, Kyle John Wilby2 and Mary H. H. Ensom1
(1)
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada
(2)
College of Pharmacy, Qatar University, Doha, Qatar
Currently recommended antimalarial agents consist of a variety of agents from different drug classes. Differences in mechanisms of action allow for synergistic combinations and increased therapeutic success. A summary of pharmacological and pharmacokinetic considerations is given in Table 2.1 for chloroquine, amodiaquine, sulfadoxine, pyrimethamine, mefloquine, quinine/quinidine, artemisinin (the artemisinin agents, artemether, artesunate, and dihydroartemisin, are closely related and summarized as a class, where applicable), lumefantrine, primaquine, atovaquone, and proguanil.
Drug | General chemistry | Mechanism of action | Clinical pharmacology | Clinical pharmacodynamics |
|---|---|---|---|---|
Chloroquine | 4-aminoquinoline | Interferes with heme detoxification. Concentrates in digestive vacuoles and binds to heme and disrupts its sequestration. Parasite killed by resulting oxidative damage to membranes, digestive proteases, or other biomolecules. Binds to and inhibits DNA and RNA polymerase | Absorption: well absorbed from gastrointestinal tract and tissues Distribution: extensively sequesters in tissues (liver, spleen, kidney, lung, melanin-containing tissues). 60 % bound to plasma proteins Metabolism: metabolized to desethylchloroquine and bidesethylchloroquine Elimination: unchanged chloroquine and desethylchloroquine account for >50 % and 25 % of urinary products. Elimination t1/2 = 3–5 days. Terminal t1/2 = 30–60 days | Mostly effective against erythrocytic forms of P. vivax, ovale, and malariae. Mostly now resistant to P. falciparum in endemic regions but maintains activity against some strains. Resistance conferred by pfcrt (P. falciparum chloroquine resistance transporter). Alleles with 4–8 mutations highly associated with resistance by encoding putative transporter that actively effluxes chloroquine away from heme target. Variant pfcrt alleles may partially confer resistance to other agents (amodiaquine, quinine) but increase susceptibility to lumefantrine and artemisinin derivatives |
Amodiaquine | Synthetic 4-aminoquinolone | Not entirely known. Considered to penetrate red blood cells and prevent parasite from polymerizing heme into hemozoin, leading to parasite death | Absorption: well absorbed from gastrointestinal tract Distribution: volume of distribution 20–40 L/kg Metabolism: high first pass metabolism via CYP2C8 to monodesethylamodiaquine. Further presumed to undergo oxidation and glucuronidation Elimination: 2 % excreted unchanged in urine. Terminal t1/2 = 9–18 days | Given in combination with artesunate for P. falciparum. Resistance documented to amodiaquine for P. falciparum but activity remains against some chloroquine-resistant strains |
Sulfadoxine | Sulfonamide | Interferes with folic acid synthesis via competitive inhibition of dihydropteroate synthase | Absorption: slow but completely absorbed (Tmax = 4 h) Distribution: apparent volume of distribution = 0.14 L/kg, 90 % plasma protein bound Metabolism: 5 % appears in plasma as acetylated metabolite, 2–3 % as glucuronide Elimination: primarily eliminated via kidneys | Synergy with pyrimethamine results from inhibition of: (1) utilization of p-aminobenzoic acid for synthesis of dihydropteroic acid and (2) reduction of dihydrofolate to tetrahydrofolate. Resistance conferred by several point mutations in dihydropteroate synthase gene. Resistance to both sulfadoxine and pyrimethamine causing decline in use |
Pyrimethamine | 2,4-diaminopyrimidine | Inhibits dihydrofolate reductase, resulting in inhibition of tetrahydrofolic acid synthesis | Absorption: well absorbed from gastrointestinal tract Distribution: extensively distributes into tissues, 80–87 % plasma protein bound Metabolism: hepatic metabolism to several metabolites Elimination: 20–30 % excreted as unchanged drug in urine. Elimination t1/2 = 80–95 h
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