Electrophysiologic Studies on the Risks and Potential Mechanism Underlying the Proarrhythmic Nature of Azithromycin.

The mechanisms underlying arrhythmia induced by the clinical use of azithromycin are poorly understood. We aimed to investigate the proarrhythmic effects of azithromycin using electrocardiogram (ECG) and ion channel models. In vivo and in vitro guinea pig ECG and current and voltage clamp recordings were carried out. Azithromycin at 114.6 mg/kg (three times the clinically relevant dose) reduced heart rate (HR) and prolonged the PR, QRS and rate-corrected QT (QTc) intervals of guinea pig ECG in vivo. In vitro technique revealed that azithromycin at 207.5 and 415 mg/L [five and ten times clinically relevant concentration (CRC)] reduced HR and prolonged the PR, QRS and QTc intervals in the isolated guinea pig heart ECG. Both arrhythmias presented bradyarrhythmic features, mainly with reduced HR and prolonged PR interval. Action potential analysis from the guinea pig cardiomyocytes indicated that azithromycin at 830 mg/L (20 times CRC) significantly prolonged the action potential durations at 50% (APD50) and 90% (APD90) of full repolarization levels with a rectangular pattern. Azithromycin significantly suppressed the L-type Ca2+ and Na+ currents from the left ventricular myocytes of guinea pig at 50% inhibiting concentrations (IC50) of 942.5 ± 68.4 mg/L (22.7 times CRC) and 1123.0 ± 87.7 mg/L (27.1 times CRC), respectively. However, azithromycin at 50 times CRC (2075 mg/L) inhibited IKr current at an inhibition rate of 30.99 ± 5.23% with an undetectable IC50. Azithromycin caused bradyarrhythmia primarily by inhibiting L-type Ca2+ and Na+ currents.