Pharmacology of Antimalarial Drugs

Introduction/Overview

Malaria remains a significant global health challenge, with an estimated 247 million cases and 619,000 deaths reported in 2021, predominantly affecting children under five years of age in sub-Saharan Africa. The pharmacology of antimalarial drugs constitutes a critical domain of study, integrating parasitology, chemotherapy, and clinical medicine. These agents target protozoan parasites of the genus Plasmodium, with P. falciparum and P. vivax representing the species of greatest clinical importance. The therapeutic landscape is complicated by widespread drug resistance, necessitating a deep understanding of drug mechanisms, pharmacokinetic properties, and rational combination strategies.

The clinical relevance of antimalarial pharmacology extends beyond acute treatment to encompass chemoprophylaxis for travelers, intermittent preventive treatment in pregnancy and infancy, and radical cure for latent hypnozoites of P. vivax and P. ovale. The evolution of resistance, particularly to chloroquine and sulfadoxine-pyrimethamine, has driven the development and deployment of artemisinin-based combination therapies (ACTs), which now form the cornerstone of global treatment guidelines. Mastery of this topic is essential for optimizing therapeutic outcomes and mitigating the spread of resistance.

Learning Objectives

• Classify antimalarial drugs based on chemical structure, mechanism of action, and clinical indication (treatment vs. prophylaxis).
• Explain the molecular and cellular mechanisms of action for major antimalarial drug classes, including their targets within the parasite’s life cycle.
• Analyze the pharmacokinetic profiles of key antimalarials and relate these properties to dosing regimens, therapeutic efficacy, and the development of resistance.
• Evaluate the clinical applications, adverse effect profiles, and major drug interactions of antimalarial agents to inform safe and effective prescribing.
• Formulate treatment and prophylaxis strategies considering special populations, including pregnant women, children, and patients with comorbid conditions.

Classification

Antimalarial drugs can be classified according to several schemas, including chemical structure, mechanism of action, and the stage of the parasitic life cycle they target. A comprehensive classification facilitates an organized approach to their study and clinical use.

Chemical and Therapeutic Classification

The primary classes are defined by their core chemical scaffolds and historical development.

• 4-Aminoquinolines: This class includes chloroquine, amodiaquine, and piperaquine. They are synthetic compounds derived from quinine, characterized by a quinoline ring structure and an amino side chain. They primarily act on the asexual blood stages (trophozoites) and are used for treatment and prophylaxis.
• 8-Aminoquinolines: Primaquine and tafenoquine belong to this group. Their distinct structure allows for activity against latent hypnozoites in the liver, enabling radical cure of P. vivax and P. ovale infections. They also possess activity against gametocytes, the sexual transmission stages.
• Artemisinin and Derivatives (Sesquiterpene Lactones): Artemisinin is a natural product isolated from Artemisia annua (sweet wormwood). Semisynthetic derivatives include artesunate, artemether, and dihydroartemisinin. These agents have the most rapid parasiticidal action and form the basis of ACTs.
• Arylaminoalcohols: Quinine and its stereoisomer quinidine, along with mefloquine and lumefantrine, constitute this group. They are often used in combination therapies and for severe malaria.
• Antifolates: This class inhibits folate synthesis in the parasite and includes two sub-groups:
  • Dihydrofolate reductase (DHFR) inhibitors: Pyrimethamine, proguanil, and chlorproguanil.
  • Dihydropteroate synthase (DHPS) inhibitors: Sulfadoxine, dapsone.

  These are typically used in fixed-dose combinations (e.g., sulfadoxine-pyrimethamine).

• Antibiotics: Agents such as doxycycline, clindamycin, and tetracycline have antimalarial activity through inhibition of prokaryotic protein synthesis in the parasite’s apicoplast. They are used primarily in prophylaxis and combination therapy for treatment.
• Naphthoquinones: Atovaquone, which is used in fixed combination with proguanil (Malarone®), inhibits mitochondrial electron transport.

Classification by Parasite Life Cycle Stage

This functional classification is clinically pertinent for selecting drugs based on therapeutic goal.

• Tissue Schizonticides (for causal prophylaxis): Drugs that act on the pre-erythrocytic liver stages (primary exoerythrocytic forms), preventing invasion of red blood cells. Primaquine and atovaquone-proguanil exhibit this activity.
• Blood Schizonticides (for clinical cure): Agents that eliminate the asexual erythrocytic stages responsible for clinical symptoms. Most antimalarials, including chloroquine, artemisinins, quinine, and mefloquine, fall into this category.
• Gametocytocides (for transmission blocking): Drugs that kill or sterilize sexual gametocytes, thereby preventing transmission to mosquitoes. Primaquine and artemisinins have gametocytocidal activity.
• Hypnozoitocides (for radical cure): Drugs that eradicate the dormant hypnozoite stage of P. vivax and P. ovale in the liver, preventing relapses. Only the 8-aminoquinolines, primaquine and tafenoquine, possess this activity.

Mechanism of Action

The mechanisms of action of antimalarial drugs are diverse, reflecting the complex biology of the Plasmodium parasite. Understanding these mechanisms is crucial for appreciating therapeutic efficacy, patterns of resistance, and rationale for drug combinations.

4-Aminoquinolines: Chloroquine and Analogs

The primary action of chloroquine is linked to the inhibition of hemozoin formation within the parasite’s acidic digestive vacuole. Following erythrocyte invasion, the parasite degrades host hemoglobin to acquire amino acids, releasing free heme (ferriprotoporphyrin IX), which is toxic. The parasite normally polymerizes this heme into an inert crystalline pigment called hemozoin (malaria pigment). Chloroquine, a weak base, diffuses freely into the parasite cytosol but becomes protonated and trapped within the acidic vacuole (pH ≈ 5.2). The accumulated drug is thought to form complexes with heme, preventing its polymerization. The resulting accumulation of toxic free heme leads to membrane damage, protease inhibition, and ultimately parasite death. Resistance to chloroquine is primarily associated with mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT), which facilitates efflux of the drug from the vacuole, reducing its concentration at the site of action.

Artemisinin and Derivatives

The exact mechanism of artemisinins is multifactorial and involves activation by heme or free iron within the parasite. The endoperoxide bridge in the artemisinin structure is cleaved by intraparasitic iron(II), generating reactive oxygen species (ROS) and carbon-centered free radicals. These highly reactive intermediates alkylate and damage critical parasite proteins and membranes. Key targets may include the PfATP6 (a sarcoplasmic-endoplasmic reticulum calcium ATPase), mitochondrial function, and redox homeostasis. A hallmark of artemisinins is their rapid killing of all erythrocytic stages, including young ring forms, which may contribute to their efficacy in severe malaria. Partial resistance, characterized by delayed parasite clearance, has been linked to mutations in the Kelch13 (PfK13) propeller domain, which is believed to affect the parasite’s stress response and protein ubiquitination pathways.

8-Aminoquinolines: Primaquine and Tafenoquine

The mechanism by which 8-aminoquinolines eliminate hypnozoites is not fully elucidated but is distinct from their activity against blood stages. These drugs require metabolic activation by cytochrome P450 enzymes (primarily CYP2D6) to generate reactive metabolites. These metabolites are believed to cause oxidative stress within the parasite mitochondria by redox cycling, generating ROS that damage mitochondrial membranes and disrupt electron transport. This mechanism is particularly effective against the metabolically active hypnozoite upon reactivation. Their gametocytocidal action also involves generating oxidative damage. The requirement for CYP2D6 activation explains cases of therapeutic failure in individuals with poor metabolizer phenotypes.

Arylaminoalcohols: Quinine, Mefloquine, and Lumefantrine

Quinine and related compounds are thought to share a common mechanism involving interference with the parasite’s heme detoxification pathway, similar to but distinct from chloroquine. They may also inhibit hemozoin formation. More recent evidence suggests they can directly bind to and inhibit the parasite’s nucleic acid and protein synthesis. Mefloquine may additionally disrupt parasite membrane function. Lumefantrine, always used in combination with artemether, likely shares this heme-binding mechanism. Resistance to these agents is complex and multifactorial.

Antifolates: Sulfadoxine-Pyrimethamine

This combination sequentially inhibits two enzymes in the parasite’s folate biosynthesis pathway, which is essential for DNA synthesis. Sulfadoxine (a sulfonamide) competitively inhibits dihydropteroate synthase (DHPS), blocking the conversion of para-aminobenzoic acid (PABA) to dihydropteroate. Pyrimethamine inhibits dihydrofolate reductase (DHFR), preventing the reduction of dihydrofolate to tetrahydrofolate. The sequential blockade creates a synergistic effect, depleting tetrahydrofolate cofactors required for thymidylate and purine synthesis. Resistance arises from point mutations in the genes encoding PfDHFR and PfDHPS that reduce drug binding.

Atovaquone-Proguanil

This combination acts synergistically on the parasite’s mitochondrial electron transport chain. Atovaquone is a structural analog of ubiquinone and inhibits the cytochrome bc₁ complex (Complex III), collapsing mitochondrial membrane potential and disrupting cellular energy metabolism. Proguanil, via its active metabolite cycloguanil, is a DHFR inhibitor. However, its primary role in the combination is to potentiate the effect of atovaquone; proguanil itself (not cycloguanil) appears to synergistically increase mitochondrial membrane collapse. Resistance to atovaquone emerges readily via single-point mutations in the cytochrome b gene, but the combination with proguanil significantly raises the genetic barrier to resistance.

Antibiotics: Doxycycline and Clindamycin

These agents target the prokaryote-derived apicoplast organelle in Plasmodium. Doxycycline inhibits protein synthesis by binding to the 30S ribosomal subunit, blocking aminoacyl-tRNA attachment. Clindamycin binds to the 50S ribosomal subunit. Inhibition of apicoplast protein synthesis does not immediately kill the blood-stage parasite but prevents the development of daughter parasites, resulting in a “delayed death” phenotype observed 48-72 hours after treatment. This slow action necessitates their use in combination with a rapidly acting schizonticide like artesunate or quinine.

Pharmacokinetics

The pharmacokinetic properties of antimalarial drugs govern their dosing schedules, efficacy, toxicity, and potential for selecting resistant parasites. Significant inter-individual variability exists, often influenced by the disease state itself.

Absorption

Absorption profiles vary widely. Artesunate and chloroquine are rapidly absorbed, leading to a quick onset of action. In contrast, lumefantrine and atovaquone are highly lipophilic and absorption is significantly enhanced by co-administration with fat. This is critical for lumefantrine, where a fatty meal can increase bioavailability up to 16-fold. In severe malaria, gastrointestinal absorption may be compromised due to vomiting, ileus, or reduced splanchnic perfusion, necessitating the use of parenteral formulations (intravenous or intramuscular artesunate, quinine, or artemether).

Distribution

Volume of distribution is typically large for most antimalarials, often exceeding total body water, indicating extensive tissue binding. Chloroquine concentrates several hundred-fold in infected erythrocytes and in tissues such as the liver, spleen, and kidney. Mefloquine has a very large volume of distribution due to high tissue binding, particularly in the brain, which may correlate with its neuropsychiatric effects. Artemisinin derivatives distribute widely and rapidly into tissues, including across the blood-brain barrier. Primaquine has a relatively smaller volume of distribution.

Metabolism

Hepatic metabolism is the primary route of elimination for most antimalarials. Cytochrome P450 enzymes play a central role. Artemisinin derivatives undergo rapid and extensive metabolism, primarily by CYP2A6, CYP2B6, and CYP3A4, to the active metabolite dihydroartemisinin (DHA). Chloroquine is metabolized to desethylchloroquine by CYP2C8, CYP3A4, and CYP2D6. Primaquine is metabolized by CYP2D6 to active metabolites; genetic polymorphisms in this enzyme can lead to treatment failure for radical cure. Atovaquone is not significantly metabolized, while proguanil is metabolized by CYP2C19 to its active form, cycloguanil. Variability in metabolizer status (e.g., CYP2C19 poor metabolizers) can affect proguanil efficacy.

Excretion and Half-Life

Elimination half-lives dictate dosing frequency and suitability for prophylaxis versus treatment.

• Very long half-life (t_1/2 > 100 hours): Mefloquine (≈ 21 days), piperaquine (≈ 23 days), tafenoquine (≈ 15 days). These drugs are suitable for weekly or single-dose prophylactic regimens and provide a long post-treatment prophylactic effect.
• Long half-life (t_1/2 50-100 hours): Chloroquine (≈ 50 days), sulfadoxine (≈ 100-200 hours), pyrimethamine (≈ 80-120 hours).
• Intermediate half-life (t_1/2 20-50 hours): Lumefantrine (≈ 3-6 days, biphasic), amodiaquine (active metabolite ≈ 9-18 days).
• Short half-life (t_1/2 < 20 hours): Artemisinin derivatives (≈ 1-3 hours for artesunate, ≈ 1 hour for DHA), quinine (≈ 11 hours), atovaquone (≈ 2-3 days, but concentration-dependent), doxycycline (≈ 18 hours), primaquine (≈ 6 hours). The short half-life of artemisinins is a key reason they are used in combination with a longer-acting partner drug to prevent recrudescence.

Renal excretion of unchanged drug is significant for chloroquine (≈ 50%), doxycycline, and proguanil. Biliary excretion and fecal elimination are important for drugs like mefloquine and lumefantrine.

Therapeutic Uses/Clinical Applications

The clinical application of antimalarial drugs is guided by the infecting Plasmodium species, regional drug resistance patterns, disease severity, and patient-specific factors. The World Health Organization (WHO) treatment guidelines provide the primary framework for decision-making.

Treatment of Uncomplicated Falciparum Malaria

Artemisinin-based combination therapies are the first-line treatment worldwide. ACTs pair a rapidly acting, short-half-life artemisinin derivative with a longer-acting partner drug. The artemisinin component rapidly reduces the parasite biomass (by up to 10⁴ per asexual cycle), providing rapid symptom relief and killing gametocytes, while the partner drug eliminates remaining parasites and protects against recrudescence. Common ACTs include:

• Artemether-lumefantrine (Coartem®)
• Artesunate-amodiaquine
• Artesunate-mefloquine
• Artesunate-sulfadoxine-pyrimethamine
• Dihydroartemisinin-piperaquine

In areas with artemisinin partial resistance, the choice of partner drug becomes critical, and therapeutic efficacy studies guide national policy.

Treatment of Severe Malaria

Severe malaria is a medical emergency requiring prompt parenteral therapy. Intravenous artesunate is the treatment of choice for adults and children, having demonstrated superior efficacy and safety compared to quinine. Intramuscular artemether is an alternative if IV artesunate is not immediately available. Parenteral therapy should be administered for a minimum of 24 hours, until the patient can tolerate oral medication, at which point a full course of an ACT is completed. Quinidine, the dextrorotatory isomer of quinine, is rarely used now due to its cardiac toxicity.

Treatment of Non-Falciparum Malaria

For chloroquine-sensitive P. vivax, P. ovale, P. malariae, and P. knowlesi, chloroquine remains effective for blood-stage clearance. However, due to widespread chloroquine-resistant P. vivax (CRPv) in some regions, ACTs are increasingly recommended as first-line for all species. A critical distinction for P. vivax and P. ovale is the need for radical cure with an 8-aminoquinoline (primaquine or tafenoquine) to prevent relapse from hypnozoites. This must be preceded by testing for glucose-6-phosphate dehydrogenase (G6PD) deficiency to avoid hemolysis.

Chemoprophylaxis

Drug selection for prophylaxis depends on travel destination, resistance patterns, duration of travel, patient comorbidities, and cost.

• Atovaquone-proguanil: Highly effective, well-tolerated, taken daily starting 1-2 days before travel. Suitable for short-term travel.
• Doxycycline: Effective, inexpensive, taken daily. Side effects include photosensitivity and gastrointestinal upset.
• Mefloquine: Taken weekly, suitable for long-term travel. Contraindicated in those with psychiatric or seizure history.
• Tafenoquine: Approved for prophylaxis, with a loading dose regimen and then weekly dosing. Requires prior G6PD testing.

Chloroquine, with or without proguanil, is now limited to very few areas with no chloroquine resistance.

Intermittent Preventive Treatment (IPT)

This public health strategy involves administering full therapeutic doses of an antimalarial at specified intervals to vulnerable populations, regardless of infection status.

• IPT in pregnancy (IPTp): Sulfadoxine-pyrimethamine is administered at each scheduled antenatal visit after the first trimester in areas of moderate-to-high transmission in Africa to reduce maternal anemia, low birth weight, and neonatal mortality.
• IPT in infants (IPTi): Sulfadoxine-pyrimethamine is given alongside routine vaccinations.
• Seasonal Malaria Chemoprevention (SMC): Amodiaquine plus sulfadoxine-pyrimethamine is given monthly during the high-transmission season to children aged 3-59 months in the Sahel sub-region.

Adverse Effects

The adverse effect profiles of antimalarial drugs range from mild, common side effects to rare but life-threatening reactions. Awareness of these effects is essential for patient counseling and monitoring.

Common Side Effects

• Chloroquine and Hydroxychloroquine: Pruritus (common in dark-skinned individuals), headache, gastrointestinal disturbances (nausea, diarrhea), blurred vision, and skin rash. Prolonged use for autoimmune diseases can cause irreversible retinopathy.
• Artemisinin Derivatives: Generally well-tolerated. Transient neutropenia and delayed hemolysis (post-artesunate delayed hemolysis) have been reported, particularly after treatment for severe malaria.
• Quinine/Quinidine: Cinchonism (tinnitus, hearing loss, headache, nausea, visual disturbances), hypoglycemia (due to hyperinsulinemia), and hypotension with rapid IV infusion. Quinidine has greater cardiotoxicity (QT prolongation, ventricular arrhythmias).
• Mefloquine: Neuropsychiatric effects are dose-related and include vivid dreams, insomnia, anxiety, depression, and, rarely, acute psychosis or seizures. Dizziness and gastrointestinal upset are also common.
• Atovaquone-Proguanil: Generally mild; abdominal pain, nausea, vomiting, headache, and elevated transaminases.
• Doxycycline: Gastrointestinal irritation, photosensitivity, vaginal candidiasis, and esophageal ulceration if not taken with adequate water.
• Primaquine and Tafenoquine: Gastrointestinal upset, headache, and methemoglobinemia (usually mild and self-limiting). The most serious adverse effect is acute hemolytic anemia in individuals with G6PD deficiency, which is an absolute contraindication without prior testing and dose adjustment.

Serious/Rare Adverse Reactions

• Black Box Warnings: Mefloquine carries a black box warning in the United States for the risk of persistent and permanent neurological and psychiatric effects, including vertigo, loss of balance, and neuropsychiatric events. Tafenoquine carries a black box warning regarding hemolytic anemia in G6PD-deficient individuals and contraindication in pregnancy.
• Severe Cutaneous Reactions: Sulfadoxine-pyrimethamine can cause Stevens-Johnson syndrome and toxic epidermal necrolysis. Amodiaquine has been associated with agranulocytosis and hepatotoxicity, limiting its use to treatment rather than prophylaxis.
• Cardiotoxicity: Halofantrine (now rarely used) and, to a lesser extent, quinine and quinidine can cause QT interval prolongation and torsades de pointes. Chloroquine in overdose or with pre-existing cardiac disease can cause cardiomyopathy and conduction defects.
• Neurotoxicity: High-dose or prolonged intravenous artemisinin derivatives in animal studies cause brainstem neurotoxicity, but this has not been a clinical issue with standard short-course human treatment.

Drug Interactions

Antimalarial drugs are involved in numerous pharmacokinetic and pharmacodynamic interactions, which can alter their efficacy or increase toxicity.

Major Drug-Drug Interactions

• Enzyme Induction/Inhibition: Artemisinin derivatives, particularly artemether, are metabolized by CYP3A4 and can induce their own metabolism and that of other drugs. They may reduce the efficacy of oral contraceptives, anticonvulsants, and antiretrovirals. Conversely, strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) can increase artemisinin levels. Chloroquine inhibits CYP2D6, potentially increasing levels of drugs like metoprolol and some antidepressants.
• QT Prolongation: Concomitant use of drugs that prolong the QT interval (e.g., antiarrhythmics, macrolide antibiotics, some antipsychotics) with quinine, quinidine, or halofantrine increases the risk of life-threatening arrhythmias.
• Antiepileptic Drugs: Enzyme-inducing antiepileptics (e.g., phenytoin, carbamazepine, phenobarbital) can significantly reduce the plasma concentrations of mefloquine, doxycycline, and proguanil, potentially leading to prophylactic or treatment failure.
• Antiretrovirals: Complex interactions exist. For example, atovaquone levels are reduced by rifampin and possibly efavirenz. Zidovudine may potentiate the bone marrow suppressive effects of pyrimethamine. Protease inhibitors may interact with artemisinins via CYP3A4.
• Antacids and Cations: Doxycycline and fluoroquinolones (sometimes used in prophylaxis) form chelation complexes with divalent and trivalent cations (e.g., in antacids, iron supplements, calcium), severely impairing absorption. These should be administered at least 2-4 hours apart.
• Warfarin: Quinine and possibly other antimalarials may potentiate the anticoagulant effect of warfarin, requiring close INR monitoring.

Contraindications

• Absolute Contraindications: Primaquine/tafenoquine in G6PD deficiency (without supervised risk-benefit assessment and dose modification for primaquine), known severe hypersensitivity to the drug, and retinopathy from chloroquine/hydroxychloroquine. Mefloquine is contraindicated in patients with a history of psychiatric disorders, seizures, or cardiac conduction abnormalities.
• Relative Contraindications: Use of mefloquine in persons performing fine motor tasks (e.g., pilots); use of sulfadoxine-pyrimethamine in patients with sulfa allergy or folate deficiency; use of doxycycline in children under 8 years (due to teeth discoloration) and in pregnancy (due to effects on fetal bone/teeth).

Special Considerations

Pregnancy and Lactation

Malaria in pregnancy carries high risks of maternal anemia, fetal loss, prematurity, and low birth weight. Treatment choices are limited by teratogenic potential.

• First Trimester: Quinine plus clindamycin is recommended for uncomplicated falciparum malaria. ACTs may be considered if other treatments are not available, with artemether-lumefantrine having the most safety data. For severe malaria, IV artesunate is recommended in all trimesters as the benefits outweigh the risks.
• Second and Third Trimesters: ACTs are recommended. Artemether-lumefantrine, artesunate-amodiaquine, and artesunate-mefloquine are considered safe.
• Chemoprophylaxis: Mefloquine is considered safe for prophylaxis in all trimesters. Chloroquine (in sensitive areas) and proguanil are also options. Doxycycline and primaquine/tafenoquine are contraindicated.
• Lactation: Most antimalarials are excreted in breast milk in small amounts. Chloroquine, quinine, and ACTs are considered compatible with breastfeeding. Primaquine should be avoided in nursing mothers unless the infant has been tested for G6PD deficiency.

Pediatric Considerations

Dosing is based on body weight, and many drugs have pediatric formulations (dispersible tablets, suspensions). Artemether-lumefantrine dispersible tablets are widely used. Doxycycline is generally avoided in children under 8 years due to the risk of permanent tooth discoloration, though short courses may be justified for life-threatening multidrug-resistant infections. Chloroquine is highly toxic in overdose, and safe storage of pediatric formulations is crucial. Taste acceptability of medications can impact adherence.

Geriatric Considerations

Age-related declines in renal and hepatic function may alter drug pharmacokinetics. Dose adjustments for chloroquine and doxycycline may be necessary in renal impairment. Increased susceptibility to QT prolongation with quinine and to neuropsychiatric effects with mefloquine may be observed. Comorbid conditions and polypharmacy increase the risk of drug interactions.

Renal and Hepatic Impairment

• Renal Impairment: Chloroquine and doxycycline require dose reduction in severe renal failure as they are renally excreted. Artesunate and its metabolite are primarily cleared by extra-renal mechanisms, so no adjustment is needed. Mefloquine and lumefantrine do not require adjustment. Quinine may accumulate, and doses should be reduced with close monitoring for cinchonism.
• Hepatic Impairment: Most antimalarials are metabolized by the liver. Caution is advised with drugs like primaquine, mefloquine, and artemisinin derivatives in severe hepatic impairment, though specific guidelines are often lacking. Dose reduction may be necessary, and monitoring for toxicity is important.

Summary/Key Points

• Antimalarial drugs are classified by chemical structure (4-/8-aminoquinolines, artemisinins, antifolates, etc.) and by their target in the parasite’s life cycle (blood schizonticides, hypnozoitocides).
• Mechanisms of action are diverse, including inhibition of heme polymerization (chloroquine), generation of free radicals (artemisinins), disruption of mitochondrial function (atovaquone, primaquine), and inhibition of folate synthesis (sulfadoxine-pyrimethamine).
• Pharmacokinetic properties, particularly half-life, critically influence clinical use. Short-acting artemisinins are combined with long-acting partner drugs in ACTs to ensure cure and prevent resistance. Long-half-life drugs like mefloquine are suited for prophylaxis.
• Artemisinin-based combination therapies are the first-line treatment for uncomplicated falciparum malaria globally. Intravenous artesunate is the treatment of choice for severe malaria.
• Radical cure of P. vivax and P. ovale requires an 8-aminoquinoline (primaquine or tafenoquine), mandating prior testing for glucose-6-phosphate dehydrogenase deficiency to avoid hemolytic anemia.
• Adverse effect profiles are drug-specific, ranging from cinchonism (quinine) and neuropsychiatric effects (mefloquine) to gastrointestinal disturbances and hemolysis in G6PD deficiency (primaquine).
• Significant drug interactions occur, particularly involving cytochrome P450 enzymes (e.g., artemisinins and CYP3A4) and QT prolongation (quinine).
• Special considerations guide use in pregnancy (avoid doxycycline and primaquine; ACTs are preferred in 2nd/3rd trimesters), children (weight-based dosing), and patients with renal/hepatic impairment.

Clinical Pearls

• Always confirm the diagnosis parasitologically before initiating treatment. Species identification guides therapy (e.g., need for radical cure).
• Adherence to the full course of ACTs is essential to prevent treatment failure and the development of resistance, even if symptoms resolve quickly.
• For travelers, chemoprophylaxis choice must be individualized based on destination, itinerary, medical history, and tolerability. Emphasize the importance of completing the post-travel prophylactic course for drugs like doxycycline and mefloquine.
• In severe malaria, a single dose of intramuscular artemether can be life-saving when IV artesunate is not available, but referral for definitive care is paramount.
• When prescribing primaquine or tafenoquine, documentation of a normal G6PD level is a critical patient safety step.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
3. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
4. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
5. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
6. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
7. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
8. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.