Chemotherapy (Parasitic): Antimalarial Drugs

Introduction/Overview

Malaria remains a global health burden, with hundreds of millions of cases annually and significant morbidity and mortality, particularly in sub‑Saharan Africa and parts of Asia. Antimalarial chemotherapy constitutes the cornerstone of both prophylaxis and treatment strategies, and a nuanced understanding of the pharmacology of these agents is essential for practitioners in medicine and pharmacy. This chapter provides a systematic review of antimalarial drugs, encompassing classification, mechanisms of action, pharmacokinetics, therapeutic applications, adverse effect profiles, drug interactions, and considerations for special patient populations. The material is intended to support advanced learning objectives and to inform clinical decision‑making.

Learning objectives

• Identify the major classes of antimalarial drugs and their chemical characteristics.
• Describe the pharmacodynamic mechanisms through which antimalarials exert parasiticidal effects.
• Summarize key pharmacokinetic parameters influencing dosing regimens.
• Recognize common and serious adverse reactions associated with antimalarial therapy.
• Appreciate drug‑drug interaction risks and special considerations in pregnancy, lactation, pediatrics, geriatrics, and patients with hepatic or renal impairment.

Classification

Drug Classes and Categories

The antimalarial armamentarium can be organized into several major pharmacologic classes, each defined by distinct structural motifs and therapeutic roles:

• Hydroxyquinolines – chloroquine, hydroxychloroquine, proguanil (as the prodrug of cycloguanil).
• Artemisinin derivatives – artesunate, artemether, dihydroartemisinin, arteether, and combinations such as artesunate–amodiaquine.
• Antifolates – pyrimethamine, sulfadoxine, and the fixed‑dose combination sulfadoxine‑pyrimethamine (Fansidar).
• Atovaquone–proguanil (Malarone) – a fixed‑dose combination targeting mitochondrial electron transport and dihydrofolate reductase pathways.
• Amphotericin B‑like agents – limited use in severe malaria; includes fosmidomycin.
• Other classes – quinine/quinidine, mefloquine, lumefantrine, and piperaquine.

Chemical Classification

From a chemical standpoint, antimalarials are diverse. Hydroxyquinolines possess a quinoline core substituted with hydroxyl groups, while artemisinins are sesquiterpene lactones containing an endoperoxide bridge. Antifolates structurally resemble folic acid analogs, and atovaquone features a hydroxylated naphthoquinone structure. Understanding these structural nuances aids in predicting pharmacokinetic behavior and potential cross‑reactivity.

Mechanism of Action

Pharmacodynamics

The antimalarial effect is mediated primarily by interference with parasite metabolism, redox balance, or nucleic acid synthesis. Each drug class targets unique pathways:

Hydroxyquinolines accumulate in the acidic digestive vacuole of the parasite, where they inhibit heme polymerization. This leads to the accumulation of toxic free heme, resulting in oxidative damage and parasite death. Chloroquine resistance is often attributed to mutations in the PfCRT transporter, limiting drug accumulation.

Artemisinin derivatives undergo endoperoxide bond cleavage in the presence of ferrous iron, generating reactive oxygen species (ROS) that damage proteins, lipids, and nucleic acids. The rapid parasiticidal activity is particularly useful in acute infections.

Antifolates inhibit dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS), blocking folate synthesis and DNA replication. Resistance emerges through mutations that reduce drug affinity.

Atovaquone disrupts the mitochondrial electron transport chain by inhibiting cytochrome bc1 complex, leading to ATP depletion. Cycloguanil, the active metabolite of proguanil, competitively inhibits DHFR.

Quinine and quinidine act by disrupting protein synthesis and interfering with nucleic acid metabolism. Lumefantrine and piperaquine, structurally related to chloroquine, share similar mechanisms but differ in pharmacokinetics.

Receptor Interactions and Cellular Effects

Unlike many chemotherapeutic agents that target host receptors, antimalarials primarily interact with parasite enzymes and membranes. For example, artemisinin endoperoxides are thought to alkylate multiple parasite proteins, leading to a cascade of proteotoxic stress. Hydroxyquinolines also bind to parasite hemoglobin‑derived heme, preventing polymerization. These interactions culminate in impaired cellular function and eventual parasite lysis.

Pharmacokinetics

Absorption

Oral bioavailability varies across classes. Hydroxyquinolines are well absorbed (>80%) with a half‑day absorption time. Artemisinin derivatives exhibit rapid absorption; artesunate peaks within 30 minutes, whereas artemether peaks around 2–3 hours. Atovaquone demonstrates poor aqueous solubility, necessitating high‑fat meals to enhance absorption. Proguanil is efficiently absorbed, but its conversion to cycloguanil requires hepatic metabolism.

Distribution

Plasma protein binding is high for most antimalarials. Chloroquine binds >90% to plasma proteins and distributes extensively into tissues, including the liver, spleen, and brain. Artemisinin derivatives have lower protein binding (~10–30%) and penetrate rapidly into red blood cells. Atovaquone’s lipophilicity facilitates distribution into adipose tissue, contributing to its prolonged half‑life. The blood‑brain barrier is variably permeable; quinine and chloroquine can accumulate in the central nervous system, which may be relevant to neurotoxicity.

Metabolism

Hepatic metabolism predominates for most agents. Chloroquine is metabolized by CYP3A4 and CYP2D6 to active metabolites such as N‑desethylchloroquine. Artemisinin derivatives undergo rapid hepatic biotransformation via CYP2B6 and CYP3A4, forming dihydroartemisinin or dihydroartemisinic acid. Atovaquone is poorly metabolized; cycloguanil is produced primarily by hepatic amidase activity. Proguanil is hydrolyzed to cycloguanil by amidases and CYP2D6.

Excretion

Renal clearance is limited for most antimalarials, with excretion largely occurring via hepatic routes or biliary excretion. Chloroquine and its metabolites are excreted in urine and feces. Artemisinin metabolites are cleared predominantly through the kidneys, with a half‑life of 1–2 hours for dihydroartemisinin. Atovaquone is eliminated slowly, with a terminal half‑life of 2–3 weeks, necessitating careful monitoring for accumulation in repeated dosing.

Half‑Life and Dosing Considerations

Short‑acting agents such as artesunate (half‑life ~1 hour) require multiple daily doses or intravenous infusion for severe malaria. Long‑acting agents, including atovaquone–proguanil (half‑life of atovaquone ~2–3 weeks, cycloguanil ~4–5 days), permit once‑daily dosing and are suitable for prophylaxis. Dosing must account for drug interactions that may alter metabolism (e.g., CYP3A4 inhibitors or inducers) and for patient factors such as renal or hepatic function, which can prolong drug exposure and increase toxicity risk.

Therapeutic Uses/Clinical Applications

Approved Indications

Antimalarial drugs are indicated for both treatment and prevention of malaria caused by Plasmodium species. The World Health Organization (WHO) recommends artemisinin‑based combination therapies (ACTs) as first‑line treatment for uncomplicated P. falciparum malaria, with specific combinations varying by region. Chloroquine remains effective for P. vivax and P. ovale in areas without resistance, while sulfadoxine‑pyrimethamine is used for prophylaxis and intermittent preventive treatment in pregnancy. Atovaquone–proguanil is indicated for treatment of uncomplicated malaria and as prophylaxis in travelers. Mefoquine, quinine, and piperaquine are reserved for severe or resistant infections.

Off‑Label and Emerging Uses

In certain high‑resistance settings, quinine and mefloquine have been employed off‑label for P. falciparum treatment. Artemisinin derivatives are also being investigated for adjunctive therapy in cerebral malaria and for their anti‑inflammatory properties. Atovaquone has shown efficacy against Babesia microti and Plasmodium vivax relapses in cases of drug‑resistant infection. Emerging data suggest that artemisinin derivatives may possess antiviral activity against certain RNA viruses, although clinical relevance remains speculative.

Adverse Effects

Common Side Effects

Hydroxyquinolines frequently cause gastrointestinal disturbances, including nausea, vomiting, and abdominal pain. Chloroquine may induce retinopathy with prolonged use, necessitating regular ophthalmologic monitoring. Artemisinin derivatives can precipitate transient dizziness and headache; severe neurotoxicity is rare but may occur with high doses. Quinine is associated with cinchonism—tinnitus, vertigo, and metallic taste—especially at elevated plasma concentrations. Atovaquone may cause gastrointestinal upset and, rarely, hepatotoxicity.

Serious or Rare Adverse Reactions

Retinal toxicity, particularly with chloroquine and hydroxychloroquine, is dose‑dependent and can lead to irreversible visual field loss. Severe hemolysis may occur in patients with glucose‑6‑phosphate dehydrogenase (G6PD) deficiency when treated with primaquine for radical cure of P. vivax. Neuropsychiatric events, including depression and psychosis, have been reported with chloroquine and hydroxychloroquine, especially at high cumulative doses. Myopathy, pulmonary fibrosis, and hypersensitivity reactions (e.g., Stevens–Johnson syndrome) can arise with sulfonamides such as sulfadoxine.

Black Box Warnings

Chloroquine and hydroxychloroquine carry black box warnings for retinopathy, cardiomyopathy, and arrhythmias. The risk of QT prolongation is particularly notable when combined with other QT‑prolonging agents. G6PD deficiency is a contraindication for primaquine, and caution is advised with mefloquine regarding neuropsychiatric adverse events.

Drug Interactions

Major Drug‑Drug Interactions

Chloroquine and hydroxychloroquine are metabolized by CYP3A4 and CYP2D6; concomitant use with potent inhibitors (e.g., ketoconazole, ritonavir) can elevate plasma levels and increase toxicity. Conversely, strong CYP3A4 inducers (e.g., rifampin, carbamazepine) may reduce therapeutic efficacy. Atovaquone–proguanil interactions include increased exposure when co‑administered with CYP3A4 inhibitors. Primaquine’s hemolytic potential is amplified in patients with G6PD deficiency. Quinidine and quinine can prolong the QT interval, particularly when combined with other QT‑prolonging agents such as azithromycin or macrolides. Artemisinin derivatives may interact with anticoagulants by affecting platelet function.

Contraindications

G6PD deficiency contraindicates primaquine and, in some guidelines, mefloquine. Severe hepatic impairment contraindicates atovaquone–proguanil due to the risk of hepatotoxicity. Known hypersensitivity to sulfonamides precludes sulfadoxine‑pyrimethamine. Severe cardiac disease and uncontrolled arrhythmias are relative contraindications for chloroquine, hydroxychloroquine, and quinine. Pregnancy is a relative contraindication for mefloquine and primaquine, though the latter is essential for radical cure of P. vivax and P. ovale; dosing adjustments and monitoring are recommended.

Special Considerations

Use in Pregnancy and Lactation

First‑trimester exposure to chloroquine and hydroxychloroquine has not been linked to teratogenicity; however, their safety profile during late pregnancy is not fully established. Mefloquine and quinine are generally considered safe in pregnancy, with data supporting efficacy and tolerability. Primaquine is contraindicated in pregnancy but remains the only drug effective for radical cure of P. vivax and P. ovale. Lactation compatibility varies: chloroquine and hydroxychloroquine are excreted in breast milk at low concentrations; mefloquine and atovaquone–proguanil have limited data but are generally considered compatible with cautious monitoring. Primaquine is contraindicated during lactation due to potential hemolysis in the infant.

Pediatric Considerations

Dosing in children is weight‑based, typically expressed as mg/kg. Hydroxychloroquine and chloroquine dosing must account for reduced renal clearance in neonates and infants. Artemisinin derivatives are preferred for severe malaria in children due to rapid parasiticidal action. Atovaquone–proguanil is approved for prophylaxis and treatment in children aged 5 years and older; younger children require alternative regimens. G6PD deficiency screening is particularly important in pediatric populations receiving primaquine.

Geriatric Considerations

Polypharmacy is common in older adults, increasing the risk of drug interactions. Age‑related decline in hepatic and renal function may prolong drug exposure, necessitating dose adjustments, particularly for atovaquone–proguanil and chloroquine. Neuropsychiatric side effects are more pronounced in the elderly, and close monitoring for dizziness, confusion, and visual disturbances is advised.

Renal and Hepatic Impairment

Hydroxyquinolines are mainly metabolized hepatically; mild to moderate hepatic impairment requires dose reduction. Severe hepatic impairment is a contraindication for atovaquone–proguanil. Renal impairment has limited impact on dosing for most antimalarials, although atovaquone’s prolonged half‑life may necessitate extended monitoring. For patients with concurrent renal disease, artesunate’s rapid metabolism and elimination mitigate accumulation risk.

Summary/Key Points

• Antimalarial drugs are heterogeneous, encompassing hydroxyquinolines, artemisinin derivatives, antifolates, and mitochondrial inhibitors.
• Mechanisms involve inhibition of heme polymerization, ROS generation, folate synthesis blockade, and mitochondrial electron transport disruption.
• Pharmacokinetics vary widely; clinicians must consider absorption enhancers, protein binding, metabolic pathways, and elimination routes when prescribing.
• Common adverse effects include gastrointestinal upset, retinopathy, and neuropsychiatric symptoms; rare but serious events include hemolysis, cardiotoxicity, and hypersensitivity reactions.
• Drug interactions are frequent; careful review of concomitant medications, particularly CYP3A4 modulators and QT‑prolonging agents, is essential.
• Special populations—pregnancy, lactation, pediatrics, geriatrics, and patients with hepatic or renal impairment—require individualized dosing and monitoring strategies.
• Artemisinin‑based combination therapies remain first‑line treatment for uncomplicated P. falciparum malaria, while chloroquine and sulfadoxine‑pyrimethamine retain roles in regions with susceptible parasite strains.
• Emerging evidence suggests potential for antimalarials beyond malaria, but clinical application remains limited and warrants further investigation.

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