Pharmacology of Chloroquine

Metabolism and Adverse Effects of Antimalarial Drugs

• Proguanil is metabolized by CYP2C19, and genetic polymorphisms may affect its metabolism.
• Adverse effects of proguanil include GI effects (nausea/vomiting/diarrhea, abdominal pain, anorexia), headache, and dizziness.

Mefloquine

• Mefloquine is effective as monotherapy for prophylaxis and treatment of multidrug-resistant P. falciparum.
• Resistant strains are prevalent in Southeast Asia.
• Mechanism of action is unknown.
• Mefloquine is well absorbed and widely distributed, undergoes entero-hepatic circulation, and has a half-life of 20 days.
• Adverse effects include nausea, vomiting, disorientation, hallucinations, and depression.

Quinine

• Quinine was originally isolated from the bark of the Cinchona tree.
• It interferes with heme polymerization, but its exact mechanism is unknown.
• Quinine is a blood schizonticide and gametocidal against P. vivax and P. ovale.
• It is reserved for severe cases (e.g., cerebral malaria) and for chloroquine-resistant cases.
• Adverse effects include nausea, vomiting, tinnitus, and vertigo.

Artemisinin

• Artemisinin is a derivative of the "sweet wormwood plant" and is recommended as a first-line treatment for multi-drug-resistant P. falciparum.
• It is used for prophylaxis of malaria and treatment of extra-intestinal amebiasis.
• Artemisinin derivatives cannot be used for prophylaxis due to their short half-life.

Chloroquine

• Chloroquine is completely and rapidly absorbed after oral administration and has a large volume of distribution.
• It penetrates CSF and crosses the placenta.
• Metabolism occurs in the liver, and some metabolic products have anti-malarial activity.
• Excretion occurs through the kidney.
• Resistance to chloroquine has become a serious medical problem in Africa, Asia, and Central and South America.

Adverse Effects of Chloroquine

• Chloroquine is a safe drug, but adverse effects occur at high doses.
• Adverse effects include gastrointestinal upset, blurred vision, and discolored nail beds after long-term use.

Atovaquone-Proguanil

• The combination of atovaquone-proguanil is effective for chloroquine-resistant strains of P. falciparum.
• Atovaquone inhibits mitochondrial processes, such as electron transport chain, thereby inhibiting ATP biosynthesis.
• Proguanil is a prodrug that inhibits dihydrofolate reductase, preventing DNA synthesis.

Mechanism of Action of Artemisinin

• Artemisinin's endoperoxide bond is cleaved by heme iron in the parasite's food vacuole, leading to the production of free radicals.
• The drug also binds to and damages parasite's proteins.

Prevention of Resistance

• Artemisinin derivatives are used in combination with other drugs to prevent resistance.

Pyrimethamine

• Pyrimethamine is a blood schizonticide and a strong sporozonticide.
• It is used in combination with sulfadoxine for treatment of P. falciparum malaria.
• Adverse effects include megaloblastic anemia (reversible with leucovorin).

Treatment and Prevention of Malaria

• Chloroquine-resistant areas: atovaquone-proguanil, doxycycline, and artemisinin derivatives are used for treatment and prevention.
• Chloroquine-sensitive areas: chloroquine is used for treatment and prevention.
• Prevention of relapse of P. vivax and P. ovale: primaquine is used.