Optimizing the Use of Hydroxychloroquine in the Management of COVID-19 Given Its Pharmacological Profile

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Ahmed S. Ali
Mahran S. Abdel-Rahman
Riyadh S. Almalikil
Abir S. Mohamed
Khalid A. Alfaifi
Abdelbabgi El. Fadil
Nagla A. El-Shitany
Huda M. Alkreathy


After the global pandemic of the new coronavirus, its rapid spread and many victims, it is necessary to find an effective vaccine or drugs to overcome it. Most specialists consider that repositioning some medications is the best, fastest and most reliable option for treating patients with the new coronavirus without delay. One of these drugs was an old antimalarial drug, hydroxychloroquine. The current review aimed to explore its potential mechanism, as well as its pharmacokinetics and toxicity, in an attempt to suggest a treatment protocol for its use in treating the COVID-19 virus effectively and safely. This study reviewed the published references on the popular search engines as well as the reference books regarding the pharmacological effects of HCQ. The results of this study suggested the following practical guidelines to optimize HCQ efficacy and safety in the management of COVID-19. HQC should be used as early as possible, i.e., once the viral infection is confirmed or suspected. A loading dose is recommended to be given in 3-4 divided doses to minimize cardiac toxicity. Maintenance daily dose (divided into two doses), should be continued until complete remission. Precautions, drug-interaction, contraindications, variable metabolic pathways in the particular population should be considered. This study suggests more clinical trials regarding the use of HCQ in the management of early identified COVID-19 patients under close medical observation to minimize HCQ cardiac toxicity.  

Hydroxychloroquine, antimalarial drugs, COVID-19, SARS-CoV-2, clinical trials, pharmacokinetics, cardiac toxicity

Article Details

How to Cite
Ali, A. S., Abdel-Rahman, M. S., Almalikil, R. S., Mohamed, A. S., Alfaifi, K. A., Fadil, A. E., El-Shitany, N. A., & Alkreathy, H. M. (2020). Optimizing the Use of Hydroxychloroquine in the Management of COVID-19 Given Its Pharmacological Profile. Journal of Pharmaceutical Research International, 32(8), 29-43. https://doi.org/10.9734/jpri/2020/v32i830468
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Luo W, et al. Clinical pathology of critical patients with novel coronavirus pneumonia (COVID-19). Preprints. 2020;2020020407.

Ciotti M, et al. COVID-19 outbreak: An overview. Chemotherapy. 2020;1-9.

Wu YC, Chen CS, Chan YJ. The outbreak of COVID-19: An overview. Journal of the Chinese Medical Association. 2020;83(3):217.

Colson P, et al. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents. 2020;105932(10.1016).

Liu Z, et al. Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS‐CoV‐2. Journal of Medical Virology. 2020;92(6): 595-601.

Hamming I, et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland. 2004;203(2):631-637.

Xu H, et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. International Journal of Oral Science. 2020;12(1):1-5.

van Doremalen N, et al. Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. New England Journal of Medicine. 2020;382(16):1564-1567.

Control CFD, Prevention Coronavirus disease 2019 (COVID-19); 2020.

Available:https://www. cdc. gov/coronavirus/2019-ncov/hcp/therapeutic-options. html

D'Arienzo M, Coniglio A. Assessment of the SARS-CoV-2 basic reproduction number, R0, based on the early phase of COVID-19 outbreak in Italy. Biosafety and Health; 2020.

Viceconte G, Petrosillo N. COVID-19 R0: Magic number or conundrum? Infectious Disease Reports. 2020;12(1).

Leung C. The difference in the incubation period of 2019 novel coronavirus (SARS-CoV-2) infection between travelers to Hubei and nontravelers: The need for a longer quarantine period. Infection Control & Hospital Epidemiology. 2020; 1-3.

Zhou F, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. The lancet; 2020.

Sun P, et al. Clinical characteristics of 50466 patients with 2019-nCoV infection. medRxiv; 2020.

Cascella M, et al., Features, evaluation and treatment coronavirus (COVID-19), in Statpearls [Internet]. StatPearls Publishing; 2020.

Mackenzie JS, Smith DW. COVID-19: A novel zoonotic disease caused by a coronavirus from China: what we know and what we don’t. Microbiology Australia. 2020;41(1):45-50.

Rabaan AA, et al. SARS-CoV-2, SARS-CoV and MERS-CoV: A comparative overview. Le Infezioni in Medicina. 2020;2:174-184.

Yao X, et al. A pathological report of three COVID-19 cases by minimally invasive autopsies. Zhonghua bing li xue za zhi= Chinese Journal of Pathology. 2020;49:E009-E009.

Roberts DJ, Hall RI. Drug absorption, distribution, metabolism, and excretion considerations in critically ill adults. Expert Opinion on Drug Metabolism & Toxicology. 2013;9(9):1067-1084.

Chen WH, et al. The SARS-CoV-2 vaccine pipeline: An overview. Current Tropical Medicine Reports. 2020;1-4.

Barlow A, et al. Review of emerging pharmacotherapy for the treatment of coronavirus disease 2019. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy; 2020.

Zhou Y, et al. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discovery. 2020;6(1):1-18.

Riva L, et al. A Large-scale drug repositioning survey for SARS-CoV-2 Antivirals. bioRxiv; 2020.

Ciliberto G, Cardone L. Boosting the arsenal against COVID-19 through computational drug repurposing. Drug Discovery Today; 2020.

Glebov O. Understanding the cell biology of SARS-CoV-2 endocytosis for COVID-19 drug repurposing: Looking beyond chloroquine. 2020.

Rosa SGV, Santos WC. Clinical trials on drug repositioning for COVID-19 treatment. Revista Panamericana de Salud Pública. 2020;44:e40.

Sanders JM, et al. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): A review. Jama; 2020.

Tobaiqy M, et al. Therapeutic Management of COVID-19 Patients: A systematic review. Infection Prevention in Practice. 2020;100061.

Gautret P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents. 2020; 105949.

D’Alessandro S, et al. The Use of Antimalarial Drugs against Viral Infection. Microorganisms, 2020;8(1):85.

Plantone D, Koudriavtseva T. Current and future use of chloroquine and hydroxychloroquine in infectious, immune, neoplastic, and neurological diseases: A mini-review. Clinical Drug Investigation. 2018;38(8):653-671.

Mégarbane B. Chloroquine and hydroxychloroquine to treat COVID-19: Between hope and caution. Clin Toxicol (Phila). 2020;1-2.

Jacobs JP, et al. Extracorporeal membrane oxygenation in the treatment of severe pulmonary and cardiac compromise in coronavirus disease 2019: Experience with 32 patients. Asaio Journal; 2020.

Hinton D, Food and D. Administration, FDA Emergency use authorization (EUA) of chloroquine and hydroxychloroquine. 28 Mar 2020; 2020.

Rosa SGV, Santos WC. Clinical trials on drug repositioning for COVID-19 treatment. Revista Panamericana de Salud Pública. 2020;44.

Ben-Zvi I, et al. Hydroxychloroquine: From Malaria to autoimmunity. Clinical Reviews in Allergy & Immunology. 2011;42:145-53.

Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: Implications for rheumatology. Nature Reviews Rheumatology. 2020;1-12.

Silva JCD, et al. Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients. Clinics. 2013;68(6):766-771.

Hughes G. Hydroxychloroquine: An update. Lupus. 2018;27(9):1402-1403.

Ye Q, Wang B, Mao J. The pathogenesis and treatment of the Cytokine Storm'in COVID-19. The Journal of Infection; 2020.

Zhou D, Dai SM, Tong Q. COVID-19: A recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. Journal of Antimicrobial Chemotherapy; 2020.

Johnson R, Charnley J. Hydroxychloroquine in prophylaxis of pulmonary embolism following hip arthroplasty. Clinical Orthopaedics and Related Research. 1979;144:174-177.

Chen J, et al. Findings of acute pulmonary embolism in COVID-19 patients. Available at SSRN 3548771; 2020.

Sundelin SP, Terman A. Different effects of chloroquine and hydroxychloroquine on lysosomal function in cultured retinal pigment epithelial cells. Apmis. 2002;110(6):481-489.

Burkard C, et al. Coronavirus cell entry occurs through the endo-/lysosomal pathway in a proteolysis-dependent manner. PLoS Pathogens. 2014;10(11).

Al‐Bari MAA. Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases. Pharmacology Research & Perspectives. 2017; 5(1).

Savarino A, et al. Effects of chloroquine on viral infections: An old drug against today's diseases. The Lancet Infectious Diseases. 2003;3(11):722-727.

Shittu MO, Afolami OI. Improving the efficacy of chloroquine and hydroxychloroquine against SARS-CoV-2 may require zinc additives-A better synergy for future COVID-19 clinical trials. Le Infezioni in Medicina. 2020;28(2):192-197.

Hu TY, Frieman M, Wolfram J. Insights from nanomedicine into chloroquine efficacy against COVID-19. Nature Nanotechnology. 2020;15(4):247-249.

Vincent MJ, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virology Journal. 2005;2(1):69.

Yao X, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical Infectious Diseases; 2020.

Yan Y, et al. Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model. Cell Research. 2013;23(2):300-302.

Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Research. Elsevier BV. 2020;177:104762.

Sahraei Z, et al. Aminoquinolines against coronavirus disease 2019 (COVID-19): chloroquine or hydroxychloroquine. Int J Antimicrob Agents. 2020;105945.

Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in the treatment of COVID-19 associated pneumonia in clinical studies. Bioscience trends; 2020.

Gautret P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020;105949.

Sarma P, et al. Virological and Clinical Cure in Covid-19 Patients Treated with hydroxychloroquine: A systematic review and meta-analysis. J Med Virol; 2020.

Molina JM, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect; 2020.

Molina J, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect. 2020;30085-8.

Mercuro NJ, et al. Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiol; 2020.

Pastick KA, et al. Review: Hydroxychloroquine and chloroquine for treatment of SARS-CoV-2 (COVID-19). Open Forum Infectious Diseases. 2020;7(4).

FDA, Fact sheet for health care providers Emergency Use Authorization (EUA) of hydroxychloroquine sulfate supplied from the strategic national stockpile for treatment of Covid-19 in certain hospitalized patients; 2020.

Schroeder R, Gerber J. Chloroquine and hydroxychloroquine binding to melanin: Some possible consequences for pathologies. Toxicology Reports. 2014;1:963-968.

Tett S, Cutler D, Day R. Antimalarials in rheumatic diseases. Bailliere's Clinical Rheumatology. 1990;4(3):467-489.

Al-Bari MAA. Chloroquine analogues in drug discovery: New directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. Journal of Antimicrobial Chemotherapy. 2015;70(6):1608-1621.

Furst DE. Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases. Lupus. 1996;5(Suppl 1):S11-5.

Costedoat‐Chalumeau N, et al. Evidence of transplacental passage of hydroxychloroquine in humans. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 2002;46(4):1123-1124.

McChesney EW, Banks Jr WF, Fabian RJ. Tissue distribution of chloroquine, hydroxychloroquine, and desethylchloroquine in the rat. Toxicology and Applied Pharmacology. 1967;10(3):501-513.

Browning DJ. Pharmacology of chloroquine and hydroxychloroquine, in Hydroxychloroquine and Chloroquine Retinopathy. 2014;35-63.

Hypoglycemia due to HCQ 2020.pdf

Po HN, Senozan N. The Henderson-Hasselbalch equation: its history and limitations. Journal of Chemical Education. 2001;78(11):1499.

Arnold SL, Buckner F. Hydroxychloroquine for treatment of SARS‐CoV‐2 infection? Improving our confidence in a model‐based approach to dose selection. Clinical and Translational Science; 2020.

Kang JS, Lee MH. Overview of therapeutic drug monitoring. The Korean Journal of Internal Medicine. 2009;24(1):1.

Durcan L, et al. Hydroxychloroquine blood levels in systemic lupus erythematosus: Clarifying dosing controversies and improving adherence. The Journal of Rheumatology. 2015;42(11): 2092-2097.

Perinel S, et al. Towards optimization of hydroxychloroquine dosing in intensive care unit COVID-19 Patients. Clinical Infectious Diseases; 2020.

Mhlwatika Z, Aderibigbe BA. Polymeric nanocarriers for the delivery of antimalarials. Molecules (Basel, Switzerland). 2018;23(10):2527.

Gouveia VM, et al. Non-biologic nano delivery therapies for rheumatoid arthritis. Journal of Biomedical Nanotechnology. 2015;11(10):1701-1721.

Luzzi GA, Peto TE. Adverse effects of antimalarials. An update. Drug Saf. 1993;8(4):295-311.

Rismanbaf A, Zarei S. Liver and Kidney Injuries in COVID-19 and Their Effects on Drug Therapy; a Letter to Editor. Archives of Academic Emergency Medicine. 2020;8(1):e17-e17.

Cascella M, et al. Features, evaluation and treatment coronavirus (COVID-19), in StatPearls. StatPearls Publishing; StatPearls Publishing LLC.: Treasure Island (FL); 2020.

Cardiology ACO. Ventricular arrhythmia risk due to hydroxychloroquine-Azithromycin Treatment For COVID-19; 2020.

Chen CY, Wang FL, Lin CC. Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia. Clin Toxicol (Phila). 2006; 44(2):173-5.

Kapoor 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 and Electrophysiology Journal; 2020.

Yam J, Kwok A. Ocular toxicity of hydroxychloroquine. Hong Kong Medical Journal. 2006;12(4):294.

Yam JC, Kwok AK. Ocular toxicity of hydroxychloroquine. Hong Kong Med J. 2006;12(4):294-304.

Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol. 2014;132(12):1453-60.

El-Solia A, Al-Otaibi K, Ai-Hwiesh AK. Hydroxychloroquine-induced hypoglycaemia in non-diabetic renal patient on peritoneal dialysis. Case Reports; 2018.

Wolfe MS, Cordero JF. Safety of chloroquine in chemosuppression of malaria during pregnancy. Br Med J (Clin Res Ed). 1985;290(6480):1466-7.

Costedoat-Chalumeau N, et al. Safety of hydroxychloroquine in pregnant patients with connective tissue diseases. Review of the literature. Autoimmun Rev. 2005;4(2): 111-5.

Costedoat-Chalumeau N, et al. Safety of hydroxychloroquine in pregnant patients with connective tissue diseases. Review of the Literature. Autoimmunity Reviews. 2005;4(2):111-115.

Peng W, et al. Breast milk concentration of hydroxychloroquine in Chinese lactating women with connective tissue diseases. Eur J Clin Pharmacol. 2019;75(11):1547-1553.

Hämmerlein A, Derendorf H, Lowenthal DT. Pharmacokinetic and pharmacodynamic changes in the elderly. Clinical Pharmacokinetics. 1998;35(1):49-64.

Cavagna L, et al. [Early electroretinografic changes in elderly RA patients treated with hydroxychloroquine]. Reumatismo. 2002; 54(3):226-31.

Griese M, et al. Prospective evaluation of hydroxychloroquine in pediatric interstitial lung diseases: Study protocol for an investigator-initiated, randomized controlled, parallel-group clinical trial. Trials. 2020;21(1):307-307.

Liccioli G, et al. The first pediatric case of acute generalized exanthematous pustulosis caused by hydroxychloroquine. Pharmacology. 2019;104(1-2):57-59.

Bourke L, et al. Hydroxychloroquine protects against cardiac ischaemia/reperfusion injury in vivo via enhancement of ERK1/2 Phosphorylation. PloS One. 2015;10(12).

Fang H, et al. Dual role of chloroquine in liver ischemia reperfusion injury: reduction of liver damage in early phase, but aggravation in late phase. Cell Death & Disease. 2013;4(6):e694-e694.

Todorovic Z, et al. Acute pretreatment with chloroquine attenuates renal I/R injury in rats. PLoS One. 2014;9(3).

Tang TT, et al. Hydroxychloroquine attenuates renal ischemia/reperfusion injury by inhibiting cathepsin mediated NLRP3 inflammasome activation. Cell Death & Disease. 2018;9(3):351-351.

Adedoyin A, et al. Chloroquine modulation of specific metabolizing enzymes activities: investigation with selective five drug cocktail. British Journal of Clinical Pharmacology. 1998;46(3):215-219.

Eichelbaum M, Gross A. The genetic polymorphism of debrisoquine/sparteine metabolism—clinical aspects. Pharmacology & Therapeutics. 1990;46(3): 377-394.

Chen Z, et al. Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers. British Journal of Clinical Pharmacology. 1991;31(4):381-390.

Otton SV, et al. CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone. Clinical Pharmacology & Therapeutics. 1993; 54(5):463-472.

Yue Q, et al. Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine. British Journal of Clinical Pharmacology. 1991;31(6):635-642.

Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14(1):72-73.

Chen J, et al. Clinical progression of patients with COVID-19 in Shanghai, China. Journal of Infection; 2020.