Hydroxychloroquine and Chloroquine: Past, Present…Future?


High-potential for toxicity remains for potential COVID-19 medication.



Currently, there is no U.S. Food and Drug Administration approved medications or best available treatment for COVID-19. The management mainly involves meticulous infection-control for prevention and aggressive supportive care. Given the rapid escalating pandemic, healthcare providers have been administering experimental medications based on in-vitro and anecdotal clinical data in the hopes they will prove effective for hospitalized patients.[1]

The antimalarial drugs, chloroquine and hydroxychloroquine, have been widely advertised as a potential treatment, despite the lack of peer-reviewed high-quality studies.[2] Just a few days after media coverage, one fatality and one hospitalization were reported in the U.S. after ingestion of anti-parasitic fish powder containing chloroquine phosphate for prophylaxis[3] and three hospitalizations of poisonings after self-treatment were reported in Lagos, Nigeria.[4]

On March 28, the FDA issued an emergency-use-authorization, allowing for the distribution of the antimalarial drugs (chloroquine and hydroxychloroquine) from the Strategic National Stockpile to hospitals.[5] The surge in stockpiling and prescription demand by hospitals and providers have already created a national shortage in the U.S.[6] With the world’s renewed interest in chloroquine, clinicians need to be cognizant of the potential for significant toxicity in the midst of the COVID-19 pandemic.



Chloroquine’s claim to fame as an anti-malarial earned its designation on the World Health Organization’s list of essential medicines, despite its narrow-therapeutic index. For decades, it was a front-line drug for the treatment and prophylaxis of malaria, but its use gradually declined due to chloroquine-resistant Plasmodium falciparum.

Hydroxychloroquine, chloroquine’s synthetic analog, is more commonly used today because of its reduced toxicity (about 40%) without an proportionate loss of therapeutic activity.[6] Other off-label uses of hydroxychloroquine include treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus.

The clinical studies on chloroquine toxicity and its management were largely derived from intentional ingestions from France. In the 1980s, France experienced a cluster of poisonings owing to the book “Suicide Mode d’Emploi” promoting chloroquine overdose as a means of suicide.[9 – 11] However since the 1970s, chloroquine has been one of the most common causes of overdoses in Africa, Asia and the South Pacific regions, since it is easily accessible without a prescription at a relatively low cost.[7,8]


Rationale for COVID-19 (Figure 1)[12, 13]

  • Blocks virus infection by increasing endosomal & lysosomal pH, altering the conditions required for virus-to-host cell fusion.
  • Interferes with glycosylation of ACE2-receptors on the virus, preventing virus-to-host cell fusion.
  • Autophagy inhibitor, which modulates acidification of endosomes -> inhibiting formation of autophagosomes -> preventing virus-to-host cell fusion.
  • Inhibits virus replication via reduction of mitogen-activated protein (MAP) kinase activation.
    • Alters M-protein maturation and interferes with virion assembly and budding.
  • Immune-modulating activity contributing to anti-inflammatory response, possibly reduction of cytokine storm.
    • Inhibits locomotion of neutrophils and chemotaxis of eosinophils.
    • Impairs complement-dependent antigen-antibody reactions.

Figure 1. Schematic representation of the possible effects of chloroquine on SARS-CoV-2 replication cycle. Obtained directly from Devaux et al. 2020.

figure 1


Where is the evidence for COVID-19 treatment?

Please see this emDocs post for further information on these medications for COVID-19.  The current literature has many limitations including lack of comparator groups, small sample sizes, and significant biases.

Table 1. Characteristics of literature studying the efficacy and safety of chloroquine or hydroxychloroquine in patients with COVID-19. CQ = chloroquine, HCQ = hydroxychloroquine, AZT = azithromycin, d = days, PNA = pneumonia, yrs = years, sx = symptoms

table 1



  • High volume of distribution (Vd) & mildly protein bound.
  • Exhibits slow distribution from blood compartment to central compartment, resulting in transiently high whole blood concentrations shortly after ingestion.
  • Absorption is rapid and almost complete with high oral bioavailability.
  • Metabolism: Hepatic; to its main metabolite desethylchloroquine.
  • Oral: Time to peak serum concentration (Tmax) = 1.5 – 2 hours.
  • Oral: Half-life (T1/2) = 3 – 5 days.
  • Excretion: Renal; theoretically enhanced with urinary acidification.


  • High Vd & mildly protein bound (mostly to albumin).
  • Absorption: Incomplete and variable ranging from 25-100%.
  • Metabolism: Hepatic to active metabolites bidesethylchloroquine, desethylhydroxychloroquine, & desethylchloroquine.
  • Oral: T1/2= 40 days
  • Excretion: renally, theoretically enhanced with urinary acidification.

Pathophysiology [14-23]

  • Acts as a Vaughan Williams Class Ia antidysrhythmic with “Quinidine-like” effect.
    • Sodium channel blockade
      • May lead to widened QRS-interval and at risk for developing tachydysrhythmias.
    • Potassium channel blockade
      • May lead to prolonged QT-interval and at risk for developing Torsade de pointes (TdP).
      • Increased insulin release leading to hypoglycemia and hypokalemia.
      • Hypokalemia results from potassium shift from the extracellular to intracellular compartments.
    • Overall: Intermediate prolongation of the action potential, negative inotropy (Figure 2).

Figure 2. Effect of Class 1a antidysrhythmics on the action potential. Red arrow showing right-ward shift at phase 0 of depolarization.

figure 2

  • Drug binds to melanin in the retinal pigment epithelium (RPE), causing damage to the macular cones outside the fovea. Characteristically, begins with photoreceptor thinning appearing as a parafoveal ring with progression to a visible bull’s eye retinopathy (Figure 3C) when the RPE becomes damaged.[21]

Figure 3. Comparison of normal fundus and hydroxychloroquine retinopathy patterns via ultra-widefield autofluorescence. Obtained directly from Melles et al. (2015).[21] Legend for images. A: Normal, B: Parafoveal pattern (i.e. Bull’s eye pattern), C: Mixed pattern, and D: pericentral pattern.

figure 3

Proposed Experimental Dosages for COVID-19 

  • PO Hydroxychloroquine sulfate
    • 200 mg TID x 10 days.[16]
    • 100-200 mg BID x 5-14 days.[17]
    • 400 mg daily x 5 days.[17, 18]
    • 400 mg BID on day 1, then 200 mg BID on days 2-5.[19]
  • PO Chloroquine phosphate
    • 500 mg BID x 10 days.[17]
    • 500 mg BID x 7 days (adults > 50 kg); 500 mg BID on days 1-2, then 500 mg daily on days 3-7 (for adults < 50 kg).[20]
    • Initially 1000 mg then 500 mg 12 hours later on day 1, then 500 mg BID on days 2-5.[17]

Therapeutic Dosing: Adverse effects [14, 24]

  • Gastrointestinal: May cause hypersensitivity hepatitis with increased liver-function enzymes, nausea/vomiting and abdominal cramps/pain.
  • Hematologic: Hemolytic anemia in glucose-6-phophate dehydrogenase (G6PD) deficiency patients, agranulocytosis, and thrombocytopenia.
  • Ocular/Ear disorders: Chronic and/or high-dose therapy has been associated with retinopathy, sensorineural deafness and tinnitus.
  • Musculoskeletal: Rarely, muscular weakness or myopathy.
  • Metabolic: Hypoglycemia.
  • Immunologic: Hypersensitivity reactions such as myocarditis.
  • CNS: Increased risk of seizures in those with epilepsy (especially when used concurrently with mefloquine).

Diagnostics[19, 20, 23]

  • Before starting therapeutic treatment, consider the possible benefits, risks, and contraindications:
    • Asian race may increase risk for peripheral retinopathy.
    • Kidney and/or liver disease may predispose to toxicity.
    • History of G6PD-deficiency.
    • Presence of retinal or visual field changes of any etiology.
    • History of cardiac disease, uncorrected hypokalemia and/or hypomagnesemia, or bradycardia (HR < 50 bpm).
    • Drug-drug interactions
      • Concomitant QT-prolonging medications.
      • Hydroxychloroquine and chloroquine are potent CYP2D6 inhibitors (i.e. may raise metoprolol levels).

Clinical Manifestations of Toxicity

Severe chloroquine poisoning is associated with:[14]

  • Ingestions of > 5 grams for adults and > 1 gram for children
  • Systolic Blood Pressure (SBP) < 80 mm Hg
  • QRS-Interval > 120 msec
  • Ventricular Fibrillation
  • Hypokalemia

Signs and Symptoms[14]

  • Time to onset of symptoms is about 1-3 hours post-ingestion.
  • Respiratory depression is common.
    • May progress rapidly to apnea, hypotension, and cardiovascular (CV) collapse.
  • EKG abnormalities: Widened QRS-interval, AV block, ST-T wave depressions, U waves, QT-interval prolongation, and TdP.
  • Neurological: CNS depression, dizziness, headache, seizures, and transient parkinsonism.
  • Ophthalmic: Peripheral retinopathy and loss of color vision is associated with chronic use.


  1. a) Gastrointestinal Decontamination:
  • Be cautious with administering 1 g/kg of PO activated charcoal because severe toxicity is associated with rapid CNS depression, seizures, and CV collapse. These patients are high-risk for fatal-aspiration charcoal pneumonitis.
  • Try to estimate the dose ingested!
    • If life-threatening ingestion of > 5 grams in adult or > 1 gram in child, consider protecting the airway with early intubation and orogastric lavage.
  1. b) Early aggressive supportive care[14, 25, 26, 31]
  • Serial blood glucose measurements for monitoring hypoglycemia
  • For severe toxicity (i.e. apneic, hypotension, cardiovascular collapse, dysrhythmias), consider:
    • EARLY endotracheal intubation and mechanical ventilation (Note: avoid barbiturates for induction as may cause sudden cardiac arrest).[10]
    • High-dose IV epinephrine at 0.25 mcg/kg/min with increasing by 0.25 mcg/kg/min until SBP > 90 mm Hg or MAP > 65 mm Hg. (normal dose range: 1-10 mcg/min).
      • Note: Epinephrine may exacerbate pre-existing hyperkalemia.
    • High-dose IV diazepam at 2 mg/kg over 30 minutes then 1-2mg/kg/day for 2-4 days.
      • Note: This may exhaust your hospital’s supply of diazepam.

Note: Combining early mechanical ventilation with administration of high-dose diazepam and high-dose epinephrine showed potential benefit with less cardiovascular toxicity.[10]

  • Diazepam is believed to have a central antagonistic effect, anticonvulsant effect, antidysrhythmic effect and interaction inverse to chloroquine/hydroxychloroquine, and decrease in chloroquine & hydroxychloroquine induced-vasodilation.
  • Watch out for the knee-jerk reflex for treating a widened-QRS!
    • Sodium bicarbonate treatment is controversial since it may exacerbate associated severe-hypokalemia.
    • Consider giving 1-2 mEq/kg IVP NaHCO3in combination with evaluating the patient’s degree of cardiotoxicity and hypokalemia.
  • Should I replete potassium? Not as straightforward…
    • Potassium supplementation is reasonable for severe hypokalemia (< 1.9 mEq/L) to prevent worsening QT-prolongation and precipitation of TdP.
    • If supplementing potassium, it is critical to anticipate rebound hyperkalemia as toxicity resolves with the redistribution of potassium from the intracellular space to extracellular.
  • Any role for Intralipids? 
    • Theoretically, intralipids should act as an “lipid-sink” since chloroquine is lipophilic. However, there is no evidence supporting intralipids in chloroquine toxicity.
  • What are the indications for extracorporeal membrane oxygenation (ECMO)?
  • If treatment is refractory to standard supportive care and the above therapies (i.e. escalation of epinephrine drip rate to > 3 mg/hr and presence of end-organ failure) then consider veno-arterial (VA) ECMO (observed in case studies to have better outcomes).


  • Chloroquine and Hydroxychloroquine are being used experimentally in hospitalized patients with COVID-19 infections.
  • As information touting both medications’ efficacy becomes widespread, there is a high-potential for toxicity from supratherapeutic ingestions, whether through self-medication, intentional, unintentional, or exploratory means.
  • In acute overdoses, toxicity includes hypokalemia and hypoglycemia with rapid CNS depression and cardiovascular collapse due to dysrhythmias.
  • Treatment includes GI decontamination when appropriate, early intubation with high-dose epinephrine and high-dose diazepam. Patients with refractory toxicity may be treated with VA-ECMO.


  1. World Health Organization. Coronavirus disease (COVID-19) outbreak. World Health Organization website. https://www.who.int/emergencies/diseases/novel-coronavirus-2019. Updated March 19, 2020. Accessed March 19, 2020.
  2. Cohen M. Trump spreads optimism for potential coronavirus drugs while public health officials cautiously wait for proof. CNN Politics Website. https://www.cnn.com/2020/04/01/politics/trump-chloroquine-drugs-coronavirus-treatment/index.html. Updated April 1, 2020. Accessed April 1, 2020.
  3. Waldrop T, Alsup D, McLaughlin EC. Fearing coronavirus, Arizona man dies after taking a form of chloroquine used to treat aquariums. CNN Health Website. https://www.cnn.com/2020/03/23/health/arizona-coronavirus-chloroquine-death/index.html. Updated March 25, 2020. Accessed April 1, 2020.
  4. Busari S, Adebayo B. Nigeria records chloroquine poisoning after Trump endorses it for coronavirus treatment. CNN World Website. https://www.cnn.com/2020/03/23/africa/chloroquine-trump-nigeria-intl/index.html. Updated March 23, 2020. Accessed April 1, 2020.
  5. US FDA Administration. Emergency Use Authorization. US FDA Administration Website. https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#covidtherapeutics. Updated March 31, 2020. Accessed April 1, 2020.
  6. Wheeler M. Current Drug Shortages: Hydroxychloroquine Sulfate Tablets. American Society of Hospital Pharmacists website. https://www.ashp.org/Drug-Shortages/Current-Shortages/Drug-Shortage-Detail.aspx?id=646. Updated March 19, 2020. Accessed March 23, 2020.
  7. McChesney EW. Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate. Am J Med. 1983;75(1A):11–18. doi:10.1016/0002-9343(83)91265-2.
  8. Ball DE, Tagwireyi D, Nhachi CF. Chloroquine poisoning in Zimbabwe: a toxicoepidemiological study. J Appl Toxicol. 2002;22(5):311–315. doi:10.1002/jat.864.
  9. Queen HF, Tapfumaneyi C, Lewis RJ. The rising incidence of serious chloroquine overdose in Harare, Zimbabwe: emergency department surveillance in the developing world. Trop Doct. 1999;29(3):139–141. doi:10.1177/004947559902900305.
  10. Meeran K, Jacobs MG. Chloroquine poisoning. Rapidly fatal without treatment. BMJ. 1993;307(6895):49-50. doi: 10.1136/bmj.307.6895.49.
  11. Riou B, Barriot P, Rimailho A, Baud FJ. Treatment of severe chloroquine poisoning. N Engl J Med. 1988;318(1):1–6. doi:10.1056/NEJM198801073180101.
  12. Clemessy JL, Taboulet P, Hoffman JR, et al. Treatment of acute chloroquine poisoning: a 5-year experience. Crit Care Med. 1996;24(7):1189–1195. doi:10.1097/00003246-199607000-00021.
  13. Wang M, Cao R, Zhang L. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020: 30, 269–271. https://doi.org/10.1038/s41422-020-0282-0.
  14. Yan, Y., Zou, Z., Sun, Y. et al. Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model. Cell Res. 2013;23:300–302 https://doi.org/10.1038/cr.2012.165
  15. Barry J. Antimalarials. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. eds. Goldfrank’s Toxicologic Emergencies, 11e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com/content.aspx?bookid=2569&sectionid=210273082. Accessed March 23, 2020.
  16. Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. [published online ahead of print, 2020 Mar 31]. medRxiv. 2020;3.22.20040758. doi: 10.1101/2020.03.22.20040758
  17. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. [In Press, Journal Pre-proof, Available online 20 March 2020] Internaitonal Journal of Antimicrobial agents. 2020. doi.org/10.1016/j.ijantimicag.2020.105949.
  18. Cortegiani A, Ingoglia G, Ippolito M et al. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care. 2020; (PubMed 32173110) (DOI 10.1016/j.jcrc.2020.03.005).
  19. Study to evaluate efficacy and safety of hydroxychloroquine for treatment of pneumonia caused by 2019-nCoV (HC-nCoV). NCT04261517. https://www.clinicaltrials.gov/ct2/show/NCT04261517.
  20. Yao X, Ye F, Zhang M et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syn-drome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020; In Press. (PubMed 32150618) (DOI 10.1093/cid/ciaa237).
  21. National Health Commission (NHC) & State Administration of Traditional Chinese Medicine (Trial Version 7). Diagnosis and treatment protocol for novel coronavirus pneumonia. (http://busan. china-consulate.org/chn/zt/4/P020200310548447287942.pdf).
  22. Melles RB, Marmor MF. Pericentral retinopathy and racial differences in hydroxychloroquine toxicity. Ophthalmology. 2015;122(1):110–116. doi:10.1016/j.ophtha.2014.07.018.
  23. Stokkermans TJ, Trichonas G. Chloroquine And Hydroxychloroquine Toxicity. NCBI Website. https://www.ncbi.nlm.nih.gov/books/NBK537086/. Updated Jun 4 2019. Accessed April 1, 2020.
  24. Marcucci C, Sandson NB, DeCaro MV, et al. Summary of Chloroquine and Hydroxychloroquine Drug-Drug Interactions. APSF Website. https://www.apsf.org/ddi/summary-of-chloroquine-and-hydroxychloroquine-drug-drug-interactions/. Updated March 27th, 2020. Accessed April 1, 2020.
  25. US FDA. ARALEN® CHLOROQUINE PHOSPHATE, USP. US FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/006002s045lbl.pdf. Updated October 2018. Accessed April 1, 2020.
  26. McBeth PB, Missirlis PI, Brar H, Dhingra V. Novel Therapies for Myocardial Irritability following Extreme Hydroxychloroquine Toxicity. Case Rep Emerg Med. 2015;2015:692948. doi:10.1155/2015/692948.
  27. Gunja N, Roberts D, McCoubrie D, et al. Survival after massive hydroxychloroquine overdose. Anaesth Intensive Care. 2009;37(1):130–133. doi:10.1177/0310057X0903700112.



Vincent R. Lee, MD (@vinleetox) is a Senior Medical Toxicology Fellow in the Department of Emergency Medicine at Northwell Health in Manhasset, New York. He trained in emergency medicine at Morristown Medical Center in Morristown, New Jersey.

Joshua N. Nogar, MD is the Medical Toxicology Fellowship Program Director at Northwell Health and is an emergency medicine physician at Long Island Jewish Medical Center and North Shore University Hospital of Northwell Health in Manhasset, New York.


  1. Char Glenn, MD on

    Thank you for all the good details in your article.
    Question– can you help me understand this?:
    You mention hypomagnesemia as a risk factor under diagnostics.
    I understand that in the ER you can probably only get a serum magnesium, not an RBC magnesium, due to turn-around-time, and serum level is not perfect.
    I don’t see a mention of magnesium for helping prevent, or treat, prolonged QT, dysrhythmmia, or torsades.
    Since the treatment for Torsades is iv magnesium and since sufficient magnesium helps maintain
    a person’s potassium level, I am puzzled by the fact that every article I have seen on
    the problems of CQ and HCQ have not mentioned magnesium.

    (Exception– there was one early treatment article that did say they monitored the potassium and magnesium levels along with the EKG and did not have prolonged QT or arrhythmmia in treated patients. But not one other paper has addressed this.)

    • Char Glenn, MD on

      So the above would be my comment to the authors.
      But, as you are looking into the data on HCQ and CQ, have you noticed the magnesium issue.
      And other question not always answered is the difference between starting a patient at first symptoms, vs starting in hospital or in ICU.

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