Chloroquine and Hydroxychloroquine in the Era of SARS - CoV2: Caution on Their Cardiac Toxicity.

Abstract

With the heightened interest of the potential use of chloroquine and hydroxychloroquine for the treatment of patients with SARS-CoV2 (COVID-19 or novel coronavirus)1 it may be prudent to reflect on the risks of therapy, particularly their cardiac toxicity. Chloroquine and hydroxychloroquine are old drugs,2, 3 used historically for malaria, rheumatoid arthritis and (systemic and discoid) lupus erythematosus, among other less common disorders. Chloroquine was synthesized in 1934 at Bayer, initially discarded but later clinically used in the 1940s. Synthesized in 1950 as a less toxic alternative to chloroquine, hydroxychloroquine was approved by the Food and Drug Administration in 1955 although it owes its roots to the discovery of quinine hundreds of years ago as a treatment for malaria. A search for alternatives to quinine for malaria treatment and prophylaxis during World War II led to the synthesis of other aminoquinoline compounds including first quinacrine then chloroquine and eventually hydroxychloroquine. Their most frequent toxicities are gastrointestinal (diarrhea, nausea) but their most serious is a retinopathy that is both dose and duration (years) dependant.4 But like quinine and its stereoisomer quinidine, both chloroquine and hydroxychloroquine are ion active, blocking IKr potassium (and other) channels (indeed, hydroxychloroquine once was proposed as a treatment for some supraventricular arrhythmias). This pharmacologic action gives both drugs the potential of causing life-threatening arrhythmias, notably torsade de pointes (TdP). Electrocardiographic documented TdP with QT interval prolongation has been reported.5, 6 On the CredibleMeds webpage,7 both chloroquine and hydroxychloroquine are listed as drugs with “known risk” of causing TdP. A brief review of the very few reported cases yielded the following characteristics. Occurrence is more than likely dose-related as is the case with most drugs causing TdP (in distinct contrast to quinidine however);8 two cases associated with hydroxychloroquine9, 10 and a case with chloroquine11 occurred during overdose. Other cases reported were in association with factors that could increase the risk of TdP such as hypokalemia (during overdose), bradycardia (hydroxychloroquine appears to block If or the so-called funny current that affects sinus node function), baseline long QT and alterations in disposition which could increase systemic exposure. Here the pharmacokinetics of chloroquine and hydroxychloroquine need mention.12, 13 These are unusual drugs in this regard, making one note the resemblance with amiodarone. The terminal half-life of both drugs is 1–2 months and they have extremely large volumes of distribution due to extensive sequestering in deep tissue stores (accumulating in lysosomes via ion trapping). Thus, if one does encounter QT interval prolongation and TdP in a patient, it is possible the patient could remain at risk for recurrence for extended times. As synthetic drugs, they are available commercially as racemic mixtures of the R and S enantiomers; elimination appears to be stereoselective but it is unknown if one or both enantiomers have selective pharmacologic actions (such as channel blockade). Hydroxychloroquine is 30–50% excreted renally as unchanged drug with the remaining fraction being metabolized through the liver by CYP 3A, CYP 2C3 and (minor) CYP 2D6. Chloroquine is similar but also probably metabolized by CY2C8 rather than CYP2C3. Both chloroquine and hydroxychloroquine increase serum digoxin concentrations, so like quinidine, these drugs probably block p-glycoprotein. This profile sets up many anticipated drug interactions but also may increase the risk of TdP in patients with renal dysfunction or advanced hepatic disease. Indeed, in those few cases5, 6 reported, liver or kidney disease appeared to be present. Preliminary evidence from a very small, nonrandomized and unblinded study suggests that the combination of hydroxychloroquine and azithromycin may be more effective than hydroxychloroquine alone for reducing viral burden in patients with COVID-19.1 Consequently, this drug combination is already being used in clinical practice to treat patients with COVID-19. Azithromycin is also on the CredibleMeds.org list of drugs “known” to cause TdP.7 Concomitant use of these QT interval-prolonging drugs may further increase the risk of QT interval prolongation and TdP.14 In addition, since both drugs are (more than likely) p-glycoprotein inhibitors, the possibility of a pharmacokinetic drug interaction exists (although one has not yet been described). Therefore, the population of patients taking this drug combination may be at enhanced risk for TdP. Life threatening arrhythmias associated with chloroquine and hydroxychloroquine appear to be rare but if these drugs were to be used much more extensively then caution and appropriate monitoring are necessary. Baseline QT interval should be measured,15 particularly in those patients with risk factors14, 16 for TdP and those with renal or hepatic disease. Where possible, and particularly in patients in whom hydroxychloroquine and azithromycin are used concomitantly to treat COVID-19, use of other QT interval-prolonging drugs should be avoided.17 Hypokalemia, hypomagnesemia and/or hypocalcemia should be corrected, and serum potassium and magnesium concentrations should be maintained at >4.0 mEq/l and 2.0 mg/dl, respectively.17 QT intervals should be monitored closely during therapy.15, 17