QUININE, first isolated from cinchona bark in 1820, remains a fundamental tool for treating malaria, especially severe disease. Quinine acts rapidly, targeting the bloodborne asexual stages of all malaria species. It is available in oral and injectable preparations and can be used in infants and pregnant women. Side effects—nausea, mood change, blurred vision, and ringing in the ears—are common but typically resolve after treatment ends.

Since P. falciparum parasites from most areas of the world respond well to quinine, short courses of the drug are often sufficient when paired with a second drug. In Southeast Asia, however, full course quinine treatment is necessary, usually given in combination with a second drug such as tetracycline.

CHLOROQUINE is a 4-aminoquinoline derivative of quinine first synthesized in 1934. It is safe in infants and pregnant women, and was the historical drug of choice for treatment of nonsevere or uncomplicated malaria and to prevent malaria in travelers. Chloroquine acts primarily against bloodborne asexual stages, although it also works against the bloodstream stage infective to mosquitoes. Because of widespread resistance to this drug, its usefulness is increasingly limited. Side effects are uncommon and generally mild.

AMODIAQUINE, which is closely related to chloroquine, fell out of favor because it caused adverse effects on bone marrow and liver when used for prophylaxis. Amodiaquine is currently being reevaluated as a co-formulation partner with artesunate. Concerns over toxicity remain.

ANTIFOL COMBINATION DRUGS include various combinations of dihydrofolate reductase inhibitors (proguanil, chlorproguanil, pyrimethamine, and trimethoprim) and sulfa drugs (dapsone, sulfalene, sulfamethoxazole, sulfadoxine, and others). The partner drugs in antifol combinations have similar mechanisms of action; consequently, they do not protect each other from resistance to the same degree as unrelated drugs. Current combinations include sulfadoxine-pyrimethamine (SP; Fansidar), sulfalene/pyrimethamine (Metakelfin), and sulfamethoxazole/trimethoprim (cotrimoxazole). Proguanil has also been used in combination with chloroquine for prophylaxis in areas of moderate chloroquine resistance, although it confers only minimal added benefit, especially with prolonged exposure