title: Proarrhythmic mechanisms of the common anti-diarrheal medication loperamide: revelations from the opioid abuse epidemic.
abstract: Loperamide is a μ-opioid receptor agonist commonly used to treat diarrhea and often available as an over-the-counter medication. Recently, numerous reports of QRS widening accompanied by dramatic QT interval prolongation, torsades de pointe arrhythmia, and death have been reported in opioid abusers consuming large amounts of the drug to produce euphoria or prevent opiate withdrawal. The present study was undertaken to determine the mechanisms of this cardiotoxicity. Using whole-cell patch clamp electrophysiology, we tested loperamide on the cloned human cardiac sodium channel (Nav1.5) and the two main repolarizing cardiac K(+) channels cloned from the human heart: KvLQT1/minK and the human ether-a-go-go-related gene (hERG) channel. Loperamide inhibited Nav1.5 with IC50 values of 297 and 239 nM at holding potentials of -90 and -70 mV, respectively. Loperamide was weakly active on KvLQT1/minK producing 17 and 65 % inhibition at concentrations of 1 and 10 μM, respectively. Conversely, loperamide was found to be a very high affinity inhibitor of the hERG channel with an IC50 value of 89 nM at room temperature and 33 nM when measured at physiological temperature. The QRS and QT interval prolongation and the attending arrhythmias, produced by loperamide, derive from high affinity inhibition of Nav1.5 and especially hERG. Since the drug has been widely available and safely used as directed for many years, we believe that the potent inhibition loperamide possesses for cardiac ion channels has only been uncovered because of the excessive misuse of the drug as a consequence of the recent opioid abuse epidemic.
authors.affiliation: Preclinical Safety, Sanofi, Inc, Waltham, MA, USA.
authors.forename: Jiesheng
authors.initials: J
authors.lastname: Kang
authors.affiliation: Preclinical Safety, Sanofi, Inc, Route 202/206, Bridgewater, NJ, 08807, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Compton
authors.affiliation: Lead Generation and Compound Realization, Sanofi, Inc, Waltham, MA, USA.
authors.forename: Roy J
authors.initials: RJ
authors.lastname: Vaz
authors.affiliation: Preclinical Safety, Sanofi, Inc, Route 202/206, Bridgewater, NJ, 08807, USA. david.rampe@sanofi.com.
authors.forename: David
authors.initials: D
authors.lastname: Rampe
mesh_terms: D000200:Action Potentials; D000930:Antidiarrheals / Q000633:toxicity*; D066126:Cardiotoxicity; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D008139:Loperamide / Q000633:toxicity*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009293:Opioid-Related Disorders / Q000150:complications* / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D012307:Risk Factors; D013997:Time Factors; D016171:Torsades de Pointes / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D014162:Transfection; D061567:Voltage-Gated Sodium Channel Blockers / Q000633:toxicity*
chemical_list: D000930:Antidiarrheals; D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D061567:Voltage-Gated Sodium Channel Blockers; D008139:Loperamide
keywords: Abuse; Arrhythmia; KvLQT1/minK; Loperamide; Nav1.5; Opioid; Torsades de pointe; hERG