Which antimalarial drug acts by inhibiting the parasite's dihydrofolate reductase enzyme?

Explanation

## Mechanism of Action **Key Point:** Pyrimethamine is a dihydrofolate reductase (DHFR) inhibitor that blocks the conversion of dihydrofolate to tetrahydrofolate, disrupting nucleotide synthesis in the parasite. ## Drug Classification Pyrimethamine belongs to the **antifolate** class of antimalarials, similar to trimethoprim in bacteria. It is primarily used in combination with sulfadiazine or dapsone for: - Treatment of chloroquine-resistant P. falciparum - Prophylaxis in high-transmission areas - Treatment of toxoplasmosis (off-label) ## Pharmacokinetic Features | Feature | Detail | |---------|--------| | **Onset** | Slow (accumulates in RBCs and tissues) | | **Half-life** | 80–100 hours | | **Metabolism** | Hepatic | | **Elimination** | Renal | **Clinical Pearl:** Pyrimethamine must always be combined with a sulfonamide (e.g., sulfadiazine) or dapsone to prevent resistance and improve efficacy. The sulfonamide inhibits bacterial DHFR in the gut flora, preventing resistance selection. **High-Yield:** Pyrimethamine + sulfadiazine is the gold standard for treating acute toxoplasmosis in HIV patients with CD4 <100 cells/μL. ## Adverse Effects - Megaloblastic anemia (folate antagonism) - Thrombocytopenia - Agranulocytosis (rare but serious) - Teratogenicity (avoid in first trimester) **Mnemonic:** **DHFR = Dihydrofolate Reductase** — the target enzyme. Pyrimethamine blocks it, starving the parasite of nucleotides.