Chloroquine has been the drug of choice for both treatment and chemoprophylaxis of malaria since the 1940s, but its usefulness against P falciparum has been seriously compromised by drug resistance. It remains the drug of choice in the treatment of sensi-tive P falciparum and other species of human malaria parasites.
Chloroquine is a synthetic 4-aminoquinoline (Figure 52–2) for-mulated as the phosphate salt for oral use. It is rapidly and almost completely absorbed from the gastrointestinal tract, reaches maxi-mum plasma concentrations in about 3 hours, and is rapidly dis-tributed to the tissues. It has a very large apparent volume of distribution of 100–1000 L/kg and is slowly released from tissues and metabolized. Chloroquine is principally excreted in the urine with an initial half-life of 3–5 days but a much longer terminal elimination half-life of 1–2 months.
When not limited by resistance, chloroquine is a highly effective blood schizonticide. It is also moderately effective against gameto-cytes of P vivax, P ovale, and P malariae but not against those of P falciparum. Chloroquine is not active against liver stage para-sites. Chloroquine probably acts by concentrating in parasite food vacuoles, preventing the biocrystallization of the hemoglobin breakdown product, heme, into hemozoin, and thus eliciting parasite toxicity due to the buildup of free heme.
Resistance to chloroquine is now very common among strains of P falciparum and uncommon but increasing for P vivax. In Pfalciparum, mutations in a putative transporter, PfCRT, have beencorrelated with resistance. Chloroquine resistance can be reversed by certain agents, including verapamil, desipramine, and chlor-pheniramine, but the clinical value of resistance-reversing drugs is not established.
Chloroquine is the drug of choice in the treatment of nonfalci-parum and sensitive falciparum malaria. It rapidly terminates fever (in 24–48 hours) and clears parasitemia (in 48–72 hours) caused by sensitive parasites. It is still used to treat falciparum malaria in some areas with widespread resistance, in particular much of Africa, owing to its safety, low cost, antipyretic proper-ties, and partial activity, but continued use of chloroquine for this purpose is discouraged, especially in nonimmune individuals. Chloroquine has been replaced by other drugs, principally artemisinin-based combination therapies, as the standard therapy to treat falciparum malaria in most endemic countries.Chloroquine does not eliminate dormant liver forms of P vivax and P ovale, and for that reason primaquine must be added for the radical cure of these species.
Chloroquine is the preferred chemoprophylactic agent in malari-ous regions without resistant falciparum malaria. Eradication of P vivax and P ovale requires a course of primaquine to clearhepatic stages.
Chloroquine reaches high liver concentrations and may be used for amebic abscesses that fail initial therapy with metronidazole .
Chloroquine is usually very well tolerated, even with prolonged use. Pruritus is common, primarily in Africans. Nausea, vomit-ing, abdominal pain, headache, anorexia, malaise, blurring of vision, and urticaria are uncommon. Dosing after meals may reduce some adverse effects. Rare reactions include hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient persons, impaired hearing, confusion, psychosis, seizures, agranulocytosis, exfoliative dermatitis, alopecia, bleaching of hair, hypotension, and electrocardiographic changes (QRS widening, T-wave abnor-malities).
The long-term administration of high doses of chloro-quine for rheumatologic diseases can result in irreversible ototoxicity, retinopathy, myopathy, and peripheral neuropathy. These abnormalities are rarely if ever seen with stan-dard-dose weekly chemoprophylaxis, even when given for pro-longed periods. Large intramuscular injections or rapid intravenous infusions of chloroquine hydrochloride can result in severe hypotension and respiratory and cardiac arrest. Parenteral admin-istration of chloroquine is best avoided, but if other drugs are not available for parenteral use, it should be infused slowly.
Chloroquine is contraindicated in patients with psoriasis or por-phyria, in whom it may precipitate acute attacks of these diseases. It should generally not be used in those with retinal or visual field abnormalities or myopathy. Chloroquine should be used with cau-tion in patients with a history of liver disease or neurologic or hematologic disorders. The antidiarrheal agent kaolin and cal-cium- and magnesium-containing antacids interfere with the absorption of chloroquine and should not be co-administered with the drug. Chloroquine is considered safe in pregnancy and for young children.