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Tuesday, August 19, 2025

Antimalarial quinolines


Introduction

Antimalarial quinolines form a critical group of drugs derived from the quinoline chemical nucleus, widely used in the prevention and treatment of malaria. Malaria, caused by Plasmodium species (P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi), remains one of the world’s most significant infectious diseases, particularly in tropical and subtropical regions. Despite the introduction of newer antimalarials such as artemisinin derivatives, quinoline-based compounds remain indispensable due to their proven efficacy, affordability, and their established role in combination regimens.

The quinolines include several subclasses, such as 4-aminoquinolines, 8-aminoquinolines, aryl amino alcohol quinolines, and related derivatives, each with distinct mechanisms of action, spectra of activity, and toxicity profiles. These agents exert their antimalarial effects by interfering with hemoglobin digestion and heme detoxification within the parasite's food vacuole, ultimately leading to parasite death.

Classification and Generic Names

Antimalarial quinolines are classified based on their structural modifications around the quinoline ring:

1. 4-Aminoquinolines

  • Chloroquine

  • Amodiaquine

  • Hydroxychloroquine

2. 8-Aminoquinolines

  • Primaquine

  • Tafenoquine

3. Quinoline Methanols (Aryl Amino Alcohols)

  • Quinine

  • Quinidine

  • Mefloquine

4. Other Quinolines and Derivatives

  • Lumefantrine (often used in artemisinin-based combinations)

  • Halofantrine (rarely used due to cardiotoxicity)

Mechanism of Action

Most quinoline antimalarials target the Plasmodium parasite during its intraerythrocytic (red blood cell) stage by interfering with hemoglobin metabolism:

  • The parasite digests host hemoglobin for amino acids, releasing toxic free heme (ferriprotoporphyrin IX).

  • Normally, the parasite detoxifies heme into inert hemozoin crystals within its acidic food vacuole.

  • Quinolines (e.g., chloroquine, quinine, mefloquine) inhibit heme polymerization, leading to accumulation of toxic free heme and parasite death.

  • Primaquine and tafenoquine differ: they generate reactive oxygen species and disrupt parasite mitochondria, targeting dormant P. vivax and P. ovale hypnozoites in the liver.

Clinical Uses

1. Treatment of Malaria

  • Chloroquine: First-line for sensitive P. vivax, P. malariae, P. ovale, and some P. falciparum. Resistance in P. falciparum is widespread.

  • Amodiaquine: Used in combination regimens, particularly in Africa.

  • Hydroxychloroquine: Less common for malaria, mainly for autoimmune diseases (e.g., lupus, rheumatoid arthritis).

  • Quinine/Quinidine: For severe P. falciparum malaria, especially in resistant cases.

  • Mefloquine: Effective against multidrug-resistant P. falciparum, often in combination therapies.

  • Lumefantrine: Used only in fixed-dose combination with artemether (artemether-lumefantrine, Coartem).

  • Primaquine/Tafenoquine: Radical cure of P. vivax/P. ovale by eliminating dormant hypnozoites; also gametocytocidal activity against P. falciparum.

2. Chemoprophylaxis

  • Chloroquine: For regions without chloroquine-resistant P. falciparum.

  • Mefloquine: Prophylaxis in areas with chloroquine resistance.

  • Tafenoquine: Long-acting prophylaxis option.

3. Non-malarial Uses

  • Hydroxychloroquine and chloroquine: Used for autoimmune diseases due to immunomodulatory properties.

  • Quinine: Historically for nocturnal leg cramps (now discouraged due to toxicity).

Dosage Guidelines (General Principles)

  • Chloroquine phosphate: 600 mg base initially, then 300 mg base at 6, 24, and 48 hours (total 1.5 g base) for treatment.

  • Hydroxychloroquine: Similar to chloroquine but lower toxicity profile.

  • Quinine sulfate: 650 mg orally every 8 hours for 3–7 days; IV quinine/quinidine for severe cases.

  • Mefloquine: 1250 mg as a single dose for treatment; 250 mg weekly for prophylaxis.

  • Primaquine: 15–30 mg daily for 14 days for radical cure (P. vivax/ovale).

  • Tafenoquine: 300 mg single dose for radical cure; 200 mg weekly for prophylaxis.

  • Lumefantrine (with artemether): 20/120 mg tablets, usually given as 4 tablets twice daily for 3 days.

(Doses vary by region, age, and resistance patterns; always guided by WHO or CDC malaria guidelines.)

Contraindications

  • Chloroquine/Hydroxychloroquine: Contraindicated in patients with retinal or visual field abnormalities.

  • Primaquine/Tafenoquine: Contraindicated in glucose-6-phosphate dehydrogenase (G6PD) deficiency due to risk of hemolytic anemia.

  • Quinidine/Quinine: Contraindicated in patients with hypersensitivity, hemoglobinuria, or a history of blackwater fever.

  • Mefloquine: Contraindicated in patients with psychiatric disorders, seizures, or conduction abnormalities.

  • Halofantrine: Contraindicated in cardiac disease due to QT prolongation.

Adverse Effects

1. Chloroquine/Hydroxychloroquine

  • Retinopathy (dose-dependent, cumulative)

  • Pruritus, GI upset, headache

  • Rare: cardiomyopathy, seizures

2. Quinine/Quinidine

  • Cinchonism (tinnitus, headache, dizziness, nausea, visual disturbances)

  • Hypoglycemia (stimulates insulin release)

  • QT prolongation, arrhythmias

  • Hemolysis in G6PD deficiency

  • Hypersensitivity (blackwater fever – hemolysis, hemoglobinuria, renal failure)

3. Mefloquine

  • Neuropsychiatric reactions (vivid dreams, anxiety, psychosis)

  • Seizures

  • Dizziness, ataxia

  • QT prolongation

4. Primaquine/Tafenoquine

  • Hemolytic anemia in G6PD deficiency

  • Methemoglobinemia

  • Abdominal discomfort, nausea

5. Halofantrine

  • Severe cardiotoxicity (torsades de pointes, arrhythmia) – rarely used.

6. Lumefantrine (in combination)

  • Generally well-tolerated; mild headache, dizziness, GI upset

  • QT prolongation possible

Precautions

  • Ophthalmologic monitoring for patients on long-term chloroquine/hydroxychloroquine.

  • G6PD screening before primaquine or tafenoquine use.

  • ECG monitoring for quinidine, halofantrine, mefloquine, and lumefantrine in at-risk patients.

  • Pregnancy: Quinine and chloroquine are considered relatively safe; mefloquine may be used; primaquine and tafenoquine are contraindicated due to fetal hemolysis risk.

Drug Interactions

  • Chloroquine/Hydroxychloroquine: Interact with digoxin, cyclosporine, and other QT-prolonging drugs.

  • Quinine/Quinidine: Potentiate warfarin and digoxin effects; risk of arrhythmias with antiarrhythmics.

  • Mefloquine: Contraindicated with other QT-prolonging drugs; interactions with anticonvulsants.

  • Primaquine/Tafenoquine: Interactions with myelotoxic or hemolytic drugs, worsening anemia risk.

  • Lumefantrine: CYP3A4 substrate – interactions with azole antifungals, macrolides, protease inhibitors.




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