Table 3.

Pharmacology of some of the main antimalarial drugs

Drug	Anti-malarial mechanism of action	Formulations	Pharmacokinetics	Toxicity	Interactions
Artemisinin Extracted from the leaves of sweet wormwood, Artemisia annua (has given way to more potent derivatives: dihydroartemisinin, artemether, artemotil and artesunate)	Potent blood schizonticide; kills all stages of the asexual parasite by inhibition of an essential calcium ATPase (PfATPase6)	Wide variety of formulations for oral, rectal, and parenteral use	Converted to inactive metabolites by CYP2B6 Potent inducer of its own metabolism Half-life (or t ½) = 1 hr	Usually safe and well tolerated Anaphylaxis in 1/3,000 cases QT prolongation and bradycardia have been reported	None known
Artesunate Sodium salt of the hemisuccinate ester of artemisinin Artemisia annua	Same as for Artemisinin	Tablets, ampoules for intramuscular, intravenous injection, and rectal capsules	Rapidly absorbed Converted almost entirely to the active metabolite dihydroartemisinin t ½ = 45 min No dose reduction with renal or hepatic impairment	As for Artemisinin Some reports of delayed hemolytic reactions and neutropenia	None known
Chloroquine 4 aminoquinoline	Interferes with parasite heme detoxification Ineffective in falciparum malaria due to widespread resistance	Tablets and ampoules for intramuscular or intravenous injection	Rapid absorption when given orally, intramuscularly, or subcutaneously Eliminated very slowly by the kidneys t ½ = 1-2 months	Low safety margin and very dangerous in overdose with multiple side-effects Unpleasant taste Rarely central nervous system toxicity, including convulsions and mental changes Acute overdose can cause cardiac arrhythmias, hypotension, and hypokalemia	Risk of arrhythmias with drugs that prolong the QT interval Risk of acute dystonic reactions with metronidazole Reduced bioavailability of ampicillin Antagonist of antiepileptic effects of carbamazepine and sodium valproate
Primaquine 8 aminoquinoline	Effective against intrahepatic forms of all types of malaria parasite Exact mechanism of action unknown	Tablets	Well absorbed from gastrointestinal tract t ½ = 3-6 hr Metabolized in the liver	Hemolytic anemia in patients with Glucose-6-phosphate dehydrogenase deficiency Abdominal pain Methemoglobinemia	Concomitant drugs liable to induce hemolysis or bone marrow suppression should be avoided
Quinine Alkaloid derived from bark of the Cinchona tree L-stereoisomer of quinidine	Proposed mechanism is inhibition of parasite heme detoxification in the food vacuole Acts principally on the mature trophozoite stage of parasite development	Tablets and ampoules for intravenous injections	Pharmacokinetic properties affected by the severity of malaria Rapid absorption with wide volume of distribution Metabolized by CYP3A4 in liver with polar metabolites excreted in urine Accumulates in renal failure	Toxicity causes a complex of symptoms known as cinchonism, including tinnitus, impaired high-tone hearing, headache, nausea, dizziness, dysphoria, and disturbed vision Hyperinsulinemic hypoglycemia in severe malaria which is particularly common in pregnancy Hypotension and cardiac arrest may result from rapid intravenous injection, therefore should be given by infusion only Prolonged QT interval and arrhythmias	Quinine increases the plasma concentration of digoxin Avoid other drugs that prolong the QT interval
Atovaquone-Proguanil (Malarone™)	Combination of drugs work synergistically Inhibits Plasmodium mitochondrial electron transport and collapses the mitochondrial membrane potential.	Tablets (containing 250 mg of Atovaquone and 100 mg of Proguanil)	Atovaquone is 99% protein bound t ½ = 66-70 hr due to enterohepatic recycling Excreted in feces as unchanged drug Proguanil is 75% protein bound. 50% excreted in urine Accumulates in renal failure with dose reduction needed	Side effects are mainly gastrointestinal including nausea vomiting, diarrhoea and abdominal pain. Can cause transient rise in amylase and transaminases	Atovaquone can displace other highly protein-bound drugs from their protein binding sites. Proguanil potentiates the effects of warfarin

Adapted from WHO guidelines for the treatment of malaria22