Chloroquine

Side effects include neuromuscular, hearing, gastrointestinal, brain, skin, eye, cardiovascular (rare), and blood reactions.[12]

• Seizures[12]
• Deafness or tinnitus.[12]
• Nausea, vomiting, diarrhea, abdominal cramps, and anorexia.[12]
• Mild and transient headache.[12]
• Skin itchiness, skin color changes, hair loss, and skin rashes.[12]
  • 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 is correlated to the malaria parasite load in blood. Some evidence indicates it has a genetic basis and is related to chloroquine action with opiate receptors centrally or peripherally.[13]
• Unpleasant metallic taste
  • This could be avoided by ‘taste-masked and controlled release’ formulations such as multiple emulsions.[14]
• Chloroquine retinopathy
  • May be irreversible.[12] This occurs with long-term use over many years or with high doses. Patients on long-term chloroquine therapy should be screened at baseline and then annually after five years of use.[15] The daily safe maximum doses for eye toxicity can be computed from one's height and weight using this calculator.[16] Patients should be screened for vision changes such as blurring of vision, difficulty focusing, or seeing half an object.[12]
• Hypotension and electrocardiographic changes[12][17]
  • This manifests itself as either conduction disturbances (bundle-branch block, atrioventricular block) or cardiomyopathy – often with hypertrophy, restrictive physiology, and congestive heart failure. The changes may be irreversible. Only two cases have been reported requiring heart transplantation, suggesting this particular risk is very low. Electron microscopy of cardiac biopsies show pathognomonic cytoplasmic inclusion bodies.
• Pancytopenia, aplastic anemia, reversible agranulocytosis, low blood platlets, neutropenia.[18]

• Antacids- may reduce absorption of chloroquine
• Kaolin- may reduce absorption of chloroquine
• Cimetidine- may inhibit metabolism of chloroquine; increasing levels of chloroquine in the body
• Ampicillin- levels may be reduced by chloroquine
• Cyclosporine- levels may be increased by chloroquine
• Mefloquine- may increase risk of convulsions[18]

Chloroquine is very dangerous in overdose. It is rapidly absorbed from the gut. In 1961, published studies showed three children who took overdoses died within 2.5 hours of taking the drug. While the amount of the overdose was not cited, the therapeutic index for chloroquine is known to be small.[21] Symptoms of overdose include headache, drowsiness, visual disturbances, nausea and vomiting, cardiovascular collapse, seizures, and sudden respiratory and cardiac arrest.[18]

A metabolite of chloroquine – hydroxychloroquine – has a long half-life (32–56 days) in blood and a large volume of distribution (580–815 L/kg).[22] The therapeutic, 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, nontoxic cases have been reported up to 39 mg/l, suggesting individual tolerance to this agent may be more variable than previously recognised.[22]

Since the first documentation of P. falciparum chloroquine resistance in the 1950s, resistant strains have appeared throughout East and West Africa, Southeast 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 P. falciparum chloroquine resistance transporter (PfCRT) gene. 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.[23] Resistant parasites also frequently have mutated products of the ABC transporter P. falciparum multidrug resistance (PfMDR1) 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 and 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.[24] Research on the mechanism of chloroquine and how the parasite has acquired chloroquine resistance is still ongoing, as other mechanisms of resistance are likely.

Other agents which have been shown to reverse chloroquine resistance in malaria are chlorpheniramine, gefitinib, imatinib, tariquidar and zosuquidar.[25]

• Absorption: Rapid and almost completely
• Distribution: Widely distributed into body tissues
• Protein binding: 55%
• Metabolism: Partially hepatic to main metabolite, desethylchloroquine
• Excretion: Urine (≥50% as unchanged drug); acidification of urine increases elimination

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 times. 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 it accumulates preferentially in the lysosomes of cells in the body. The pK_a for the quinoline nitrogen of chloroquine is 8.5, meaning it is about 10% deprotonated at physiological pH as calculated by the Henderson-Hasselbalch equation. This decreases to about 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. (A quantitative treatment of this phenomenon involves the pK_as 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 antimalarial activity; the drug concentrates in the acidic food vacuole of the parasite and interferes with essential processes. Its lysosomotropic properties further allow for its use for in vitro experiments pertaining to intracellular lipid related diseases,[26][27] autophagy, and apoptosis.[28]

Brand names include Chloroquine FNA, Resochin, and Dawaquin.

Chloroquine was discovered in 1934 by Hans Andersag and coworkers at the Bayer laboratories, who named it "Resochin".[32] 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 antimalarial drug development showed unequivocally that chloroquine has a significant therapeutic value as an antimalarial drug. It was introduced into clinical practice in 1947 for the prophylactic treatment of malaria.[33]

• History of malaria
• Quinine
• Artemether

• "Chloroquine". Drug Information Portal. U.S. National Library of Medicine.