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QUININE & QUINIDINE
Quinine and quinidine remain important therapies for falciparum malaria—especially severe disease—although toxicity may complicate therapy. Resistance to quinine is uncommon but may be increasing.
Quinine is derived from the bark of the cinchona tree, a tradi-tional remedy for intermittent fevers from South America. Thealkaloid quinine was purified from the bark in 1820, and it has been used in the treatment and prevention of malaria since that time. Quinidine, the dextrorotatory stereoisomer of quinine, is at least as effective as parenteral quinine in the treatment of severe falciparum malaria. After oral administration, quinine is rapidly absorbed, reaches peak plasma levels in 1–3 hours, and is widely distributed in body tissues. The use of a loading dose in severe malaria allows the achievement of peak levels within a few hours. The pharmacokinetics of quinine varies among populations. Individuals with malaria develop higher plasma levels of the drug than healthy controls, but toxicity is not increased, apparently because of increased protein binding. The half-life of quinine also is longer in those with severe malaria (18 hours) than in healthy controls (11 hours). Quinidine has a shorter half-life than qui-nine, mostly as a result of decreased protein binding. Quinine is primarily metabolized in the liver and excreted in the urine.
Quinine is a rapid-acting, highly effective blood schizonticide against the four species of human malaria parasites. The drug is gametocidal against P vivax and P ovale but not P falciparum. It is not active against liver stage parasites. The mechanism of action of quinine is unknown.
Increasing in vitro resistance of parasites from a number of areas suggests that quinine resistance will be an increasing prob-lem. Resistance to quinine is already common in some areas of Southeast Asia, especially border areas of Thailand, where the drug may fail if used alone to treat falciparum malaria. However, qui-nine still provides at least a partial therapeutic effect in most patients.
For many years, quinine dihydrochloride or quinidine gluconate have been the treatments of choice for severe falciparum malaria, although intravenous artesunate now provides an alternative for this indication. Quinine can be administered slowly intravenously or, in a dilute solution, intramuscularly, but parenteral prepara-tions of this drug are not available in the USA. Quinidine has been the standard therapy in the USA for the parenteral treatment of severe falciparum malaria. The drug can be administered in divided doses or by continuous intravenous infusion; treatment should begin with a loading dose to rapidly achieve effective plasma concentrations. Because of its cardiac toxicity and the rela-tive unpredictability of its pharmacokinetics, intravenous quini-dine should be administered slowly with cardiac monitoring. Therapy should be changed to an effective oral agent as soon as the patient has improved and can tolerate oral medications.
Quinine sulfate is appropriate therapy for uncomplicated falci-parum malaria except when the infection was transmitted in an area without documented chloroquine-resistant malaria. Quinine is commonly used with a second drug (most often doxycycline or in children, clindamycin) to shorten quinine’s duration of use (usually to 3 days) and limit toxicity. Quinine is less effective than chloroquine against other human malarias and is more toxic. Therefore, it is not used to treat infections with these parasites.
Quinine is not generally used in chemoprophylaxis owing to its toxicity, although a daily dose of 325 mg is effective.
Quinine is first-line therapy, in combination with clindamycin, in the treatment of infection with Babesia microti or other human babesial infections.
Therapeutic dosages of quinine and quinidine commonly cause tinnitus, headache, nausea, dizziness, flushing, and visual distur-bances, a constellation of symptoms termed cinchonism. Mild symptoms of cinchonism do not warrant the discontinuation of therapy. More severe findings, often after prolonged therapy, include more marked visual and auditory abnormalities, vomiting, diarrhea, and abdominal pain. Hypersensitivity reactions include skin rashes, urticaria, angioedema, and bronchospasm. Hematologic abnormalities include hemolysis (especially with G6PD defi-ciency), leukopenia, agranulocytosis, and thrombocytopenia. Therapeutic doses may cause hypoglycemia through stimulation of insulin release; this is a particular problem in severe infections and in pregnant patients, who have increased sensitivity to insulin. Quinine can stimulate uterine contractions, especially in the third trimester. However, this effect is mild, and quinine and quinidine remain drugs of choice for severe falciparum malaria even during pregnancy. Intravenous infusions of the drugs may cause throm-bophlebitis.
Severe hypotension can follow too-rapid intravenous infusions of quinine or quinidine. Electrocardiographic abnormalities (QT interval prolongation) are fairly common with intravenous quini-dine, but dangerous arrhythmias are uncommon when the drug is administered appropriately in a monitored setting.
Blackwater fever is a rare severe illness that includes markedhemolysis and hemoglobinuria in the setting of quinine therapy for malaria. It appears to be due to a hypersensitivity reaction to the drug, although its pathogenesis is uncertain.
Quinine (or quinidine) should be discontinued if signs of severe cinchonism, hemolysis, or hypersensitivity occur. It should be avoided if possible in patients with underlying visual or auditory problems. It must be used with great caution in those with under-lying cardiac abnormalities. Quinine should not be given concur-rently with mefloquine and should be used with caution in a patient with malaria who has previously received mefloquine chemoprophylaxis. Absorption may be blocked by aluminum-containing antacids. Quinine can raise plasma levels of warfarin and digoxin. Dosage must be reduced in renal insufficiency.
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