Chloroquine

Not to be confused with Hydroxychloroquine.

Chloroquine
Names
Pronunciation/ˈklɔːrəkwiːn/
Trade namesAralen, other
Other namesChloroquine phosphate
IUPAC name
  • (RS)-N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamine
Clinical data
Drug class4-aminoquinoline[1]
Main usesMalaria, rheumatoid arthritis, lupus erythematosus[2][1]
Side effectsMuscle problems, loss of appetite, diarrhea, skin rash[1]
Routes of
use		By mouth
Defined daily dose500 mg (by mouth or injection)[3]
External links
AHFS/Drugs.comMonograph
Legal
License data
Legal status
Pharmacokinetics
MetabolismLiver
Elimination half-life1-2 months
Chemical and physical data
FormulaC18H26ClN3
Molar mass319.872 g·mol−1
3D model (JSmol)
SMILES
  • Clc1cc2nccc(c2cc1)NC(C)CCCN(CC)CC
InChI
  • InChI=1S/C18H26ClN3/c1-4-22(5-2)12-6-7-14(3)21-17-10-11-20-18-13-15(19)8-9-16(17)18/h8-11,13-14H,4-7,12H2,1-3H3,(H,20,21) checkY
  • Key:WHTVZRBIWZFKQO-UHFFFAOYSA-N checkY

Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects.[1] Certain types of malaria, resistant strains, and complicated cases typically require different or additional medication.[1] Chloroquine is also occasionally used for amebiasis that is occurring outside the intestines, rheumatoid arthritis, and lupus erythematosus.[1] While it has not been formally studied in pregnancy, it appears safe.[1][4] It is also being studied to treat COVID-19 as of 2020.[5] It is taken by mouth.[1]

Common side effects include muscle problems, loss of appetite, diarrhea, and skin rash.[1] Serious side effects include problems with vision, muscle damage, seizures, and low blood cell levels.[1][6] Chloroquine is a member of the drug class 4-aminoquinoline.[1] 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.[1] How it works in rheumatoid arthritis and lupus erythematosus is unclear.[1]

Chloroquine was discovered in 1934 by Hans Andersag.[7][8] It is on the World Health Organization's List of Essential Medicines.[9] It is available as a generic medication.[1] The wholesale cost in the developing world is about US$0.04.[10] In the United States, it costs about US$5.30 per dose.[1]

Medical uses

Malaria

Distribution of malaria in the world:[11]
♦ Elevated occurrence of chloroquine- or multi-resistant malaria
♦ Occurrence of chloroquine-resistant malaria
♦ No Plasmodium falciparum or chloroquine-resistance
♦ No malaria

Chloroquine has been used in the treatment and prevention of malaria from Plasmodium vivax, P. ovale, and P. malariae. It is generally not used for Plasmodium falciparum as there is widespread resistance to it.[12][13]

Chloroquine has been extensively used in mass drug administrations, which may have contributed to the emergence and spread of resistance. It is recommended to check if chloroquine is still effective in the region prior to using it.[14] In areas where resistance is present, other antimalarials, such as mefloquine or atovaquone, may be used instead. The Centers for Disease Control and Prevention recommend against treatment of malaria with chloroquine alone due to more effective combinations.[15]

Amebiasis

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.[16]

Rheumatic disease

As it mildly suppresses the immune system, chloroquine is used in some autoimmune disorders, such as rheumatoid arthritis and has an off label indication for lupus erythematosus.[1]

Dosage

The defined daily dose is 500 mg (by mouth) or 500 mg (parenteral)[3] For malaria the recommended dose is 10 mg/kg of the base on the 1st and 2nd day followed by 5 mg/kg on day three.[2]

The conversion is 155 mg of the base equals 200 mg of the sulfate or 250 mg of the phophate or diphosphate form.[2]

Side effects

Chloroquine-induced keratopathy-a) Anterior stromal nerves with atypical shape b) chloroquine deposits were detectable in epithelium

Side effects include blurred vision, nausea, vomiting, abdominal cramps, headache, diarrhea, swelling legs/ankles, shortness of breath, pale lips/nails/skin, muscle weakness, easy bruising/bleeding, hearing and mental problems.[17][18]

  • Unwanted/uncontrolled movements (including tongue and face twitching) [17]
  • Deafness or tinnitus.[17]
  • Nausea, vomiting, diarrhea, abdominal cramps[18]
  • Headache.[17]
  • Mental/mood changes (such as confusion, personality changes, unusual thoughts/behavior, depression, feeling being watched, hallucinating)[17][18]
  • Signs of serious infection (such as high fever, severe chills, persistent sore throat)[17]
  • Skin itchiness, skin color changes, hair loss, and skin rashes.[18][19]
    • 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.[20]
  • Unpleasant metallic taste
    • This could be avoided by "taste-masked and controlled release" formulations such as multiple emulsions.[21]
  • Chloroquine retinopathy
  • Electrocardiographic changes[22]
    • 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.
  • Pancytopenia, aplastic anemia, reversible agranulocytosis, low blood platelets, neutropenia.[23]

Pregnancy

Chloroquine has not been shown to have any harmful effects on the fetus when used in the recommended doses for malarial prophylaxis.[24] 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.[23][25] Women who are pregnant or planning on getting pregnant are still advised against traveling to malaria-risk regions.[24]

Elderly

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.[23]

Interactions

Chloroquine has a number of drug–drug interactions that might be of clinical concern:

Overdose

Chloroquine, in overdose, has a risk of death of about 20%.[26] It is rapidly absorbed from the gut with an onset of symptoms generally within an hour.[27] Symptoms of overdose may include sleepiness, vision changes, seizures, stopping of breathing, and heart problems such as ventricular fibrillation and low blood pressure.[26][27] Low blood potassium may also occur.[26]

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.[26] In children as little as a single tablet can cause problems.[27]

Treatment recommendations include early mechanical ventilation, cardiac monitoring, and activated charcoal.[26] Intravenous fluids and vasopressors may be required with epinephrine being the vasopressor of choice.[26] Seizures may be treated with benzodiazepines.[26] Intravenous potassium chloride may be required, however this may result in high blood potassium later in the course of the disease.[26] Dialysis has not been found to be useful.[26]

Pharmacology

Absorption of chloroquine is rapid and primarily happens in the gastrointestinal tract.[28] It is widely distributed in body tissues.[29] Protein binding in plasma ranges from 46% to 79%.[30] Its metabolism is partially hepatic, giving rise to its main metabolite, desethylchloroquine.[31] 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.

Accumulation of the drug may result in deposits that can lead to blurred vision and blindness. It and related quinines have been associated with cases of retinal toxicity, particularly when provided at higher doses for longer times. With long-term doses, routine visits to an ophthalmologist are recommended.

Chloroquine is also a lysosomotropic agent, meaning it accumulates preferentially in the lysosomes of cells in the body. The pKa for the quinoline nitrogen of chloroquine is 8.5, meaning it is about 10% deprotonated at physiological pH (per the Henderson-Hasselbalch equation). This decreases to about 0.2% at a lysosomal pH of 4.6. Because the deprotonated form is more membrane-permeable than the protonated form, a quantitative "trapping" of the compound in lysosomes results.

Mechanism of action

Medical quinolines

Malaria

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,[32][33] autophagy, and apoptosis.[34]

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.[35] Parasites that do not form hemozoin are therefore resistant to chloroquine.[36]

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. They effectively neutralize the drug via a mechanism that drains chloroquine away from the digestive vacuole. Chloroquine-resistant cells efflux chloroquine at 40 times the rate of chloroquine-sensitive cells; the related mutations trace back to transmembrane proteins of the digestive vacuole, including sets of critical mutations in the P. falciparum chloroquine resistance transporter (PfCRT) gene. The mutated protein, but not the wild-type transporter, transports chloroquine when expressed in Xenopus oocytes (frog's eggs) and is thought to mediate chloroquine leak from its site of action in the digestive vacuole.[37] Resistant parasites also frequently have mutated products of the ABC transporter P. falciparum multidrug resistance (PfMDR1) gene, although these mutations are thought to be of secondary importance compared to Pfcrt. Verapamil, a Ca2+ channel blocker, has been found to restore both the chloroquine concentration ability and sensitivity to this drug. Recently, an altered chloroquine-transporter protein CG2 of the parasite has been related to chloroquine resistance, but other mechanisms of resistance also appear to be involved.[38] Research on the mechanism of chloroquine and how the parasite has acquired chloroquine resistance is still ongoing, as other mechanisms of resistance are likely.

Other agents which have been shown to reverse chloroquine resistance in malaria are chlorpheniramine, gefitinib, imatinib, tariquidar and zosuquidar.[39]

Antiviral

Chloroquine has antiviral effects against some viruses.[40] 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.[41][42]

Chloroquine also seems to act as a zinc ionophore that allows extracellular zinc to enter the cell and inhibit viral RNA-dependent RNA polymerase.[43][44]

Other

Chloroquine inhibits thiamine uptake.[45] It acts specifically on the transporter SLC19A3.

Against rheumatoid arthritis, it operates by inhibiting lymphocyte proliferation, phospholipase A2, antigen presentation in dendritic cells, release of enzymes from lysosomes, release of reactive oxygen species from macrophages, and production of IL-1.

History

In Peru, the indigenous people extracted the bark of the Cinchona tree (Cinchona officinalis)[46] 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.[47] The quinoline antimalarial drug quinine was isolated from the extract in 1820, and chloroquine is an analogue of this.

Chloroquine was discovered in 1934, by Hans Andersag and coworkers at the Bayer laboratories, who named it Resochin.[48] It was ignored for a decade, because it was considered too toxic for human use. Instead, the DAK 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.[49][50] United States government-sponsored clinical trials for antimalarial drug development showed unequivocally that chloroquine has a significant therapeutic value as an antimalarial drug. It was introduced into clinical practice in 1947 for the prophylactic treatment of malaria.[51]

Society and culture

Resochin tablet package

Formulations

Chloroquine comes in tablet form as the phosphate, sulfate, and hydrochloride salts. Chloroquine is usually dispensed as the phosphate.[52]

Names

Brand names include Chloroquine FNA, Resochin, Dawaquin, and Lariago.[53]

Other animals

Chloroquine, in various chemical forms, is used to treat and control surface growth of anemones and algae, and many protozoan infections in aquariums,[54] e.g. the fish parasite Amyloodinium ocellatum.[55]

Research

COVID-19

See also: Hydroxychloroquine § COVID-19, Coronavirus disease 2019 § Research, and COVID-19 drug repurposing research
Further information: Trump administration communication during the COVID-19 pandemic § Chloroquine and hydroxychloroquine

There is limited evidence on the use of chloroquine in people with COVID-19.[56][57] Chloroquine has been approved by Chinese, South Korean and Italian health authorities for the experimental treatment of COVID-19.[58][59] These agencies noted contraindications for people with heart disease or diabetes.[60] However, use of chloroquine is only recommended in the setting of an approved trial or under the details outlined by Monitored Emergency Use of Unregistered Interventions.[5] On 1 April 2020, the European Medicines Agency (EMA) issued guidance that chloroquine and hydroxychloroquine are only to be used in clinical trials or emergency use programs.[61] On 29 May 2020, the EMA stated that patients already taking chloroquine for unrelated conditions, should continue to do so, always under the supervision of their doctor.[62]

Health experts warned against the misuse of the non-pharmaceutical versions of chloroquine phosphate after a husband and wife consumed a fish tank antiparasitic containing chloroquine phosphate on 24 March, with the intention of it being prophylaxis against COVID-19. One of them died and the other was hospitalized.[63] Chloroquine has a relatively narrow therapeutic index and it can be toxic at levels not much higher than those used for treatment—which raises the risk of inadvertent overdose.[64][65] On 27 March 2020, the US Food and Drug Administration (FDA) issued guidance, "do not use chloroquine phosphate intended for fish as treatment for COVID-19 in humans".[66]

The FDA has cautioned against using the drug outside a hospital setting or clinical trial after reviewing adverse events including ventricular tachycardia, ventricular fibrillation, and deaths.[67] On 28 March 2020 the FDA authorized the use of hydroxychloroquine and chloroquine under an emergency use authorization (EUA).[68] The treatment has not been approved by the FDA.[69] The experimental treatment is authorized only for emergency use for people who are hospitalized but not able to receive treatment in a clinical trial.[70] In anticipation of product shortages, the FDA issued product-specific guidance for chloroquine phosphate and for hydroxychloroquine sulfate for generic drug manufacturers.[71] On 15 June 2020, the FDA revoked the emergency use authorization for chloroquine and hydroxychloroquine.[72][73][74][75]

A study of chloroquine in 81 people hospitalized before confirmation of COVID-19, compared high dose chloroquine to low-dose chloroquine. People were also treated with ceftriaxone and azithromycin. By the sixth day of treatment, seven people in the high-dose group and four people in the low-dose group had died, leading to an immediate end to the trial.[76][77]

On 29 May 2020, the EMA issued a public health statement reminding healthcare professionals to closely monitor people with COVID-19 who are receiving chloroquine.[78] It also published a list of references of observational studies of chloroquine and hydroxychloroquine in people with COVID-19.[79]

On 4 June 2020, there was a retraction of a major multinational analysis that clearly stated having found no clinical benefit while administrating chloroquine, hydroxychloroquine, alone or accompanied by a macrolide and in contrast did raise the percentages of high risk side effects, most prominently cardiac dysrrythmias.[80][81]

On 15 June 2020, the FDA updated the fact sheets for the emergency use authorization of remdesivir to warn that using chloroquine or hydroxychloroquine with remdesivir may reduce the antiviral activity of remdesivir.[82]

Chloroquine has been under investigation for its purposed role of a potential COVID-19 therapeutic regimen. One of the trials currently going on is the Solidarity Trial, organised and performed by WHO.[83] On 23 May 2020, the Trial's directors decided to temporarily pause hydroxychloroquine administration, due to safety concerns.[84]

Other viruses

Chloroquine had been also proposed as a treatment for SARS, with in vitro tests inhibiting the SARS-CoV virus.[85][86] 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.[85]

Chloroquine was being considered in 2003, in pre-clinical models as a potential agent against chikungunya fever.[87]

Other

The radiosensitizing and chemosensitizing properties of chloroquine are beginning to be exploited in anticancer strategies in humans.[88][89] In biomedicinal science, chloroquine is used for in vitro experiments to inhibit lysosomal degradation of protein products.

References

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