|Year : 2021 | Volume
| Issue : 1 | Page : 3-7
Implications of the use of hydroxychloroquine on cardioactive drugs
Soumitra Ghosh1, Ashutosh Yadav2, Cliojis Francis3, Anunay Gupta3, Preeti Gupta3, Sourabh Agstam3
1 Department of Cardiology, PGIMER, Chandigarh, Punjab, India
2 Department of Cardiology, Fortis Hospital, Mohali, Punjab, India
3 Department of Cardiology, VMMC and Safdarjung Hospital, New Delhi, India
|Date of Submission||25-Aug-2020|
|Date of Decision||24-Feb-2021|
|Date of Acceptance||12-Mar-2021|
|Date of Web Publication||24-Apr-2021|
Department of Cardiology, VMMC and Safdarjung Hospital, New Delhi
Source of Support: None, Conflict of Interest: None
Hydroxychloroquine (HCQ) is a relatively safe drug, and has been emerged as one of the treatment options for the management of COVID-19. This review is from the viewpoint of cardiologists, and it covers the pharmacokinetics, pharmacodynamics, and mechanism of drug interaction of HCQ with the commonly used cardioactive drugs.
Keywords: Drug interactions, hydroxychloroquine, pharmacodynamics, pharmacokinetics
|How to cite this article:|
Ghosh S, Yadav A, Francis C, Gupta A, Gupta P, Agstam S. Implications of the use of hydroxychloroquine on cardioactive drugs. J Pract Cardiovasc Sci 2021;7:3-7
|How to cite this URL:|
Ghosh S, Yadav A, Francis C, Gupta A, Gupta P, Agstam S. Implications of the use of hydroxychloroquine on cardioactive drugs. J Pract Cardiovasc Sci [serial online] 2021 [cited 2021 Jun 25];7:3-7. Available from: https://www.j-pcs.org/text.asp?2021/7/1/3/314479
| Introduction|| |
The Indian Council of Medical Research proposed the use of hydroxychloroquine (HCQ) as chemoprophylaxis against coronavirus disease (COVID-19) among the health-care workers, frontline workers, and close contacts of confirmed COVID cases. Off-label use was recommended in severe cases of COVID-19. This has led to the upsurge in the prescription of the HCQ. Although it is a safe drug, QTc prolongation is by far the most dangerous adverse effect, resulting in Torsades de pointes (TdP) and sudden cardiac death. Along with this, we are concerned about the drug interactions of HCQ with the commonly used cardiac drugs.
| Metabolism of Hydroxychloroquine|| |
HCQ is metabolized by cytochrome P450 isoenzymes (CYPs) CYP2C8, CYP3A4/5, and CYP2D6 and it inhibits CYP2D6. CYP3A4 and CYP2D6 are the main isoforms involved in the metabolism of HCQ., It has a long elimination half-life (40–50 days) and variable interindividual pharmacokinetics due to the genetic difference and the drug interaction leading to delayed actions and variable clinical response., In 194 patients with systemic lupus erythematosus (SLE), the patients having CYP2D6 variants showed a faster metabolism of the active metabolite of HCQ. In 164 malaria-infected patients treated with HCQ, a 20% less reduction in gametocytemia levels was observed on patients with low-activity alleles of CYP2C8 (*2, *3, and *4). Nearly 20% of individuals of European descent had the CYP2D6 *4 nonfunctional allele and these patients may have a higher risk.
HCQ is an inhibitor of permeability glycoprotein (P-glycoprotein) transport system. P-glycoprotein is a potent transport system that aids in the export of drugs from the cells located in the gut, blood–brain barrier, liver, and renal tubules. A wide range of drugs such as steroids, antiarrhythmics, anticoagulants, and statins are P-glycoprotein substrates and their interactions are clinically significant. Research on mouse models and P-glycoprotein expressing cell line proved that there is an elevation in digoxin concentration in patients receiving quinidine by reducing P-glycoprotein-mediated efflux of digoxin into gut and kidney, resulting in higher intestinal absorption and reduced elimination of digoxin.
”Pharmacogenetics” of HCQ also plays a role in the efficiency of the drug. Pharmacogenetics is a study of a single gene or multiple genes in response to a drug. Missense mutations in interleukin 10 or tumor necrosis factor gene yield increased effectiveness of HCQ.
| Hydroxychloroquine and QTc Prolongation|| |
The most serious adverse effect of HCQ is the prolongation of QTc interval and TdP, and combination with other QT-prolonging drugs can accentuate this risk. It should be taken into account that the patient who develops QTc prolongation with HCQ will not necessarily develops arrhythmia as the risk of TdP is not linearly related to baseline QTc or change in drug-related QTc interval.
Indian Heart Rhythm Society has categorized patients into three groups. Group A: low risk, without QTc prolongation; Group B: moderate-risk group, having QTc up to 500 ms; and Group C: high-risk group, QTc interval more than 500 ms. Some risk factors predispose to HCQ toxicity like structural heart disease, history of syncope or ventricular arrhythmia, coadministration of other QT prolonging medications like erythromycin, azithromycin, fluoroquinolones, antihistaminics, antiarrhythmics, and dyselectrolytemia like hypokalemia, hypomagnesemia, hypocalcemia. No risk stratification is needed for Group A. For group B, HCQ can be given with caution after addressing correctable risk factors like dyselectrolytemia. For Group C, clinical evaluation as per the above-mentioned risk factors is done and HCQ should be used only for the high-risk COVID patients.
There are various guidelines regarding the monitoring and managing the QT prolongation of HCQ in COVID-19 patients, yet the protocols are very inconclusive.,, Before starting HCQ, a baseline electrocardiogram (ECG) is preferable and the calculation of QTc interval is done by Bazett's formula. QTc interval more than 460 ms for females and 450 ms for males is considered prolonged. Giudicessi et al. proposed an algorithm for patients before initiation with QTc prolonging drugs. It recommends to take a baseline ECG, electrolyte measurement, discontinuation of any QTc prolonging medication, and documenting cardiac and comorbid conditions. QTc measurements of <470 ms in males and less than 480 ms in females are used as cutoff level to prescribe or continue therapy. It should include withholding other QTc-prolonging drugs, management of dyselectrolytemia, and telemetric monitoring. The recent meta-nalysis revealed that HCQ prolongs QTc interval but is not associated with TDP; however, we should be cautious about this rare side effect.
The QT-prolonging mechanism of HCQ is not very well understood. Capel et al. observed the HCQ inhibitory actions on the hyperpolarization-activated current (if current), along with delayed rectifier K + currents (I Kr), and L-type calcium ion currents (I CaL) on sinus node cells in an animal model. HCQ appears to block the HERG channel responsible for IKr, and molecular work has permitted on creating drug models affecting HERG. Drug interaction with HERG is identified with X-ray crystallography and site-directed mutagenesis. However, ultimately close QT interval monitoring in the ECG is very vital in monitoring patients on chronic therapy with HCQ.
| Safety in Older Adults|| |
The elderly are considered to be most susceptible to COVID-19 presenting with a severe course of infection. HCQ is under investigation for the treatment COVID-19.,, As discussed previously, the effect of HCQ on CYP2D6 and P-glycoprotein leads to many drug–drug interactions (DDI). Polypharmacy being prevalent among 50% of the elderly population, usage of HCQ can create many DDI. Velasco-González et al. conducted a retrospective study analyzing the interaction between chronic medication in the elderly with HCQ for 377 patients. The study showed that amiodarone, rifampicin, phenobarbital, phenytoin, and carbamazepine should not be co-administered with HCQ, while digoxin, citalopram, dabigatran, hydroxyzine, and nortriptyline require a close monitoring. There are many other drugs that are known to cause potential interaction with HCQ and clinicians must be vigilant of these potential DDI while prescribing for the elderly.
| Digoxin|| |
Digoxin has long been used for chronic heart failure and rapid atrial fibrillation, especially in rheumatic heart disease patients. It has a very narrow therapeutic index. Earlier studies showed that the addition of quinidine (structural similarity to HCQ) to chronic digoxin therapy resulted in an elevation of digoxin levels by 2.5 fold. Quinidine decreased the renal glycoside clearance and the elevation in digoxin levels suggested a 30%–50% reduction in digoxin dosage. Interaction between digoxin and 4-aminoquinine derivatives (HCQ and chloroquine) has been vastly studied. Leden in 1981 reported two cases in patients with rheumatoid arthritis who showed serum digoxin elevation after the addition of HCQ. After the cessation of HCQ, the serum digoxin concentration normalized to a therapeutic range.,, It is prudent to closely monitor serum digoxin levels and reduce the dose of digoxin as necessary in patients currently receiving combination therapy.
| Beta-Blockers|| |
Beta-blockers are essential drugs for heart failure, myocardial infarction, and cardiac arrhythmias. Many of the beta-blockers are CYP2D6 enzyme substrates such as metoprolol, timolol, propranolol, labetalol, and carvedilol. HCQ inhibits CYP2D6 and increases the bioavailability and peak plasma concentration of beta-blockers.
Somer et al. conducted a crossover study, in which seven healthy extensive metabolizer CYP2D6 phenotypes received 400 mg HCQ or placebo 8 days twice and on the 9th day received 100 mg metoprolol orally. The average area under the curve (AUC) was increased by 65%, indicating increased bioavailability of metoprolol. In a study performed by Lancaster et al., chloroquine inhibited metoprolol oxidation in human microsomes. Intraperitoneal injection of chloroquine to anesthetized rats significantly reduced metoprolol clearance. Similarly, Lennard et al. performed pharmacokinetic studies to see the effect of CYP2D6 *4 allele on metoprolol and showed up to twofold increase in AUC and minimum and average steady-state concentration in heterozygotes. Administration of HCQ with metoprolol can increase the bioavailability of the latter. Carvedilol and bisoprolol are stereoselectively catalyzed by CYP2D6, with a resultant increase in their levels with HCQ use. The intrinsic sinus rate slowing property of HCQ as seen in animal studies and increased beta-blocker levels can lead to significant bradycardia. Therefore, it is crucial to evaluate the benefit versus harm during coadministration of HCQ and beta-blockers.
| Antiarrhythmics|| |
The ultimate goal of antiarrhythmic drugs is to restore the normal rhythm of the heart by increasing or decreasing cardiac conduction velocity. These drugs act by blocking membrane sodium, potassium, and calcium channels. Most of the antiarrhythmics are metabolized by CYP2D6 and can cause potential drug interactions. Dean et al. noted an increased plasma concentration of propafenone (class IC antiarrhythmic) in CYP2D6 poor metabolizers and those taking CYP2D6 inhibitor drugs leading to cardiac arrhythmia. Similarly, the retrospective analysis of HCQ with amiodarone postulate that coadministration of HCQ and amiodarone could increase the effect of antiarrhythmic medication. These would worsen the adverse effect of amiodarone such as QT prolongation, pulmonary toxicity, and interstitial pneumonitis. Furthermore, Miranda-Aquino et al. reported long QT resulting from amiodarone and HCQ interaction. QT prolongation and proarrhythmia will also be significantly expected to increase by drugs with QT-prolonging action such as sotalol, ibutilide, disopyramide, ajmaline, amakalant, and dofetilide. Other antiarrhythmic drugs that are metabolized by CYP2D6 are diltiazem, encainide, flecainide, mexiletine, and procainamide, which will be elevated and further increase the proarrhythmic risk.
| Statins|| |
Statins are essential medications for both primary cardiovascular prevention and secondary cardiovascular prevention. The most frequent side effect of statins is myotoxicity which can be mild-to-severe disease. In the most severe form, it can lead to rhabdomyolysis., Membrane excitability, mitochondrial dysfunction, impaired calcium metabolism, induction of apoptosis, and genetic susceptibility are the causes of myotoxicity. Certain factors that increase the risk are female sex, diabetes, low body mass index, treatment with CYP450 inhibitors, and renal and liver dysfunction. HCQ had an association with myopathy, and the risk of myopathy may increase with concurrent use of HCQ and statins.
HCQ has antilipidemic effects like statins. Migkos et al. reported that HCQ use in Sjögren Syndrome leads to a significant decrease in total cholesterol, an increase in high-density cholesterol, and the improvement in the atherogenic index. The exact mechanism is unknown. A possible mechanism is the inhibition of cholesterol biosynthesis in hepatocytes by HCQ.
| Antiplatelets|| |
The antiplatelet actions of chloroquine have been known for more than 50 years. In vitro experiments showed inhibition of serotonin uptake by platelets on the addition of chloroquine., At therapeutic blood levels, it strongly inhibited platelet aggregation by adenosine diphosphate (ADP), collagen, and ristocetin.
Multiple mechanisms have been suggested for the antiplatelet actions of chloroquine and HCQ, for instance, interaction with membrane glycoprotein GpIIb/IIIa, preventing ADP mediated platelet aggregation, inhibition of phospholipase A2 and arachidonic acid metabolites, inhibition of phosphokinase C, membrane stabilization, inhibition of granular release, inhibition of membrane-bound calcium, and preventing the association of fibrinogen to platelets.,
In the 1970s to 80s, multiple clinical studies showed the benefit of HCQ (in a dosage of 600–1200/day) in preventing deep-vein thrombosis after intra-abdominal surgery; however, no benefit was seen after knee or hip replacement., Multiple cohort studies in patients with SLE have shown a reduced risk of arterial thrombosis in patients receiving HCQ. Achuthan et al. evaluated the efficacy of HCQ in healthy volunteers as an antiplatelet action. In this study, patients were given HCQ alone and combination with aspirin; and compared it with aspirin alone and aspirin and clopidogril. HCQ showed a significant increase in inhibition of platelet aggregation when added to aspirin in comparison to aspirin alone.
The HCQ is metabolized by CYP2C8, CYP3A4/5, and CYP2D6. Clopidogrel can affect the metabolism of HCQ by inhibiting CYP2C8 and CYP3A4. Coadministration of clopidogrel with HCQ may potentially raise serum concentrations of HCQ and higher levels of HCQ can lead to QT prolongation. The potential risk should be kept in mind during prescribing HCQ in patients receiving clopidogrel. Similar interactions in the metabolism of HCQ have been not observed with prasugrel and ticagrelor due to difference in metabolic pathways, suggesting a preferential use of prasugrel and ticagrelor in patients receiving HCQ.
| Conclusion|| |
HCQ is a relatively safe drug when used alone. The risk of QTc prolongation increases twothreefold with the use of concomitant QTc-prolonging medications. Interactions of HCQ with digoxin, beta-blockers, and statins should be kept in mind when considering use in cardiac patients. There is a theoretical increased risk of bleeding in patients on antiplatelets and close monitoring is needed.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Ministry of Health and Family Welfare. Revised National Clinical Management Guideline for COVID19. Available from: https://www.mohfw.gov.in/pdf/
. [Last accessed on 2020 Mar 31].
Kim KA, Park JY, Lee JS, Lim S. Cytochrome P450 2C8 and CYP3A4/5 are involved in chloroquine metabolism in human liver microsomes. Arch Pharm Res 2003;26:631-7.
Furst DE. Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases. Lupus 1996;5 Suppl 1:S11-5.
Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: Implications for rheumatology. Nat Rev Rheumatol 2020;16:155-66.
Lee JY, Vinayagamoorthy N, Han K, Kwok SK, Ju JH, Park KS, et al
. Association of polymorphisms of cytochrome P450 2D6 with blood hydroxychloroquine levels in patients with systemic lupus erythematosus. Arthritis Rheumatol 2016;68:184-90.
Sortica VA, Lindenau JD, Cunha MG, Ohnishi MD, Ventura AM, Ribeiro-Dos-Santos ÂK, et al
. The effect of SNPs in CYP450 in chloroquine/primaquine Plasmodium vivax
malaria treatment. Pharmacogenomics 2016;17:1903-11.
Sistonen J, Sajantila A, Lao O, Corander J, Barbujani G, Fuselli S. CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure. Pharmacogenet Genomics 2007;17:93-101.
Fromm MF, Kim RB, Stein CM, Wilkinson GR, Roden DM. Inhibition of P-glycoprotein-mediated drug transport: A unifying mechanism to explain the interaction between digoxin and quinidine [seecomments]. Circulation 1999;99:552-7.
Davila L, Ranganathan P. Pharmacogenetics: Implications for therapy in rheumatic diseases. Nat Rev Rheumatol 2011;7:537-50.
Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart 2003;89:1363-72.
Kapoor A, Pandurangi U, Arora V, Gupta A, Jaswal A, Nabar A, et al
. Cardiovascular risks of hydroxychloroquine in treatment and prophylaxis of COVID-19 patients: A scientific statement from the Indian Heart Rhythm Society. Indian Pacing Electrophysiol J 2020;20:117-20.
Lakkireddy DR, Chung MK, Gopinathannair R. Guidance for cardiac electrophysiology during the coronavirus (COVID-19) pandemic from the Heart Rhythm Society COVID-19 Task Force; Electrophysiology Section of the American College of Cardiology; and the Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology, American Heart Association. Heart Rhythm 2020;17:e233-41.
Giudicessi JR, Noseworthy PA, Friedman PA, Ackerman MJ. Urgent guidance for navigating and circumventing the QTc-prolonging and torsadogenic potential of possible pharmacotherapies for coronavirus disease 19 (COVID-19). Mayo Clin Proc 2020;95:1213-21.
Agstam S, Yadav A, Kumar MP, Gupta A. Hydroxychloroquine and QTc prolongation in patients with COVID-19: A systematic review and meta-analysis. Indian Pacing Electrophysiol J 2021;21:36-43.
Capel RA, Herring N, Kalla M, Yavari A, Mirams GR, Douglas G, et al
. Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current If: Novel electrophysiological insights and therapeutic potential. Heart Rhythm 2015;12:2186-94.
Stansfeld PJ, Sutcliffe MJ, Mitcheson JS. Molecular mechanisms for drug interactions with hERG that cause long QT syndrome. Expert Opin Drug Metab Toxicol 2006;2:81-94.
Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro
. Cell Discov 2020;6:16.
Verde Z, García de Diego L, Chicharro LM, Bandrés F, Velasco V, Mingo T, et al
. Physical performance and quality of life in older adults: Is there any association between them and potential drug interactions in polymedicated octogenarians. Int J Environ Res Public Health 2019;16:4190.
Velasco-González V, Fernández-Araque A, Sainz-Gil M, Jimeno N, Martín LH, Verde Z. Hydroxychloroquine and potential drug interactions in older adults. Arch Bronconeumol 2020;56:679-81.
Doering W. Quinidine-digoxin interaction: Pharmacokinetics, underlying mechanism and clinical implications. N Engl J Med 1979;301:400-4.
Leden I. Digoxin-hydroxychloroquine interaction? Acta Med Scand 1982;211:411-2.
Brodde OE, Kroemer HK. Drug-drug interactions of βadrenoceptor blockers. Arzneimittelforschung 2003;53:814-22.
Somer M, Kallio J, Pesonen U, Pyykkö K, Huupponen R, Scheinin M. Influence of hydroxychloroquine on the bioavailability of oral metoprolol. Br J Clin Pharmacol 2000;49:549-54.
Lancaster DL, Adio RA, Tai KK, Simooya OO, Broadhead GD, Tucker GT, et al
. Inhibition of metoprolol metabolism by chloroquine and other antimalarial drugs. J Pharm Pharmacol 1990;42:267-71.
Lennard MS, Tucker GT, Woods HF, Silas JH, Iyun AO. Stereoselective metabolism of metoprolol in Caucasians and Nigerians ± relationship to debrisoquine oxidation phenotype. Br J Clin Pharmacol 1989;27:613-6.
Rasool MF, Khalil F, Läer S. Predicting stereoselective disposition of carvedilol in adult and pediatric chronic heart failure patients by incorporating pathophysiological changes in organ blood flows – A physiologically based pharmacokinetic approach. Drug Metab Dispos 2016;44:1103-15.
Dean L. Propafenone therapy and CYP2D6 genotype. 2017 Apr 4. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kane MS, Kattman BL, et al
., editors. Medical Genetics Summaries. Bethesda (MD): National Center for Biotechnology Information (US); 2012.
Range FT, Hilker E, Breithardt G, Buerke B, Lebiedz P. Amiodarone-induced pulmonary toxicity – A fatal case report and literature review. Cardiovasc Drugs Ther 2013;27:247-54.
Miranda-Aquino T, Pérez-Topete SE, Ortega-Pantoja W, Gómez-Vázquez CA, Meneses-Pérez LG, González-Padilla C. Long QT syndrome secondary to drug interaction between hydroxychloroquine and amiodarone. Rev Mex Cardiol 2018;29:98-101.
Sathasivam S. Statin induced myotoxicity. Eur J Intern Med 2012;23:317-24.
Tomaszewski M, Stępień KM, Tomaszewska J, Czuczwar SJ. Statin-induced myopathies. Pharmacol Rep 2011;63:859-66.
Estes ML, Ewing-Wilson D, Chou SM, Mitsumoto H, Hanson M, Shirey E, et al
. Chloroquine neuromyotoxicity. Clinical and pathologic perspective. Am J Med 1987;82:447-55.
Migkos MP, Markatseli TE, Iliou C, Voulgari PV, Drosos AA. Effect of hydroxychloroquine on the lipid profile of patients with Sjögren syndrome. J Rheumatol 2014;41:902-8.
Bridges JM, Baldini M. Effect of quinidine and related compounds on uptake and release of serotonin by blood platelets. Nature 1966;210:1364-5.
Nosál' R, Jancinová V, Danihelová E. Chloroquine: A multipotent inhibitor of human platelets in vitro
. Thromb Res 2000;98:411-21.
Bertrand E, Cloitre B, Ticolat R, Bile RK, Gautier C, Abiyou GO, et al
. Antiaggregation action of chloroquine. Med Trop (Mars) 1990;50:143-6.
Winocour PD, Kinlough-Rathbone RL, Mustard JF. The effect of phospholipase inhibitor mepacrine on platelet aggregation, the platelet release reaction and fibrinogen binding to the platelet surface. Thromb Haemost 1981;45:257-62.
Carter AE, Eban R. Prevention of postoperative deep venous thrombosis in legs by orally administered hydroxychloroquine sulphate. Br Med J 1974;3:94-5.
Johnson R, Charnley J. Hydroxychloroquine in prophylaxis of pulmonary embolism following hip arthroplasty. Clin Orthop Relat Res 1979;144:174-7.
Petri M. Use of hydroxychloroquine to prevent thrombosis in systemic lupus erythematosus and in antiphospholipid antibody-positive patients. Curr Rheumatol Rep 2011;13:77-80.
Achuthan S, Ahluwalia J, Shafiq N, Bhalla A, Pareek A, Chandurkar N, et al
. Hydroxychloroquine's efficacy as an antiplatelet agent study in healthy volunteers: A proof of concept study. J Cardiovasc Pharmacol Ther 2015;20:174-80.
Lee CH, Franchi F, Angiolillo DJ. Clopidogrel drug interactions: A review of the evidence and clinical implications. Expert Opin Drug Metab Toxicol 2020;16:1079-96.