4-aminoquinoline drug used in the treatment or prevention of malaria.
Uses
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. Its lysomotropic properties further allow for its utilization in in vitro experiments pertaining to intracellular lipid related diseases , autophagy and apoptosis
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.
Another serious side-effect is toxicity to the eye (specifically, central serous retinopathy). This only occurs with long term use over many years. Patients on long term chloroquine therapy should be screened at baseline and every five year. The daily safe maximum doses for eye toxicity can be computed from one's height and weight using this calculator.
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 2 1⁄2 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 research published in the journal PLoS ONE, 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.
A metabolite of chloroquine - hydroxycloroquine - has a long half life (32–56 days) in blood and a large volume of distribution (580-815 L/kg). The theraputic, toxic and lethal ranges are usually considered to be 0.03 to 15 mg/L, 3.0 to 26 mg/L and 20 to 104 mg/L respectively. However non toxic cases have been reported in the range 0.3 to 39 mg/L suggesting that individual tolerance of this agent may be more variable than previously recognised.
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.
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.
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.
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. Its lysomotropic properties further allow for its utilization in in vitro experiments pertaining to intracellular lipid related diseases , autophagy and apoptosis
Prevention Of Malaria
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 14 years of age or below, the dose of chloroquine is 600 mg per week.
Adverse effects
At the doses used for prevention of malaria, side-effects include gastrointestinal problems, stomach ache, itch, headache, nightmares 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.
Another serious side-effect is toxicity to the eye (specifically, central serous retinopathy). This only occurs with long term use over many years. Patients on long term chloroquine therapy should be screened at baseline and every five year. The daily safe maximum doses for eye toxicity can be computed from one's height and weight using this calculator.
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 2 1⁄2 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 research published in the journal PLoS ONE, 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.
A metabolite of chloroquine - hydroxycloroquine - has a long half life (32–56 days) in blood and a large volume of distribution (580-815 L/kg). The theraputic, toxic and lethal ranges are usually considered to be 0.03 to 15 mg/L, 3.0 to 26 mg/L and 20 to 104 mg/L respectively. However non toxic cases have been reported in the range 0.3 to 39 mg/L suggesting that individual tolerance of this agent may be more variable than previously recognised.
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.
Resistance
Since the first documentation of P. falciparum chlorquine resistance in the 1950s, resistant strains have appeared throughout East and West Africa, South East Asia, and South America. The effectiveness of chloroquine against P. falciparum 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. Chloroquine-resistant cells efflux chloroquine at 40 times the rate of chloroquine-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. 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.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.
