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

Abstract

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% (APD) and 90% (APD) of full repolarization levels with a rectangular pattern. Azithromycin significantly suppressed the L-type Ca and Na currents from the left ventricular myocytes of guinea pig at 50% inhibiting concentrations (IC) 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 I current at an inhibition rate of 30.99 ± 5.23% with an undetectable IC. Azithromycin caused bradyarrhythmia primarily by inhibiting L-type Ca and Na currents.

Considerations for Drug Interactions on QTc in Exploratory COVID-19 Treatment

“…13 Basic electrophysiologic studies suggest that both drugs can provoke proarrhythmia via mechanisms beyond block of IKr implicated in usual cases of torsade de pointes. 14,15 The effect of the combination of these agents on QT or arrhythmia risk has not been studied. There are very limited data evaluating the safety of combination therapy.…”

Considerations for Drug Interactions on QTc Interval in Exploratory COVID-19 Treatment

“…13 Basic electrophysiologic studies suggest that both drugs can provoke proarrhythmia via mechanisms beyond block of I Kr implicated in usual cases of torsade de pointes. 14,15 The effect of the combination of these agents on QT or arrhythmia risk has not been studied. There are very limited data evaluating the safety of combination therapy.…”

COVID-19: Present and Future Challenges for Dental Practice

“…This antibiotic is considered relatively safe in adults, children, and pregnant women [13]. However, a number of side effects have been identified especially with intravenous administration, which may be associated with gastrointestinal disturbances, ototoxicity, and pain and inflammation of the injection site [14] The development of resistant bacteria, [15] and its association with proarrhythmic events [16] have also been reported. The latter risk has been attributed to QT prolongation (summation of action potential of ventricular myocytes), which can lead to a life-threatening arrhythmia; however, susceptible patients usually have other co-factors such as old age, heart disease, and exposure to other QT prolonging drugs [17].…”