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Classification of Antimalarial Drugs - Pharmacology

Overview: Classification by Stage of Action

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Classification by Chemical Structure

1. 4-Aminoquinolines

• Concentrate in parasite food vacuoles
• Prevent biocrystallization of heme (from hemoglobin breakdown) into hemozoin (inert crystal)
• Free heme accumulates and is toxic to the parasite
• Highly effective blood schizonticides; NOT active against liver stages or gametocytes

• Oral absorption is rapid and near-complete; t½ = 1-2 months (very long)
• Volume of distribution: 100-1000 L/kg (extensive tissue binding)
• Drug of choice for sensitive P. falciparum, P. vivax, P. ovale, P. malariae
• Resistance: Widespread in P. falciparum (reduced drug accumulation via PfCRT transporter mutation)
• Uses: Treatment + chemoprophylaxis in chloroquine-sensitive areas (Central America west of Panama Canal, Hispaniola, Egypt, parts of Middle East)
• Adverse effects: Nausea, pruritus (especially in dark-skinned patients), ECG QT prolongation, postural hypotension; long-term high-dose: irreversible retinopathy
• Serious toxicity: High doses - hypotension, cardiac arrhythmias; overdose can be rapidly fatal

• Used for some chloroquine-resistant strains
• Available in fixed combination with artesunate (ASAQ)

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2. Quinoline Methanols

• Similar to chloroquine - interfere with heme detoxification in food vacuole
• Mefloquine: exact mechanism unknown but strong blood schizonticidal activity
• Both are blood schizonticides only - not active against liver stages or gametocytes

• Oral and IV administration; well absorbed orally
• Binds plasma proteins; excreted in urine
• Uses: Treatment of P. falciparum (oral and IV); still used in severe malaria if artemisinin resistance suspected (combined with artesunate)
• Adverse effects - "Cinchonism": Tinnitus, high-tone hearing loss, headache, nausea, dysphoria, visual disturbances - occur even at therapeutic doses
• Serious toxicity: Hypoglycemia (stimulates insulin release), arrhythmias, blackwater fever (massive hemolysis + hemoglobinuria)
• Contraindications: Avoid with mefloquine (both prolong QT); reduce dose in renal insufficiency

• Oral only (severe local irritation with parenteral use)
• t½ approximately 20 days - allows weekly dosing; highly protein-bound
• Uses: Chemoprophylaxis + treatment of chloroquine-resistant P. falciparum; part of artesunate-mefloquine combination (WHO-recommended ACT)
• Adverse effects: Nausea, dizziness, sleep disturbances, epigastric pain; neuropsychiatric toxicity (seizures, psychosis) - FDA issued black box warning in 2013
• Resistance: Uncommon except in Southeast Asia (border regions of Thailand)

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3. 8-Aminoquinolines

• Active against hepatic stages (hypnozoites and liver schizonts)
• Gametocidal
• Exact mechanism not fully elucidated; likely involves oxidative damage via reactive metabolites

• Oral absorption adequate; metabolized to active products
• Uses: Radical cure of P. vivax and P. ovale (eliminates hypnozoites, preventing relapse); terminal prophylaxis; alternative primary chemoprophylaxis
• Dose: 52.6 mg (30 mg base) daily for 14 days
• Critical toxicity: Hemolytic anemia in G6PD-deficient patients - G6PD testing MANDATORY before use
• Contraindications: Pregnancy, G6PD deficiency

• Newer 8-aminoquinoline with longer half-life
• Single-dose (300 mg) radical cure for P. vivax and P. ovale
• Also used for chemoprophylaxis: 200 mg daily x 3 days, then weekly
• Same hemolysis risk as primaquine in G6PD deficiency

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4. Bisquinolines

• Long half-life
• Available only in fixed combination with dihydroartemisinin (DHA-PPQ) - a first-line ACT
• Blood schizonticide; used for P. falciparum and P. vivax

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5. Artemisinins (Sesquiterpene Lactone Endoperoxides)

• Endoperoxide bridge cleaved by intraparasitic heme iron, generating free radicals
• Free radicals alkylate and damage parasite proteins
• Fastest acting of all antimalarials; active against all blood stages including young ring forms
• Also active against gametocytes of P. falciparum
• NOT active against liver stages

• Artesunate IV is first-line for severe/complicated malaria (superior to quinine in trials)
• Always used in combination (ACTs) to prevent resistance; very short t½ requires partner drug

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6. Folate Synthesis Inhibitors

• Pyrimethamine + Proguanil - inhibit plasmodial dihydrofolate reductase (DHFR), blocking folate synthesis
• Proguanil is a prodrug - converted to active triazine metabolite cycloguanil
• Sulfadoxine (sulfonamide) - inhibits dihydropteroate synthase (DHPS)
• Combining DHFR + DHPS inhibitors provides synergistic blockade of folate pathway

• Fansidar (Sulfadoxine-Pyrimethamine, SP): Long t½ of sulfadoxine (~170 h); used for intermittent preventive therapy (IPTp) in pregnancy in endemic areas; widespread resistance limits treatment use
• Malarone (Atovaquone + Proguanil): Highly effective for treatment AND chemoprophylaxis of P. falciparum; taken daily; shorter pre/post-travel dosing window than mefloquine; proguanil also has some causal prophylactic activity against liver stages

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7. Naphthoquinone

• Selectively inhibits parasite mitochondrial electron transport at cytochrome bc1 complex (Complex III)
• Collapses parasite mitochondrial membrane potential
• Blood schizonticide; proguanil (partner drug) acts synergistically

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8. Tetracyclines (Antibiotics with Antimalarial Activity)

• Slow-acting blood schizonticides
• Inhibit parasite protein synthesis (target apicoplast protein synthesis)
• Used as combination therapy with quinine for P. falciparum
• Used alone for chemoprophylaxis in multidrug-resistant areas (e.g., Thai-Myanmar border)
• Dose: Doxycycline 100 mg daily
• Contraindications: Pregnancy, children <8 years (tooth discoloration, bone effects)

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9. Aryl Alcohol

• Only available in fixed combination with artemether (Coartem/Riamet)
• First-line treatment for uncomplicated P. falciparum malaria worldwide
• t½ = 3-4 days; oral absorption improved significantly with fatty food (must be taken with food)
• Blood schizonticide
• Generally well tolerated; minor QT prolongation

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10. Mannich Base Acridine

• Available in fixed combination with artesunate (Pyramax)
• t½ approximately 8 days; renal elimination
• Efficacy comparable to other leading ACTs
• Adverse effects: eosinophilia, transaminitis

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Summary Classification Table

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Artemisinin-Based Combinations (ACTs) - WHO Recommended

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• Katzung's Basic and Clinical Pharmacology, 16th Edition, Chapter 52 (Antiprotozoal Drugs)
• Harrison's Principles of Internal Medicine 22E, Table 231-7

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Download the Full Interactive File

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What's Inside (9 Sections)

① Master Classification Table

② Classification by Stage of Action (Flowchart)

ANTIMALARIAL DRUGS
├── LIVER STAGES (Tissue schizonticides)
│   ├── Primaquine, Tafenoquine → Kill hypnozoites (P. vivax / P. ovale)
│   └── Proguanil, Atovaquone → Kill developing liver forms (causal prophylaxis)
├── BLOOD STAGES (Blood schizonticides)
│   ├── FAST: Artemisinins (all blood stages)
│   ├── QUINOLINES: Chloroquine, Quinine, Mefloquine, Piperaquine, Lumefantrine
│   ├── ANTIFOLATES: Pyrimethamine + Sulfadoxine
│   ├── ANTIBIOTICS (slow): Doxycycline, Clindamycin
│   └── MITOCHONDRIAL: Atovaquone
├── GAMETOCIDES (kill sexual stages)
│   ├── Primaquine, Tafenoquine (P. falciparum gametocytes)
│   └── Artemisinins (partial)
└── CAUSAL PROPHYLACTICS
    └── Malarone, Primaquine, Tafenoquine

③ Chemical Classification Flowchart

ANTIMALARIALS
├── QUINOLINE DERIVATIVES
│   ├── 4-Aminoquinolines: Chloroquine, Amodiaquine
│   ├── Quinoline Methanols: Quinine, Mefloquine
│   ├── 8-Aminoquinolines: Primaquine, Tafenoquine
│   └── Bisquinolines: Piperaquine
├── ARTEMISININS (Endoperoxides)
│   └── Artesunate, Artemether, DHA, Artemotil
├── ANTIFOLATES
│   ├── DHFR inhibitors: Pyrimethamine, Proguanil
│   ├── DHPS inhibitors: Sulfadoxine, Dapsone
│   └── Combos: Fansidar (SP), Malarone
└── OTHER AGENTS
    ├── Naphthoquinone: Atovaquone
    ├── Aryl alcohol: Lumefantrine
    ├── Mannich base: Pyronaridine
    └── Antibiotics: Doxycycline, Clindamycin

④ Drug Profile Cards (12 cards)

⑤ WHO ACT Combinations Table

⑥ Treatment Selection Flowchart

⑦ Chemoprophylaxis Comparison Table

⑧ Mechanisms of Action Map

⑨ Adverse Effects & Contraindications Table

• G6PD testing (primaquine/tafenoquine)
• WHO ban on artemisinin monotherapy
• Artemisinin partial resistance in SE Asia/Africa

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