Antimalarial Agents: Heme Metabolism Inhibitors

Antimalarial Agents - Inhibitors of Heme Metabolism

• Antimalarial agents target metabolic processes of heme to increase toxicity to malaria-causing plasmodia.
• Chloroquine is effective against all malaria species but has widespread resistance, especially in P. falciparum across Africa, Asia, and South America.
• As a weak base, chloroquine is protonated in the acidic environment of the parasite's food vacuole, trapping it inside.
• Protonated chloroquine binds to ferriprotoporphyrin IX (heme), preventing its polymerization which results in toxic accumulation and oxidative cell damage.
• Chloroquine solely kills the erythrocytic stage of malaria infections and has therapeutic and prophylactic uses.
• Resistance mechanisms in P. falciparum include the substitution of threonine for lysine in the PfCRT protein, which reduces chloroquine accumulation.
• Chloroquine's side effects include AV block, heart failure, prolonged QT interval, Stevens-Johnson syndrome, neutropenia, seizures, and retinopathy.
• Due to its toxicity at high doses and availability, chloroquine has been misused for suicide.

Quinine and Quinidine

• Quinine and quinidine target P. falciparum, utilizing a similar mechanism to chloroquine but also intercalating into DNA, inhibiting essential cellular processes.
• These agents treat acute blood-stage malaria but are not used for prophylaxis.
• Contradindications include patients with G6PD deficiency and myasthenia gravis.
• Side effects associated with quinine and quinidine include arrhythmias, agranulocytosis, thrombocytopenia, disseminated intravascular coagulation, hemolysis, thrombotic thrombocytopenic purpura, hepatotoxicity, renal failure, and cinchonism (characterized by tinnitus, headaches, nausea, and vision changes).

Mefloquine

• Mefloquine is specifically effective against chloroquine-resistant malaria by inhibiting heme polymerization into hemozoin in malarial parasites.
• It can be used for both therapeutic and prophylactic purposes.
• Notable side effects include prolonged QT interval, seizures, suicide risk, pneumonitis, gastrointestinal symptoms, dizziness, nightmares, and insomnia; it carries an FDA black box warning due to its risk profile.

Artemisinin Compounds

• Artemisinin, artesunate, artemether, and dihydroartemisinin are effective against all malaria species.
• These compounds generate carbon-centered free radicals that alkylate heme, disrupting plasmodial function.
• They are first-line treatments for both uncomplicated and complicated malaria in conjunction with another antimalarial but are not recommended for prophylaxis.
• Possible side effects include hemolytic anemia, bradycardia, and neurotoxic effects.

This quiz explores antimalarial agents, focusing on the mechanism by which they inhibit heme metabolism in plasmodia. It includes details about chloroquine, its action, and the importance of trapping it within the parasite's food vacuole. Test your knowledge on how these medications combat malaria effectively.