Cardiac disorders
We observed 19 cases of CV ADRs, in particular “QT prolongation”. In these cases, the most frequently reported suspected COVID-19 medications were HCQ, azithromycin, lopinavir/ritonavir and darunavir/cobicistat, which are, based on their pharmacokinetic and pharmacodynamic properties, commonly associated to CV events.
HCQ acute toxicity occurs most frequently when therapeutic or high doses are administered rapidly through parenteral routes. HCQ doses of >5 g given parenterally usually are fatal. Toxic manifestations relate primarily to the CV system, including hypotension, suppressed myocardial function, arrhythmias, and eventual cardiac arrest. Due to its long elimination half-life (>40 days) [26], prolonged treatment with high doses may also cause ADRs such as widening of the QRS interval, and T-wave abnormalities. In fact, it is well known that HCQ inhibits human ether-a-go-go related gene (hERG) potassium channels. Inhibition of hERG can block the outward flow of potassium, which leads to intracellular accumulation of potassium and ventricular repolarization and results in QT prolongation and torsade de pointes (TdP) [27]. These complications usually disappear shortly after the drug withdrawal. HCQ may also inhibit CYP2D6, interacting with a variety of different COVID-19 and non-COVID-19 medications.
The macrolide azithromycin is a weak inhibitor of CYP3A4. In this case, in connection with its effect on QT prolongation, the potential for DDIs is associated to azithromycin pharmacodynamic characteristics. As such, caution should always be observed when combining azithromycin with other molecules that increase the QT interval, such as HCQ. In particular, QT prolongation seems to be significantly higher in patients who received the two medications concomitantly [28]. The exact mechanism by which azithromycin and other macrolides prolong the QT interval is through a blockade of the rapid component, IKr, of the delayed rectifier potassium current IK, which is encoded by the hERG [29], similarly to HCQ.
Special caution must be used when administering protease inhibitors, such as lopinavir/ritonavir, due to their potential of inducing QT interval prolongation, particularly when used in combination with other pro-arrhythmic medications, such as HCQ and azithromycin. In fact, lopinavir/ritonavir may increase concentrations of the co-administered medicinal products and this may result in an increase of their associated cardiac ADRs. This can be explained by the ability of lopinavir/ritonavir to modulate enzymes, in particular CYP3A4 and P-glycoprotein (P-gp). Lopinavir/ritonavir may also inhibit BCRP and OATP1B1 transporters [30]. These pharmacokinetic characteristics were also observed for darunavir/cobicistat [31], leading to a comparable profile in terms of DDIs and potentially related CV ADRs.
In general, attention should be exercised when COVID-19 treatments are combined with drugs known to increase the PR or QT intervals, as they also cause conduction and repolarization disorders by themselves. Considering that QT prolongation could be an asymptomatic and potentially fatal event, it should be always strictly monitored. The risk factors for QT prolongation and TdS are female sex, older age, heart disease, exposure to QT interval prolonging drugs or metabolic inhibitors, bradycardia, and electrolyte disturbance [28]. The cornerstone of the management of acquired QT prolongation includes the identification and discontinuation of any suspected drug and the prompt correction of any metabolic abnormalities [32]. Short-term treatment includes the administration of intravenous magnesium sulphate and potassium chloride to manage a possible hypomagnesemia or hypokalemia. Thus, ECG and serum potassium levels should be frequently checked.