Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medication. Chloroquine is also occasionally used for amebiasis that is occurring outside the intestines, rheumatoid arthritis, and lupus erythematosus. While it has not been formally studied in pregnancy, it appears safe. It was studied to treat COVID-19 early in the pandemic, but these studies were largely halted in the summer of 2020, and is not recommended for this purpose. It is taken by mouth.
Common side effects include muscle problems, loss of appetite, diarrhea, and skin rash. Serious side effects include problems with vision, muscle damage, seizures, and low blood cell levels. Chloroquine is a member of the drug class 4-aminoquinoline. As an antimalarial, it works against the asexual form of the malaria parasite in the stage of its life cycle within the red blood cell. How it works in rheumatoid arthritis and lupus erythematosus is unclear.
Distribution of malaria in the world: ♦ Elevated occurrence of chloroquine- or multi-resistant malaria ♦ Occurrence of chloroquine-resistant malaria ♦ No Plasmodium falciparum or chloroquine-resistance ♦ No malaria
In treatment of amoebic liver abscess, chloroquine may be used instead of or in addition to other medications in the event of failure of improvement with metronidazole or another nitroimidazole within 5 days or intolerance to metronidazole or a nitroimidazole.
Chloroquine-induced itching is very common among black Africans (70%), but much less common in other races. It increases with age, and is so severe as to stop compliance with drug therapy. It is increased during malaria fever; its severity is correlated to the malaria parasite load in blood. Some evidence indicates it has a genetic basis and is related to chloroquine action with opiate receptors centrally or peripherally.
Unpleasant metallic taste
This could be avoided by "taste-masked and controlled release" formulations such as multiple emulsions.
This manifests itself as either conduction disturbances (bundle-branch block, atrioventricular block) or Cardiomyopathy – often with hypertrophy, restrictive physiology, and congestive heart failure. The changes may be irreversible. Only two cases have been reported requiring heart transplantation, suggesting this particular risk is very low. Electron microscopy of cardiac biopsies show pathognomonic cytoplasmic inclusion bodies.
Chloroquine has not been shown to have any harmful effects on the fetus when used in the recommended doses for malarial prophylaxis. Small amounts of chloroquine are excreted in the breast milk of lactating women. However, this drug can be safely prescribed to infants, the effects are not harmful. Studies with mice show that radioactively tagged chloroquine passed through the placenta rapidly and accumulated in the fetal eyes which remained present five months after the drug was cleared from the rest of the body. Women who are pregnant or planning on getting pregnant are still advised against traveling to malaria-risk regions.
There is not enough evidence to determine whether chloroquine is safe to be given to people aged 65 and older. Since it is cleared by the kidneys, toxicity should be monitored carefully in people with poor kidney functions.
While the usual dose of chloroquine used in treatment is 10 mg/kg, toxicity begins to occur at 20 mg/kg, and death may occur at 30 mg/kg. In children as little as a single tablet can cause problems.
Absorption of chloroquine is rapid and primarily happens in the gastrointestinal tract. It is widely distributed in body tissues. Protein binding in plasma ranges from 46% to 79%. Its metabolism is partially hepatic, giving rise to its main metabolite, desethylchloroquine. Its excretion is ≥50% as unchanged drug in urine, where acidification of urine increases its elimination. It has a very high volume of distribution, as it diffuses into the body's adipose tissue.
Hemozoin formation in P. falciparum: many antimalarials are strong inhibitors of hemozoin crystal growth.
The lysosomotropic character of chloroquine is believed to account for much of its antimalarial activity; the drug concentrates in the acidic food vacuole of the parasite and interferes with essential processes. Its lysosomotropic properties further allow for its use for in vitro experiments pertaining to intracellular lipid related diseases, autophagy, and apoptosis.
Inside red blood cells, the malarial parasite, which is then in its asexual lifecycle stage, must degrade hemoglobin to acquire essential amino acids, which the parasite requires to construct its own protein and for energy metabolism. Digestion is carried out in a vacuole of the parasitic cell.
Hemoglobin is composed of a protein unit (digested by the parasite) and a heme unit (not used by the parasite). During this process, the parasite releases the toxic and soluble molecule heme. The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the parasite biocrystallizes heme to form hemozoin, a nontoxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals.
Chloroquine enters the red blood cell by simple diffusion, inhibiting the parasite cell and digestive vacuole. Chloroquine then becomes protonated (to CQ2+), as the digestive vacuole is known to be acidic (pH 4.7); chloroquine then cannot leave by diffusion. Chloroquine caps hemozoin molecules to prevent further biocrystallization of heme, thus leading to heme buildup. Chloroquine binds to heme (or FP) to form the FP-chloroquine complex; this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic FP-chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion. Parasites that do not form hemozoin are therefore resistant to chloroquine.
Resistance in malaria
Since the first documentation of P. falciparum chloroquine resistance in the 1950s, resistant strains have appeared throughout East and West Africa, Southeast Asia, and South America. The effectiveness of chloroquine against P. falciparum has declined as resistant strains of the parasite evolved.
Resistant parasites are able to rapidly remove chloroquine from the digestive vacuole using a transmembrane pump. Chloroquine-resistant parasites pump chloroquine out at 40 times the rate of chloroquine-sensitive parasites; the pump is coded by the P. falciparum chloroquine resistance transporter (PfCRT) gene. The natural function of the chloroquine pump is to transport peptides: mutations to the pump that allow it to pump chloroquine out impairs its function as a peptide pump and comes at a cost to the parasite, making it less fit.
Resistant parasites also frequently have mutation in the ABC transporterP. falciparum multidrug resistance (PfMDR1) gene, although these mutations are thought to be of secondary importance compared to PfCRT. An altered chloroquine-transporter protein, CG2 has been associated with chloroquine resistance, but other mechanisms of resistance also appear to be involved.
Chloroquine has antiviral effects against some viruses. It increases late endosomal and lysosomal pH, resulting in impaired release of the virus from the endosome or lysosome – release of the virus requires a low pH. The virus is therefore unable to release its genetic material into the cell and replicate.
In Peru, the indigenous people extracted the bark of the Cinchona tree (Cinchona officinalis) and used the extract to fight chills and fever in the seventeenth century. In 1633 this herbal medicine was introduced in Europe, where it was given the same use and also began to be used against malaria. The quinoline antimalarial drug quinine was isolated from the extract in 1820.: 130–131
After World War I, the German government sought alternatives to quinine. Chloroquine, a synthetic analogue with the same mechanism of action was discovered in 1934, by Hans Andersag and coworkers at the Bayer laboratories, who named it Resochin. It was ignored for a decade, because it was considered too toxic for human use. Instead, in World War II, the German Africa Corps used the chloroquine analogue 3-methyl-chloroquine, known as Sontochin. After Allied forces arrived in Tunis, Sontochin fell into the hands of Americans, who sent the material back to the United States for analysis, leading to renewed interest in chloroquine. United States government-sponsored clinical trials for antimalarial drug development showed unequivocally that chloroquine has a significant therapeutic value as an antimalarial drug.: 61–66 It was introduced into clinical practice in 1947 for the prophylactic treatment of malaria.
The first synthesis of chloroquine was disclosed in a patent filed by IG Farben in 1937. In the final step, 4,7-dichloroquinoline was reacted with 1-diethylamino-4-aminopentane.
By 1949, chloroquine manufacturing processes had been established to allow its widespread use.
Society and culture
Resochin tablet package
Chloroquine comes in tablet form as the phosphate, sulfate, and hydrochloride salts. Chloroquine is usually dispensed as the phosphate.
Brand names include Chloroquine FNA, Resochin, Dawaquin, and Lariago.
Chloroquine, in various chemical forms, is used to treat and control surface growth of anemones and algae, and many protozoan infections in aquariums, e.g. the fish parasite Amyloodinium ocellatum. It is also used in poultry malaria.: 1237
Cleavage of the SARS-CoV-2 S2spike protein required for viral entry into cells can be accomplished by proteasesTMPRSS2 located on the cell membrane, or by cathepsins (primarily cathepsin L) in endolysosomes. Hydroxychloroquine inhibits the action of cathepsin L in endolysosomes, but because cathepsin L cleavage is minor compared to TMPRSS2 cleavage, hydroxychloroquine does little to inhibit SARS-CoV-2 infection.
Several countries initially used chloroquine or hydroxychloroquine for treatment of persons hospitalized with COVID‑19 (as of March 2020), though the drug was not formally approved through clinical trials. From April to June 2020, there was an emergency use authorization for their use in the United States, and was used off label for potential treatment of the disease. On 24 April 2020, citing the risk of "serious heart rhythm problems", the FDA posted a caution against using the drug for COVID‑19 "outside of the hospital setting or a clinical trial".
Their use was withdrawn as a possible treatment for COVID‑19 infection when it proved to have no benefit for hospitalized patients with severe COVID-19 illness in the international Solidarity trial and UK RECOVERY Trial. On 15 June, 2020, the FDA revoked its emergency use authorization, stating that it was "no longer reasonable to believe" that the drug was effective against COVID-19 or that its benefits outweighed "known and potential risks". In fall of 2020, the National Institutes of Health issued treatment guidelines recommending against the use of hydroxychloroquine for COVID-19 except as part of a clinical trial.
In 2021, hydroxychloroquine was part of the recommended treatment for mild cases in India.
Chloroquine was originally proposed as a treatment for SARS, with in vitro tests inhibiting the SARS-CoV virus. In October 2004, a group of researchers at the Rega Institute for Medical Research published a report on chloroquine, stating that chloroquine acts as an effective inhibitor of the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) in vitro.
Chloroquine was being considered in 2003, in pre-clinical models as a potential agent against chikungunya fever.
The radiosensitizing and chemosensitizing properties of chloroquine are beginning to be exploited in anticancer strategies in humans. In biomedicinal science, chloroquine is used for in vitro experiments to inhibit lysosomal degradation of protein products. Chloroquine and its modified forms have also been evaluated as treatment options for inflammatory conditions like rheumatoid arthritis and inflammatory bowel disease.
^Ajayi AA (September 2000). "Mechanisms of chloroquine-induced pruritus". Clinical Pharmacology and Therapeutics. 68 (3): 336. PMID11014416.
^Vaziri A, Warburton B (1994). "Slow release of chloroquine phosphate from multiple taste-masked W/O/W multiple emulsions". Journal of Microencapsulation. 11 (6): 641–8. doi:10.3109/02652049409051114. PMID7884629.
^Projean, Denis; Baune, Bruno; Farinotti, Robert; Flinois, Jean-Pierre; Beaune, Philippe; Taburet, Anne-Marie; Ducharme, Julie (June 2003). "In vitro metabolism of chloroquine: identification of CYP2C8, CYP3A4, and CYP2D6 as the main isoforms catalyzing N-desethylchloroquine formation". Drug Metabolism and Disposition. 31 (6): 748–754. doi:10.1124/dmd.31.6.748. PMID12756207. S2CID2115928.
^ abInstitute of Medicine (US) Committee on the Economics of Antimalarial Drugs; Arrow, K. J.; Panosian, C.; Gelband, H. (2004). Arrow, K.J.; Panosian, C.B.; Gelband, H. (eds.). Saving lives, buying time : economics of malaria drugs in an age of resistance. National Academies Press. doi:10.17226/11017. ISBN9780309092180. PMID25009879.
^DE patent 683692, Andersag, Hans; Breitner, Stefan & Jung, Heinrich, "Process for the preparation of quinoline compounds containing amino groups with basic substituents in the 4-position", issued 1939-11-13, assigned to IG Farbenindustrie AG
^Kenyon, R.L.; Wiesner, J.A.; Kwartler, C.E. (1 April 1949). "Chloroquine manufacture". Industrial & Engineering Chemistry. 41 (4): 654–662. doi:10.1021/ie50472a002.((cite journal)): CS1 maint: date and year (link)
^"Chloroquine". nih.gov. National Institutes of Health. Retrieved 24 March 2020.