Article: Chloroquine

Chloroquine
Systematic (IUPAC) name
N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamine
Identifiers
CAS number	54-05-7
ATC code	P01BA01
PubChem	2719
DrugBank	APRD00468
Chemical data
Formula	C18H26N3Cl
Mol. weight	319.872 g/mol
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Half life	1-2 months
Excretion	?
Therapeutic considerations
Pregnancy cat.	?
Legal status
Routes	?

Chloroquine is a commonly used form of medication against malaria. As it also mildly suppresses the immune system, it is used in some autoimmune disorders, such as rheumatoid arthritis and Lupus erythematosus.

Pharmacology

Chloroquine has a very high volume of distribution, as it diffuses into the body's adipose tissue. Chloroquine and related quinines have been associated with cases of retinal toxicity, particularly when provided at higher doses for longer timeframes. Accumulation of the drug may result in deposits that can lead to blurred vision and blindness. With long term doses, routine visits to an ophthalmologist are recommended.

Malaria prevention

Chloroquine can be used for preventing malaria from Plasmodium vivax, ovale and malariae. Many areas of the world have widespread strains of chloroquine-resistant Plasmodium falciparum, so other antimalarials like mefloquine or atovaquone may be advisable instead. Combining chloroquine with proguanil is also feasible.

Side effects

At the doses used for prevention of malaria, side effects include gastrointestinal problems such as stomach ache, itch, headache and blurred vision. These may be more pronounced with higher doses used for treatment. Chloroquine tablets have an unpleasant metallic taste.

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 parasitical 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 polymerises 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 polymerisation 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 ultimatly parasite cell autodigestion. Basically the parasite cell drowns in its own metabolic products.

The effectiveness of chloroquine against the parasite has declined as some resistant forms of the parasite can effectively neutralize the drug by developing a 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).

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 or the parasite's inability to polymerise heme after chloroquine complexation.

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.