Chloroquine (Chloroquine Phosphate)

Chloroquine (Chloroquine Phosphate)

Last Updated on June 16, 2020 by Sagar Aryal

Medical Disclaimer: The information presented on the website is only for academic and study purposes and must not be used for the purpose of treatment. If you are not feeling well, please consult with your physician or doctor.

Update: FDA Revokes Emergency Use Authorization for Chloroquine and Hydroxychloroquine

Introduction

  • Chloroquine also is known as chloroquine phosphate was discovered by Hans Andersag in 1934.
  • It is a lysosomotropic antimalaria drug used for malaria therapy. Some forms of malaria are resistant to chloroquine and therefore they require combined therapy of chloroquine and other drugs.
  • In areas where sensitivity to chloroquine is observed, hydroxychloroquine has been used.
  • Chloroquine has also been used in the treatment of amoebiasis that occurs outside the intestines, treatment of rheumatoid arthritis and lupus erythematosus.

Properties of Chloroquine (Chloroquine Phosphate)

  • It is rapidly absorbed by body cells and tissues.
  • It is a weak lipophilic base that is easy to absorb through the lipid, fat and protein membranes of cells.
  • It is mainly broken down and metabolized in the liver
  • It binds proteins at 55%.
  • Its metabolism is partially hepatic, giving rise to its main metabolite, desethylchloroquine.
  • It is a lysosomotropic agent hence it can accumulate in the lysosomes of the cells of the body.
  • It is a deprotonated form hence it is membrane-permeable.
  • Its ability to accumulate in cells can cause blurred vision and impaired eyesight.
  • Its excretion in urine is above 50% because most of it is an unchanged form. its elimination is increased by the acidity of urine.

Uses of Chloroquine (Chloroquine Phosphate)

Chloroquine usage may be under a physician’s prescription. It is normally used in the treatment of the following:

  1. Malaria treatment
  • Chloroquine is used as suppressive treatment and acute treatment of malaria caused by P. vivax, P.malariae, P. ovale, and most commonly in areas where susceptible strains of P. falciparum are common.
  • It is used extensively in mass administration which has resulted in chloroquine-resistant malaria and the spread of chloroquine malaria resistance. However, it is effective in some areas, areas where it has become resistant, mefloquine or atovaquone are used.
  • It is recommended by the CDC to use chloroquine alone without drug combinations for better efficacy.
  1. Rheumatoid Disease treatment
  • Chloroquine is used in suppressing autoimmune disorders like Rheumatoid arthritis and lupus erythematosus.
  • It is also the second-line agent in the treatment of Rheumatoid Arthritis.
  • It suppresses the inflammatory effects produced by Lupus erythematous
  1. Amebiasis treatment
  • When amoebiasis occurs outside the intestines, chloroquine has been used occasionally as a treatment course.
  • For amoebic liver abscess. it is used as an additional drug with metronidazole and nitroimidazole which fail to show improvement after usage within 5 days. Sometime when the body can not tolerate metronidazole or nitroimidazole, chloroquine is used.

Mechanism of action of Chloroquine (Chloroquine Phosphate)

  • Chloroquine has a lysosomotropic effect which is associated with it being a weak lipophilic base. Chloroquine interferes with lysosomal activity, apoptosis, and autophagy, interacting with the membrane stability and altering signaling pathways and transcriptional activity, causing an acidic environment in parasites, which interferes with its essential processes.
  • Chloroquine also interferes with the formation of hemozoin pigment formed by the parasite. The malaria parasite, in its asexual phase (trophozoite), infects the red blood cells and starts to utilize the hemoglobin pigment of blood, producing heme moiety (consisting of a porphyrin ring called Fe(II)-protoporphyrin IX (FP)) which is toxic to the parasite.
  • So, the parasite biocrystallizes the heme forming a hemozoin pigment (malaria pigment) which is none toxic to the parasite, accumulating it as an insoluble crystal in the food vacuoles.
  • The function of chloroquine is to prevent the hemozoin crystallization by entering the blood cells via diffusion inhibiting the parasite cell and digestive vacuoles. In the blood cells, chloroquine becomes protonated into CQ2+, an acidic compound that can not leave the cell 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 parasitic cell and disrupts membrane function. The 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.
  • This lysosomotropic effects also inhibit cytokine production and modulation of certain co-modulating molecules, hence used as a treatment for Rheumatoid arthritis and lupus erythematosus.

Malaria Resistance to Chloroquine (Chloroquine Phosphate)

  • Malaria resistance was first documented in the 1950s in East, West Africa and Southeast Asia and South America, showing the ineffectiveness of Plasmodium falciparum. The decline in its effectiveness has been linked to the evolving strains of Plasmodium falciparum.
  • The parasite neutralizes the drug through a mechanism that drains chloroquine from the digestive vacuoles causing chloroquine-resistant cell efflux, 40 times the rate of chloroquine-sensitive cells. Mutations have been traced back to the transmembrane proteins of the digestive vacuole, including sets of critical mutations in the P. falciparum chloroquine resistance transporter (PfCRT) gene.
  • 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. Research is still ongoing to understand further the mechanisms of parasitic resistance to chloroquine.
  • Other agents that show reversing of chloroquine-resistant malaria include chlorpheniramine, gefitinib, imatinib, tariquidar, and zosuquidar.

Antiviral effects of Chloroquine

  • Chloroquine has antiviral effects whereby they increase the pH of the lysosomes and the late endosome, cause the impaired release of viruses from the lysosome or the endosome. This makes the virus unable to release its genetic material into the cell and replicate.
  • Chloroquine also acts as a zinc ionophore that allows extracellular zinc to enter the cell and inhibit viral RNA-dependent RNA polymerase.

Other chloroquine mechanisms include:

  • Inhibition of thiamine uptake by acting on the transporter thiamine transporter called solute carrier family 19 member 3 (SLC19A3).
  • On the protection against rheumatoid arthritis chloroquine inhibits lymphocyte proliferation, inhibits phospholipase A2, antigen presentation in the dendritic cells, releasing of enzymes from lysosomes, releasing of reactive oxygen species from macrophages and production of IL-1.

Side effects of Chloroquine (Chloroquine Phosphate)

Common side effects arise from the overdose, allergic reactions to components of the drug, contraindications of underlying disorders and interaction with drugs for treating other diseases. They can range from mild to adversely severe effects.

These include:

  • Common and mild side effects: Nausea, vomiting, abdominal cramping, headaches, diarrhea, loss of appetite, skin rash, muscle cramping, pain, and atrophies
  • Adverse side effects: Blurred vision, swelling of ankles and legs, shortness of breath, pale skin/nails/lips, muscle weakness, easy bruising and bleeding, impaired hearing, mental problems, deafness, mood swings associated with confusion, personality, behavioral change, depression, withdrawal syndrome, hallucinations.
  • Serious signs of infection include high fever, severe chills, persistent sore throat, lowered blood cell levels.
  • Skin itching associated with chloroquine especially in black Africans, with symptoms of skin color change, hair loss, skin rashes. It is not common among other races and its effects increase with age, and it can be severe to the point of stopping drug administration. Skin associated problems also increase when individuals experience high fevers which are correlated to the parasite load in blood. Research evidence indicates a link between the genetic makeup and the action of chloroquine with the central and peripheral opiate receptors in the brain.
  • A metallic taste that is unpleasant in the mouth experienced by some individuals. this can be prevented by taking taste-masked and controlled release” formulations such as multiple emulsions.
  • Chloroquine retinopathy caused by long term consumption of chloroquine. the damage to the retina may remain permanent.
  • Irreversible electrocardiographic changes may occur causing cardiomyopathy, which is a hypertrophic restriction of the cardiac muscles and congestive heart failure. Electron microscopic observation of cardiac biopsies indicates pathognomonic cytoplasmic inclusion bodies.
  • Reduction of red blood cell (pancytopenia) numbers may occur, aplastic anemia whereby the bone marrow can not produce red blood cells leading to a deficiency, reduction of granulocytic cells in the blood (agranulocytosis), lowered blood platelets, neutropenia (reduction of neutrophils).
  • Overdosing has been attributed to at least 20%  of deaths from chloroquine prescriptions

Pregnancy and breastfeeding

  • There are no adverse harmful side effects noted when taking chloroquine in the right doses and recommended. However, some quantities of chloroquine are secreted in breast milk. The drug, however, has been prescribed to infants with no harmful effects.

Elderly

  • There are no harmful side effects reported but monitoring their systemic organs is advises especially the kidneys where the drug is eliminated to avoid toxic accumulations.

Chloroquine Interactions

Chloroquine can interact with some drugs causing clinical concerns such as:

  • Ampicillin may reduce chloroquine levels.
  • Antacids may reduce chloroquine absorption
  • Cimetidine which is used to treat stomach ulcers and heartburns, may inhibit chloroquine metabolism and increase chloroquine levels in the body.
  • Cyclosporine an immunosuppressant for Crohn’s disease, can increase the levels of chloroquine.
  • Mefloquine which is used to treat and prevent malaria may increase the risk of convulsions.

Chloroquine contraindications

  • Chloroquine being a 4-aminoglycoside, it not be used for individuals with hypersensitive reactions and inflammatory disorders.
  • It should be given in low dosages for people with Diabetes and persons with cardiovascular disorders.
  • A study of chloroquine in 81 hospitalized people in Brazil was halted. About 40 people with coronavirus got a 600 milligrams dose for 10 days dose. By the sixth day of treatment, 11 of them had died, leading to an immediate end to the high-dose segment of the trial. The other about 40 people had got a dose of 450 milligrams of chloroquine twice daily for five days.

Chloroquine and COVID-19

  • For the limited research done so far, there is some evidence of inhibition of the terminal glycosylation of the ACE2 receptor, which the SARS-CoV-2 targets to gain entry into the host cell. Unglycosylated ACE2 interacts less with SARS-CoV-2.
  • Exploratory research is ongoing in most countries with its use showing good efficacy against SARS-CoV-2.
  • Chloroquine has been approved by Chinese, South Korean, and Italian health authorities for the experimental treatment of COVID-19, noting contraindications in persons with heart diseases and diabetes.

Chloroquine (Chloroquine Phosphate)

Figure: Chloroquine: Potential Mechanisms of Action Against Coronaviruses, Image created using biorender.com

Chloroquine and other viruses

  • Chloroquine had been also proposed as a treatment for SARS which has shown in vitro, the inhibition of the SARS-CoV virus.
  • In preliminary studies for the treatment of chikungunya fever, chloroquine was also considered for treatment.

Cancer treatment

  • Radiosensizised and chemosensitizing chloroquine is being explored as an anticancer treatment in humans because of its inhibitory properties of lysosomal protein degradation.

References and Sources

  • https://pubchem.ncbi.nlm.nih.gov/compound/Chloroquine#section=Drug-and-Medication-Information
  • https://medlineplus.gov/druginfo/meds/a682318.html
  • https://www.scientificamerican.com/article/could-chloroquine-treat-coronavirus/
  • https://www.nature.com/articles/s41584-020-0372-x
  • https://www.drugbank.ca/drugs/DB00608
  • https://www.ncbi.nlm.nih.gov/pubmed/8361993

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