Chloroquine phosphate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
Overview
Chloroquine is a 4-aminoquinoline drug long used in the treatment or prevention of malaria. As it also mildly suppresses the immune system, it is used in some autoimmune disorders, such as rheumatoid arthritis and lupus erythematosus. After the malaria parasite Plasmodium falciparum started to develop widespread resistance to chloroquine, new potential utilisations of this cheap and widely available drug have been investigated. For example, chloroquine is in clinical trials as an investigational antiretroviral in humans with HIV-1/AIDS and as a potential antiviral agent against chikungunya fever. Moreover, the radiosensitizing and chemosensitizing properties of chloroquine are beginning to be exploited in anticancer strategies in humans.
Category
Antimalarial
US Brand Names
CHLOROQUINE®
FDA Package Insert
Description | Clinical Pharmacology | Microbiology | Indications and Usage | Contraindications | Warnings and Precautions | Adverse Reactions | Drug Interactions | Overdosage | Clinical Studies | Dosage and Administration | How Supplied | Labels and Packages
Mechanism of Action
Inside the red blood cells, the malarial parasite must degrade the hemoglobin for the acquisition of essential amino acids, which the parasite requires to construct its own protein and for energy metabolism. This is essential for parasitic growth and division inside the red blood cell. It is carried out in the digestive vacuole of the parasite cell.
During this process, the parasite produces 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 polymerizes heme to form hemozoin, a non-toxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals.
Chloroquine enters the red blood cell, inhabiting parasite cell, and digestive vacuole by simple diffusion. 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 polymerization of heme, thus leading to heme build up. Chloroquine binds to heme (or FP) to form what is known as 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. In essence, the parasite cell drowns in its own metabolic products.
The effectiveness of chloroquine against the parasite has declined as resistant strains of the parasite evolved which effectively neutralized the drug via mechanism that drains chloroquine away from the digestive vacuole. CQ-Resistant cells efflux chloroquine at 40 times the rate of CQ-Sensitive cells, this is related to a number of mutations that trace back to transmembrane proteins of the digestive vacuole, including an essential mutation in the PfCRT gene (Plasmodium falciparum Chloroquine Resistance Transporter). This mutated protein may actively pump chloroquine from the cell. Resistant parasites frequently have mutated products or amplified expression of ABC transporters that pump out the chloroquine, typically PfMDR1 and PfMDR2 (Plasmodium falciparum Multi-Drug Resistance genes). Resistance has also been conferred by reducing the lower transport activity of the intake mechanism, so less chloroquine is imported into the parasite[3].
Research on the mechanism of chloroquine and how the parasite has acquired chloroquine resistance is still ongoing, and this article is not by any means fact. Other theories of chloroquine's mechanism of action suggest DNA intercalation or a combination of the disrupted membrane function of the lysosome.
Against rheumatoid arthritis, it operates by inhibiting lymphocyte proliferation, phospholipase A, release of enzymes from lysosomes, release of reactive oxygen species from macrophages, and production of IL-1.
As an antiviral agent, it impedes the completion of the viral life cycle by inhibiting some processes occurring within intracellular organelles and requiring a low pH. As for HIV-1, chloroquine inhibits the glycosylation of the viral envelope glycoprotein gp120, which occurs within the Golgi apparatus.
The mechanisms behind the effects of chloroquine on cancer are currently being investigated. The best know effects (investigated in clinical and pre-clinical studies) include radiosensitising effects through lysosome permeabilisation, and chemosensitising effects through inhibition of drug efflux pumps (ATP-binding cassette transporters)or other mechanisms (reviewed in the second-to-last reference below).