FIGURE 39-3 Chemical structure of antimalarial quinolines and related compounds.
pigment termed hemozoin, and quinolines likely interfere with heme handling. Failure to inactivate heme or even enhanced toxicity of drug—heme complexes is thought to kill the parasites via oxidative damage to membranes.
Resistance of erythrocytic asexual forms of P. falciparum to antimalarial quinolines, especially chloroquine, now is common. Chloroquine resistance results from mutations in the gene encoding a chloroquine resistance transporter, designated crt. Multiple mutations are needed to confer resistance. Chloroquine-resistant P. vivax isolates do not have alterations in their crt ortholog and may have a different resistance mechanism. P-glycoprotein and other transporters may modulate chloroquine resistance.
ABSORPTION, FATE, AND EXCRETION
Chloroquine is well absorbed after oral, intramuscular, and subcutaneous administration. It distributes relatively slowly into a very large apparent volume (over 100 L/kg) and is extensively sequestered in tissues, particularly liver, spleen, kidney, lung, and to a lesser extent, brain and spinal cord. Chloroquine binds moderately (60%) to plasma proteins and is biotransformed via hepatic CYPs to two active metabolites, desethylchloroquine and bisdesethylchloroquine. Renal clearance of chloroquine is about half of total clearance. Unchanged chloroquine and its major metabolites account for >50% and 25% of urinary drug products, respectively, and their renal excretion is increased by urine acidification.
Plasma levels of chloroquine shortly after dosing are determined primarily by the rate of distribution rather than the rate of elimination. Because of extensive tissue binding, a loading dose is used to achieve effective concentrations in plasma. After parenteral administration, rapid entry together with slow exit of chloroquine from a small central compartment can result transiently in potentially lethal drug concentrations in plasma. Hence, parenteral chloroquine is given either by constant intravenous infusion or in small divided doses by the subcutaneous or intramuscular route. Chloroquine is safer when given orally because the rates of absorption and distribution are more closely matched; peak plasma levels are achieved in ~3-5 hours after dosing by this route. The t122 of chloroquine increases from a few days to weeks as plasma levels decline, reflecting the transition from slow distribution to even slower elimination from extensive tissue stores. The terminal t122 ranges from 30 to 60 days, and traces of the drug can be found in the urine for years after a therapeutic regimen.
THERAPEUTIC USES Chloroquine is inexpensive and safe, but its usefulness has declined in those parts of the world where strains of P. falciparum are resistant. Except in areas where resistant strains of P. vivax are reported (Table 39-2), chloroquine is very effective in prophylaxis or treatment of acute attacks of malaria caused by P. vivax, P. ovale, and P. malariae. Chloroquine has no activity against primary or latent liver stages of the parasite. To prevent relapses in P. vivax and P. ovale infections, primaquine can be given either with chloroquine or reserved for use until after a patient leaves an endemic area. Chloroquine rapidly controls the clinical symptoms and para-sitemia of acute malarial attacks. Most patients become afebrile within 24-48 hours after receiving therapeutic doses. If patients fail to respond by the second day of chloroquine therapy, resistance of P. falciparum should be suspected and therapy instituted with quinine or another rapidly acting blood schizontocide. Although parenteral chloroquine can be given safely to comatose or vomiting patients until it can be taken orally, quinidine gluconate usually is given in the U.S. In comatose children, chloroquine is well absorbed when given via nasogastric tube. Tables 39-1 and 39-2 provide information about recommended prophylactic and therapeutic dosage regimens for chloroquine.
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