Potent Inhibition of hERG Channels by the Over-the-Counter Antidiarrheal Agent Loperamide

Abstract

Objectives: The aim of this study was to determine the in vitro electrophysiological properties of loperamide. The authors' hypothesis was that loperamide is a potent blocker of the current carried by the human ether-à-go-go-related gene (hERG) potassium channel.

Background: Loperamide is a peripherally-acting μ-opioid agonist available worldwide as an over-the-counter treatment for diarrhea. Like most opioids, it is not currently known to be proarrhythmic. Recent cases of torsade de pointes in association with high-dose loperamide raise concern given its structural similarity to methadone, another synthetic opioid with an established arrhythmia risk.

Methods: Effects of loperamide on blockade of the hERG potassium channel ion current were assessed in Chinese Hamster Ovary (CHO) cells stably expressing hERG to elucidate current amplitude and kinetics. The concentration required to produce 50% inhibition of hERG current was assessed from the amplitude of tail currents and the impact on action potential duration was assessed in isolated swine ventricular cardiomyocytes.

Results: The 50% inhibitory concentration for loperamide inhibition of hERG ionic tail currents was approximately 40 nmol/l. In current-voltage measurements, loperamide reduced steady and tail currents and shifted the current activation to more negative potentials. Loperamide (10 nmol/l) also increased the action potential duration, assessed at 90% of repolarization, in ventricular myocytes by 16.4 ± 1.7% (n = 6; p < 0.004). The maximum rate of rise of phase 0 of the action potential, however, was not significantly altered at any tested concentration of loperamide.

Conclusions: Loperamide is a potent hERG channel blocker. It significantly prolongs the action potential duration and suggests a causal association between loperamide and recent clinical cases of torsade de pointes.

Keywords: QT; action potential; hERG; loperamide; torsade de pointes.