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.