Antimalarial Drugs

Antimalarial drugs treat and prevent infection with Plasmodium species. They act on different parasite stages: blood schizonticides cure the symptomatic infection, gametocidal drugs reduce transmission, hypnozoitocidal drugs prevent relapse of vivax and ovale malaria, and causal prophylactic drugs act on the liver stage. Combination therapy delays resistance.

Classes.

• Artemisinins (artesunate, artemether, dihydroartemisinin): rapid parasite clearance, activated by haem iron to produce free radicals.
• Aryl amino alcohols and 4-aminoquinolines (lumefantrine, piperaquine, amodiaquine, chloroquine, quinine, mefloquine): blood schizonticides that interfere with haem detoxification.
• 8-aminoquinolines (primaquine, tafenoquine): hypnozoitocidal and gametocidal.
• Antifolates (sulphadoxine with pyrimethamine, proguanil) and atovaquone: inhibit folate synthesis and mitochondrial electron transport.
• Antibiotics (doxycycline, clindamycin): slow partner drugs.

• Uncomplicated Plasmodium falciparum malaria: a 3-day artemisinin-based combination.
• Severe malaria: intravenous artesunate 2.4 mg/kg at 0, 12 and 24 hours, then daily (3 mg/kg for children under 20 kg), for at least 24 hours, then a full oral combination course.
• Quinine: 20 mg salt/kg intravenous loading dose over 4 hours, then 10 mg/kg every 8 hours, when artesunate is unavailable.
• Vivax and ovale: chloroquine (or an artemisinin-based combination where chloroquine fails) plus primaquine.
• Prevention in pregnancy: sulphadoxine 1500 mg with pyrimethamine 75 mg, each scheduled antenatal visit from the second trimester, at least 1 month apart.
• Traveller prophylaxis: atovaquone with proguanil, doxycycline or mefloquine.

Principles. Confirm infection by rapid test or microscopy before treating. Treat promptly: severe malaria is a medical emergency. Hypoglycaemia is common in children, in pregnancy and with quinine, so check glucose.

Resistance. Artemisinin partial resistance (delayed clearance with kelch13 mutations) has been reported in parts of East Africa, including Rwanda, Uganda, Eritrea and north-west Tanzania. Delayed clearance at day 3, or recurrent parasitaemia within 28 days, needs review of adherence, drug quality and a switch to another combination.

Transmission blocking. Single low-dose primaquine 0.25 mg/kg with the combination in selected settings; safe in the common African G6PD deficiency variant.

Region. In East Africa, Plasmodium falciparum causes most disease. Plasmodium vivax is mainly in the Horn of Africa. Antimalarial prescribing follows national treatment policy, with supply of artemether with lumefantrine usually widest.

Class safety.

• Artemisinins: well tolerated; delayed haemolysis 1 to 3 weeks after intravenous artesunate in severe malaria.
• Quinine: cinchonism (tinnitus, headache, nausea), hypoglycaemia, QT prolongation.
• Mefloquine: neuropsychiatric effects, seizures.
• Primaquine and tafenoquine: haemolysis in G6PD deficiency.
• Chloroquine: pruritus, QT prolongation, cardiotoxicity in overdose.

Monitoring. Parasite count and glucose in severe malaria; haemoglobin weekly for 4 weeks after intravenous artesunate; ECG when combining QT-prolonging drugs.

Special groups.

• Pregnancy: artemether with lumefantrine is used in all trimesters; quinine with clindamycin is an alternative; avoid primaquine and tafenoquine.
• Breastfeeding: most antimalarials are compatible; primaquine and tafenoquine need a G6PD-normal infant.
• Children: weight-based dosing; treat severe malaria with intravenous artesunate first.
• Kidney impairment: no reduction for artemisinins; quinine needs reduction after 48 hours.

Referral and escalation. Refer severe malaria, treatment failure, and malaria in pregnancy with complications.