        • Gould R.J.
        • Snyder S.H.
        Loperamide: blockade of calcium channels as a mechanism for antidiarrheal effects.
        J Pharmacol Exp Ther. 1984; 231: 628-632
        • Killinger J.M.
        • Weintraub H.S.
        • Fuller B.L.
        Human pharmacokinetics and comparative bioavailability of loperamide hydrochloride.
        J Clin Pharmacol. 1979; 19: 211-218
        • Heel R.C.
        • Brogden R.N.
        • Speight T.M.
        • et al.
        Loperamide: a review of its pharmacological properties and therapeutic efficacy in diarrhoea.
        Drugs. 1978; 15: 33-52
        • Jaffe J.H.
        • Kanzler M.
        • Green J.
        Abuse potential of loperamide.
        Clin Pharmacol Ther. 1980; 28: 812-819
        • Korey A.
        • Zilm D.H.
        • Sellers E.M.
        Dependence liability of two antidiarrheals, nufenoxole and loperamide.
        Clin Pharmacol Ther. 1980; 27: 659-664
        • Lee V.R.
        • Vera A.
        • Alexander A.
        • et al.
        Loperamide misuse to avoid opioid withdrawal and to achieve a euphoric effect: high doses and high risk.
        Clin Toxicol. 2019; 57: 175-180
        • Daniulaityte R.
        • Carlson R.
        • Falck R.
        • et al.
        “I just wanted to tell you that loperamide will work”: a web-based study of extra-medical use of loperamide.
        Drug Alcohol Depend. 2013; 130: 241-244
        • Borron S.W.
        • Watts S.H.
        • Tull J.
        • Baeza S.
        • Diebold S.
        • Barrow A.
        Intentional misuse and abuse of loperamide: a new look at a drug with “low abuse potential”.
        J Emerg Med. 2017; 53: 73-84
        • Eggleston W.
        • Palmer R.
        • Dubé P.A.
        • et al.
        Loperamide toxicity: recommendations for patient monitoring and management.
        Clin Toxicol. 2020; 58: 355-359
        • Vandenbossche J.
        • Huisman M.
        • Xu Y.
        • et al.
        Loperamide and P-glycoprotein inhibition: assessment of the clinical relevance.
        J Pharm Pharmacol. 2010; 62: 401-412
        • Kim K.A.
        • Chung J.
        • Jung D.H.
        • et al.
        Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes.
        Eur J Clin Pharmacol. 2004; 60: 575-581
        • Sadeque A.J.
        • Wandel C.
        • He H.
        • et al.
        Increased drug delivery to the brain by P-glycoprotein inhibition.
        Clin Pharmacol Ther. 2000; 68: 231-237
        • Tayrouz Y.
        • Ganssmann B.
        • Ding R.
        • et al.
        Ritonavir increases loperamide plasma concentrations without evidence for P-glycoprotein involvement.
        Clin Pharmacol Ther. 2001; 70: 405-414
        • Niemi M.
        • Tornio A.
        • Pasanen M.K.
        • et al.
        Itraconazole, gemfibrozil and their combination markedly raise the plasma concentrations of loperamide.
        Eur J Clin Pharamcol. 2006; 62: 463-472
      1. Herr_Doktor421. Wouldn’t say that this is anything amazing: loperamide & black pepper.
        (Available at:)
        Date: May 4, 2016
        Date accessed: January 29, 2022
      2. Space_Vaccine. Loperamide + black pepper extract = feeling really nice! February 8, 2014.
        (Available at)
        • Bhardwaj R.K.
        • Glaeser H.
        • Becquemont L.
        • et al.
        Piperine a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4.
        J Pharmacol Exp Ther. 2002; 302: 645-650
        • Bauer M.
        • Zeitlinger M.
        • Todorut D.
        • et al.
        Pharmacokinetics of single ascending doses of the P-glycoprotein inhibitor tariquidar in healthy subjects.
        Pharmacology. 2013; 91: 12-19
        • Kang J.
        • Compton D.R.
        • Vaz R.J.
        • et al.
        Proarrythmic mechanisms of the common antidiarrheal medication loperamide: revelations from the opioid abuse epidemic.
        Naunyn Schmiedebergs Arch Pharmacol. 2016; 389: 1133-1137
        • Klein M.G.
        • Haigney M.C.P.
        • Mehler P.S.
        • et al.
        Potent inhibition of hERG channels by the over-the-counter antidiarrheal agent loperamide.
        JACC Clin Electrophysiol. 2016; 2: 784-789
        • Yu J.H.
        • Kim H.J.
        • Lee S.
        • et al.
        LC-MS determination and bioavailability study of loperamide hydrochloride after oral administration of loperamide capsules in human volunteers.
        J Pharm Biomed Anal. 2004; 36: 421-427
        • Nattel S.
        An emerging malignant arrhythmia epidemic due to loperamide abuse: underlying mechanisms and clinical relevance.
        JACC Clin Electrophysiol. 2016; 2: 790-792
        • Wightman R.S.
        • Hoffman R.S.
        • Howland M.A.
        • et al.
        Not your regular high: cardiac dysrhythmias caused by loperamide.
        Clin Toxicol. 2016; 54: 454-458
        • Minhas A.S.
        • Schulman S.P.
        Syncope with unusual wide complex arrhythmia in a young woman.
        Circulation. 2018; 183: 2289-2292
        • Bishop-Freeman S.C.
        • Feaster M.S.
        • Beal J.
        • et al.
        Loperamide-related deaths in North Carolina.
        J Anal Toxicol. 2016; 40: 677-686
        • Wu P.E.
        • Juurlink D.N.
        Clinical review: loperamide toxicity.
        Ann Emerg Med. 2017; 70: 245-252
        • Simon M.
        • Rague J.
        A case report of torsade de pointes and Brugada pattern associated with loperamide misuse and supratherapeutic loperamide concentrations.
        J Emerg Med. 2021; 61: e54-e59
        • Kozak P.M.
        • Harris A.E.
        • McPherson J.A.
        • et al.
        Torsades de pointes with high-dose loperamide.
        J Electrocardiol. 2017; 50: 355-357
        • Ollitrault P.
        • Dolladille C.
        • Chrétien B.
        • et al.
        Cardiovascular toxicities associated with loperamide: analysis of the World Health Organization pharmacovigilance database.
        Circulation. 2021; 143: 403-405
        • Eggleston W.
        • Nacca N.
        • Marraffa J.M.
        Loperamide toxicokinetics: serum concentrations in the overdose setting.
        Clin Toxicol. 2015; 53: 495-496
        • Juurlink D.N.
        Activated charcoal for acute overdose: a reappraisal.
        Br J Clin Pharmacol. 2016; 82: 482-487
        • Suarez K.
        • Mack R.
        • Hardegree E.L.
        • et al.
        Isoproterenol suppresses recurrent torsades de pointes in a patient with long QT syndrome type 2.
        HeartRhythm Case Rep. 2018; 4: 576-579
      3. DrugBank. Loperamide. Available at: Accessed January 23, 2022.

        • Litovitz T.
        • Clancy C.
        • Korberly B.
        • et al.
        Surveillance of loperamide ingestions: an analysis of 216 poison center reports.
        J Toxicol Clin Toxicol. 1997; 35: 11-19
        • Parker B.M.
        • Rao T.
        • Matta A.
        • et al.
        Loperamide induced cardiac arrhythmia successfully supported with veno-arterial ECMO (VA-ECMO), molecular adsorbent recirculating system (MARS) and continuous renal replacement therapy (CRRT).
        Clin Toxicol. 2019; 57: 1118-1122
        • Enakpene E.O.
        • Riaz I.B.
        • Shirazi F.M.
        • et al.
        The long QT teaser: loperamide abuse.
        Am J Med. 2015; 128: 1083-1086
        • Vaughn P.
        • Solik M.M.
        • Bagga S.
        • et al.
        Electrocardiographic abnormalities, malignant ventricular arrhythmias and cardiomyopathy associated with loperamide abuse.
        J Cardiovasc Electrophysiol. 2016; 27: 1230-1233