Anti-Malarial Drugs

I. Classification

A. By Chemical Class

B. By Stage of Parasite Life Cycle Targeted

C. By Clinical Use

II. Artemisinin

Background

• Artesunate - water-soluble; oral, IV, IM, rectal
• Artemether - lipid-soluble; oral, IM, rectal
• Dihydroartemisinin (DHA) - water-soluble; oral (active metabolite of both)
• Arteether - lipid-soluble; IM

Mechanism of Action (MoA)

1. Endoperoxide bridge activation: Inside the parasite's digestive vacuole, heme iron (released during hemoglobin digestion) cleaves the artemisinin endoperoxide bridge, generating highly reactive carbon-centered free radicals.
2. Alkylation and oxidation: These free radicals promiscuously alkylate and oxidize a wide variety of parasite proteins and macromolecules, causing widespread cellular damage.

• Artemisinins act on asexual erythrocytic stages of all human malaria parasites - they are blood schizonticides with no activity on liver or sporozoite stages.
• They are also active against young (but not mature) gametocytes of P. falciparum, which may reduce onward transmission.
• They produce a 4-log10 reduction in parasite burden per 48-hour intraerythrocytic cycle, requiring 3-4 cycles (6-8 days) as monotherapy for complete parasite clearance.
• Artemisinins are the fastest-acting antimalarials currently available.

Pharmacokinetics

• Rapidly absorbed; peak plasma levels occur promptly after oral dosing
• Oral bioavailability typically 30% or less
• Short plasma half-life: DHA t₁/₂ ~1-2 hours
• Both artesunate and artemether are metabolized to DHA (the active form)
• Protein binding: 43-82%
• With repeated dosing, artemisinin induces its own CYP-mediated metabolism (via CYP2B6 and CYP3A4), increasing clearance up to 5-fold
• Short t₁/₂ makes them unsuitable for chemoprophylaxis

Adverse Effects

Therapeutic Uses

1. Severe/complicated P. falciparum malaria: IV artesunate is the drug of choice (FDA approved 2020). Large RCTs and meta-analyses show IV artesunate is superior to IV quinine for both parasite clearance time and patient survival, with a better safety profile.
2. Uncomplicated falciparum malaria: Used exclusively as ACT (see below) - never as monotherapy due to high recrudescence rates from short t₁/₂.
3. Multidrug-resistant P. falciparum: Artemisinins remain effective against chloroquine-sensitive and chloroquine-resistant strains.
4. P. vivax malaria: Effective against asexual erythrocytic stages; must be combined with primaquine/tafenoquine for radical cure of liver hypnozoites.
5. Gametocyte carriage reduction: Decreases gametocyte carriage, potentially reducing transmission.

Artemisinins are not used for prophylaxis due to their very short half-lives.

III. Note on Artemisinin-Based Combination Therapy (ACT)

Rationale for ACT

1. Short t₁/₂ of artemisinins: When given alone, 7+ days of therapy are needed to fully eliminate parasites (recrudescence is common with shorter courses). A partner drug with a longer t₁/₂ "covers" the tail period after the artemisinin is eliminated.
2. Prevention of resistance: Combining two drugs with distinct mechanisms protects each drug from resistance selection. Monotherapy is strongly discouraged by the WHO.
3. Synergistic efficacy: The rapid-acting artemisinin dramatically reduces parasite burden within the first 24-48 hours, allowing the slower-acting partner to mop up remaining parasites.

WHO-Recommended ACT Regimens

ACT in Special Situations

• Severe malaria: IV artesunate for initial treatment, followed by completion of oral ACT
• Pregnancy (1st trimester): ACTs generally avoided; accumulating evidence for artemether-lumefantrine safety may change this
• P. vivax/ovale: ACT addresses blood stages; must add primaquine or tafenoquine for liver stages
• Resistance concerns: Delayed clearance of P. falciparum after artemisinin therapy - initially in SE Asia, now identified in East Africa - is a serious public health threat. Decreased efficacy of artesunate-mefloquine and DHA-piperaquine in SE Asia has been reported.

Partner Drug Profiles

• Lumefantrine: t₁/₂ 4-5 days; structurally similar to mefloquine/halofantrine; absorption markedly increased with high-fat food
• Amodiaquine: t₁/₂ ~14 days; 4-aminoquinoline class
• Mefloquine: t₁/₂ ~14 days; relatively poor tolerability limits wider use
• Piperaquine: t₁/₂ ~28 days (longest); bisquinoline; provides extended post-treatment prophylaxis

• Goodman & Gilman's The Pharmacological Basis of Therapeutics, pp.1312-1314 (Artemisinin and Its Derivatives)
• Katzung's Basic and Clinical Pharmacology, 16th ed., pp.1434-1438 (ARTEMISININ & ITS DERIVATIVES, ACT tables)
• Lippincott Illustrated Reviews: Pharmacology, pp.1174-1176 (G. Artemisinin)