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Tuesday, August 19, 2025

Antimalarial agents


Introduction

Malaria remains one of the world’s most significant infectious diseases, caused by protozoan parasites of the Plasmodium genus, including Plasmodium falciparum, P. vivax, P. malariae, P. ovale, and the zoonotic P. knowlesi. It is transmitted through the bite of infected female Anopheles mosquitoes. Despite global eradication efforts, malaria continues to cause hundreds of millions of infections and hundreds of thousands of deaths each year, particularly in sub-Saharan Africa, South Asia, and parts of South America.

Antimalarial agents encompass a diverse group of pharmacological compounds used both for the treatment and prevention of malaria. These agents differ in their chemical classes, mechanisms of action, efficacy against different Plasmodium species, and stages of the parasite’s life cycle they target. Some are effective against blood schizonts (erythrocytic stages), others against liver schizonts (hepatic stages), and a few are active against gametocytes, thereby blocking transmission.

The evolution of drug-resistant strains of P. falciparum and to some extent P. vivax has necessitated the development of new therapies and combinations. Modern management relies heavily on artemisinin-based combination therapies (ACTs) to overcome resistance and enhance treatment efficacy.

Classification of Antimalarial Agents

Antimalarial agents can be classified by:

1. By Stage of Action

  • Tissue schizonticides (act on exo-erythrocytic hepatic forms)

  • Blood schizonticides (act on erythrocytic forms causing symptoms)

  • Gametocytocides (eliminate gametocytes, reducing transmission)

  • Sporontocides (inhibit development in the mosquito vector)

2. By Chemical Class

  • Quinolines (chloroquine, quinine, mefloquine, primaquine, tafenoquine, amodiaquine)

  • Artemisinin and derivatives (artemether, artesunate, dihydroartemisinin)

  • Antifolates (pyrimethamine, proguanil, sulfadoxine)

  • Antibiotics (doxycycline, clindamycin, tetracycline)

  • Naphthoquinones (atovaquone)

  • Miscellaneous agents (lumefantrine, halofantrine, pyronaridine, artemisone)

Major Antimalarial Agents

1. Chloroquine

  • Mechanism of action: Concentrates in parasite food vacuoles, preventing detoxification of heme into hemozoin, leading to toxic heme accumulation.

  • Uses: Previously first-line therapy for P. vivax, P. malariae, and P. ovale. Still effective against P. vivax and P. ovale in non-resistant areas.

  • Limitations: Widespread resistance in P. falciparum.

  • Generic name: chloroquine phosphate.

2. Quinine and Quinidine

  • Mechanism: Similar to chloroquine; interferes with parasite’s ability to digest hemoglobin.

  • Uses: Reserved for severe falciparum malaria when artemisinins are unavailable.

  • Limitations: Toxicity (cinchonism—tinnitus, headache, nausea), hypoglycemia, QT prolongation.

  • Generic names: quinine sulfate, quinidine gluconate.

3. Mefloquine

  • Mechanism: Damages parasite membranes, exact action unclear.

  • Uses: Effective for chloroquine-resistant P. falciparum and P. vivax. Used in prophylaxis.

  • Limitations: Resistance in Southeast Asia, neuropsychiatric adverse effects.

  • Generic name: mefloquine hydrochloride.

4. Primaquine and Tafenoquine

  • Mechanism: Disrupts parasite mitochondrial electron transport and causes oxidative damage.

  • Uses: Only agents effective against dormant hypnozoites in liver (P. vivax and P. ovale), preventing relapse. Also gametocytocidal for P. falciparum.

  • Limitations: Contraindicated in G6PD deficiency (risk of hemolysis).

  • Generic names: primaquine phosphate, tafenoquine succinate.

5. Artemisinin and Derivatives

  • Drugs: artemisinin, artesunate, artemether, dihydroartemisinin.

  • Mechanism: Generates free radicals within parasite food vacuole, rapidly killing blood schizonts.

  • Uses: Cornerstone of therapy; given in ACTs with partner drugs to delay resistance. First-line for P. falciparum.

  • Limitations: Resistance emerging in parts of Southeast Asia.

  • Generic names: artesunate, artemether, dihydroartemisinin.

6. Lumefantrine

  • Mechanism: Interferes with heme detoxification.

  • Uses: Partner drug with artemether in ACT (artemether-lumefantrine, widely used).

  • Generic name: lumefantrine.

7. Atovaquone-Proguanil

  • Mechanism: Atovaquone inhibits mitochondrial electron transport; proguanil enhances activity by inhibiting dihydrofolate reductase.

  • Uses: Treatment and prophylaxis, especially for multidrug-resistant malaria.

  • Generic names: atovaquone, proguanil hydrochloride.

8. Pyrimethamine-Sulfadoxine

  • Mechanism: Both are antifolates; pyrimethamine inhibits dihydrofolate reductase, sulfadoxine inhibits dihydropteroate synthase.

  • Uses: Intermittent preventive therapy in pregnancy; not commonly used due to resistance.

  • Generic names: pyrimethamine, sulfadoxine.

9. Antibiotics (Doxycycline, Clindamycin, Tetracycline)

  • Mechanism: Inhibit protein synthesis in the parasite’s apicoplast organelle.

  • Uses: Used in combination therapy (e.g., doxycycline with quinine).

  • Limitations: Slow-acting, used as adjuncts.

  • Generic names: doxycycline hyclate, clindamycin, tetracycline.

Combination Therapy (ACTs)

To prevent resistance and ensure high efficacy, artemisinin-based combination therapies (ACTs) are standard:

  • Artemether + Lumefantrine

  • Artesunate + Amodiaquine

  • Artesunate + Mefloquine

  • Dihydroartemisinin + Piperaquine

  • Artesunate + Sulfadoxine-Pyrimethamine

These combinations exploit the rapid schizonticidal action of artemisinins with the prolonged half-life of partner drugs.

Clinical Uses of Antimalarial Agents

  1. Treatment of Acute Malaria

    • Uncomplicated falciparum malaria: ACTs (e.g., artemether-lumefantrine).

    • Complicated/severe malaria: IV artesunate (preferred) or IV quinidine/quinine if unavailable.

    • Vivax/ovale malaria: Chloroquine (where sensitive) + primaquine/tafenoquine for relapse prevention.

    • Malariae/knowlesi malaria: Chloroquine effective.

  2. Chemoprophylaxis

    • For travelers to endemic regions: atovaquone-proguanil, doxycycline, or mefloquine, depending on resistance patterns.

  3. Radical Cure

    • Primaquine/tafenoquine eliminates dormant liver stages of P. vivax and P. ovale.

  4. Transmission Blocking

    • Primaquine or tafenoquine as gametocytocides for P. falciparum.

Limitations and Challenges

  • Resistance: Major barrier to malaria control. Widespread resistance to chloroquine and sulfadoxine-pyrimethamine; artemisinin resistance emerging.

  • Toxicities: Neuropsychiatric effects (mefloquine), hemolysis in G6PD deficiency (primaquine), QT prolongation (quinine, lumefantrine, halofantrine).

  • Pregnancy Use: Artemisinin derivatives are safe in 2nd and 3rd trimesters; quinine and clindamycin are alternatives in 1st trimester. Primaquine and tafenoquine are contraindicated.

Future Perspectives

Research is ongoing for next-generation antimalarials:

  • New artemisinin derivatives with longer half-lives.

  • Novel targets: PI4K inhibitors (KAF156), spiroindolones (cipargamin).

  • Malaria vaccines: RTS,S/AS01 (Mosquirix) and R21/Matrix-M as complementary preventive measures.

Generic Names Summary

  • Quinolines: chloroquine, quinine, quinidine, mefloquine, primaquine, tafenoquine, amodiaquine.

  • Artemisinin derivatives: artesunate, artemether, dihydroartemisinin, artemisinin.

  • Antifolates: pyrimethamine, proguanil, sulfadoxine.

  • Naphthoquinone: atovaquone.

  • Combination drugs: lumefantrine, piperaquine, pyronaridine.

  • Antibiotics: doxycycline, tetracycline, clindamycin.



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