Chloroquine

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.

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 time frames. Accumulation of the drug may result in deposits that can lead to blurred vision and blindness. With long term doses, routine visits to an optometrist or ophthalmologist are recommended.

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

(Note that a quantitative treatment of this phenomenon involves the pKas of all nitrogens in the molecule; this treatment, however, suffices to show the principle)

The lysosomotropic character of chloroquine is believed to account for much of its anti-malarial activity; the drug concentrates in the acidic food vacuole of the parasite and interferes with essential processes.

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 P. falciparum, so other antimalarials like mefloquine or atovaquone may be advisable instead. Combining chloroquine with proguanil may be more effective against chloroquine-resistant Plasmodium falciparum than treatment with chloroquine alone, but is no longer recommended by the CDC due to the availability of more effective combinations.

Doses
Per the Centers for Disease Control (CDC): Directions for Use The adult dosage is 500 mg chloroquine phosphate once a week. - Take the first dose of chloroquine 1 week before arrival in the malaria-risk area. - Take chloroquine once a week, on the same day of the week, while in the malaria-risk area. - Take chloroquine once a week for 4 weeks after leaving the malaria-risk area. Chloroquine should be taken on a full stomach to lessen nausea.

Chloroquine produced by Global Pharm is a white, round tablet with 7010 printed on one side. It is recommended that you do not chew the tablet, because it tastes horrible, and bitter.

Adverse effects
At the doses used for prevention of malaria, side effects include gastrointestinal problems such as stomach ache, itch, headache and blurred vision. When doses are extended over a number of months it is important to watch out for a slow onset of "changes in moods" (i.e.depression, anxiety). These may be more pronounced with higher doses used for treatment. Chloroquine tablets have an unpleasant metallic taste.

A serious side effect is also a rare toxicity in the eye (generally with chronic use), and requires regular monitoring even when symptom-free. The daily safe maximum doses for eye toxicity can be computed from one's height and weight using this calculator. The use of Chloroquine has also been associated with the development of Central Serous Retinopathy.

Chloroquine is very dangerous in overdose. It is rapidly absorbed from the gut and death often occurs within 2½ hours of taking the drug. The therapeutic index for chloroquine is small and just doubling the normal dose of chloroquine can be fatal.

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.

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).