Chloroquine

Chloroquine

File:(±)-Chloroquine Enantiomers Structural Formulae V.1.svg
Systematic (IUPAC) name
N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamine
Pharmacokinetic data
Metabolism	Liver
Biological half-life	1-2 months
Identifiers
CAS Number	54-05-7
ATC code	P01BA01 (WHO)
PubChem	CID 2719
DrugBank	APRD00468
ChemSpider	2618
Chemical data
Formula	C18H26ClN3
Molar mass	319.872 g/mol[[]]
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Chloroquine (pronounced /ˈklɔrəkwɪn/) is a 4-aminoquinoline drug used in the treatment or prevention of malaria.

History

Chloroquine (CQ), N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamine was discovered in 1934 by Hans Andersag and co-workers at the Bayer laboratories who named it "Resochin". It was ignored for a decade because it was considered too toxic for human use. During World War II United States government-sponsored clinical trials for anti-malarial drug development showed unequivocally that CQ has a significant therapeutic value as an anti-malarial drug. It was introduced into clinical practice in 1947 for the prophylactic treatment of malaria.

Uses

• It has long been used in the treatment or prevention of malaria. 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. Chloroquine has been extensively used in mass drug administrations which may have contributed to the emergence and spread of resistance.

• As it mildly suppresses the immune system, it is used in some autoimmune disorders, such as rheumatoid arthritis and lupus erythematosus.

• Chloroquine is in clinical trials as an investigational antiretroviral in humans with HIV-1/AIDS and as a potential antiviral agent against chikungunya fever.

• The radiosensitizing and chemosensitizing properties of chloroquine are beginning to be exploited in anticancer strategies in humans.

Pharmacokinetics

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 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, a quantitative "trapping" of the compound in lysosomes results.

(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. Popular drugs based on chloroquine phosphate (also called nivaquine) are Chloroquine FNA, Resochin and Dawaquin. 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. For children of 14 years or below age,dose of chloroquine is 600 mg per week.

Adverse effects

At the doses used for prevention of malaria, side-effects include gastrointestinal problems such as stomach ache, itch, headache, and blurred vision.

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 correlated to the malaria parasite load in blood. There is evidence that it has a genetic basis and is related to chloroquine action with opiate receptors centrally or peripherally.

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. In 1961, studies were published showing that three children who took overdoses died within 2½ hours of taking the drug. While the amount of the overdose was not cited, it is known that the therapeutic index for chloroquine is small.

According to the PloS One Journal and cited by Scientific American, an overuse of Chloroquine treatment has led to the development of a specific strain of E. coli that is now resistant to the powerful antibiotic Ciprofloxacin

Mechanism of action

Antimalarial

Inside red blood cells, the malarial parasite 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 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 biocrystallizes 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 biocrystallization of heme, thus leading to heme buildup. 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. They effectively neutralize the drug via a mechanism that drains chloroquine away from the digestive vacuole. CQ-Resistant cells efflux chloroquine at 40 times the rate of CQ-Sensitive cells; the related mutations trace back to transmembrane proteins of the digestive vacuole, including sets of critical mutations in the PfCRT gene (Plasmodium falciparum Chloroquine Resistance Transporter). The mutated protein, but not the wild-type transporter, transports chloroquine when expressed in Xenopus oocytes and is thought to mediate chloroquine leak from its site of action in the digestive vacuole. Resistant parasites also frequently have mutated products of the ABC transporter PfMDR1 (Plasmodium falciparum Multi-Drug Resistance gene) although these mutations are thought to be of secondary importance compared to Pfcrt.

Research on the mechanism of chloroquine and how the parasite has acquired chloroquine resistance is still ongoing, and there are likely to be other mechanisms of resistance.

Disease-modifying antirheumatic drugs (DMARDs)

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

Antiviral

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.

Antitumor

The mechanisms behind the effects of chloroquine on cancer are currently being investigated. The best-known 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).

Resistance

Chloroquine resistance among plasmodia has been slow in developing. However, P. falciparum has acquired significant resistance and resistant strains have become prevalent specially in eastern America. Some of these have also acquired resistance to proguanil, pyrimithamine and mepacrine (multi drug resistance strain). Because falciparum produces the more severe forms of malaria with considerable mortality, emergence of such a strain is the biggest threat to the antimalarial programs, and is the focus of attention for current research efforts. Mechanism: resistance in P. falciparum is associated with a decreased ability of the parasite to accumulate chloroquine. Verapamil, a Ca²⁺ channel blocker, has been found to restore both the chloroquine concentration ability as well as 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.

External links

• Chloroquine Anti-HIV action
• Chloroquine and imatinib

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