Chloroquine and hydroxychloroquine provoke arrhythmias at concentrations higher than those clinically used to treat COVID‐19: A simulation study


Clinical and Translational Science


Jun‐ichi Okada, Takashi Yoshinaga, Takumi Washio, Kohei Sawada, Seiryo Sugiura, Toshiaki Hisada



The risk of fatal arrhythmias is the major concern for using chloroquine (CQ) or hydroxychloroquine (HCQ) to treat coronavirus disease 2019 (COVID‐19), but the reported number of life‐threatening arrhythmic events or deaths is relatively small. The objective of this study was to assess the arrhythmogenic risk of these two drugs using a multiscale heart simulation, which allows testing even at high concentrations, including those that cause fatal arrhythmias. We measured the inhibitory action of CQ, HCQ, and HCQ with 30 ÎŒM azithromycin (AZ) on six ion currents (fast [INa] and late [INa,L] components of the sodium current, L‐type calcium current [ICa,L], rapid [IKr/hERG], and slow [IKs] components of delayed rectifier potassium, and inward rectifier potassium [IK1]) over a wide range of concentrations using the automated patch‐clamp system. Using the concentration–inhibition relationship that was thus obtained, we simulated the drug effects while increasing the concentration until the life‐threatening arrhythmia, Torsade de Pointes (TdP), was observed. The obtained threshold concentrations for TdP were 12.5, 35, and 22.5 ÎŒM for CQ, HCQ, and HCQ with AZ, respectively. Adding therapeutic concentrations of mexiletine or verapamil successfully prevented the occurrence of TdP, and verapamil was more effective. CQ, HCQ, and HCQ with AZ thresholds for TdP were larger than both antiviral concentrations that were reported by in vitro experiments and free plasma concentrations that were attained by the clinically used dosage. The current simulation data provided a safety margin to the currently used clinical dose for CQ and HCQ/AZ.

Go to journal

Get in Touch

We strive to provide the best for our customers, and we are always ready to help. Please let us know if you have a question for us.

Follow us