Mechanism of Action
Chemically, the drug is a diaminopyrimidine derivative. Its primary target in the parasite is folate metabolism.
Pyrimethamine competitively inhibits the enzyme dihydrofolate reductase, preventing the conversion of folic acid into its active form. As a result, nucleic acid synthesis (DNA and RNA) is disrupted, halting parasite reproduction.
Use in Malaria
The drug has the broadest spectrum of activity among antimalarial agents, affecting multiple stages of the Plasmodium life cycle:
- Erythrocytic stage (blood schizonticidal action): Inhibits the development of all Plasmodium species, suppressing clinical manifestations. However, the effect develops slowly, making pyrimethamine unsuitable for monotherapy of severe acute conditions (e.g., severe falciparum malaria). In such cases, quinine (administered intravenously for rapid effect) is the drug of choice.
- Tissue stage (tissue schizonticidal action): Affects the hepatic cycle of parasite development and is used for relapse prevention.
- Sexual forms (gametocidal action): Damages gametocytes, blocking parasite development in the mosquito's gut (disrupting sporogony). This effect is used for mass drug administration/chemoprophylaxis to prevent vector infection and halt transmission in a population. It is also used for personal prophylaxis when infection risk is present.
Use in Toxoplasmosis
The causative agent is Toxoplasma gondii (with cats as definitive hosts shedding oocysts in feces).
The gold standard for etiotropic pharmacotherapy is the combination: pyrimethamine + sulfadiazine.
If the classical regimen is not feasible, alternative combinations include:
- Pyrimethamine + clindamycin (an antibiotic active against toxoplasma and plasmodia in high doses).
- Co-trimoxazole (sulfamethoxazole + trimethoprim).
- Macrolides (clarithromycin or azithromycin).
Antifolate Drug Combinations
To achieve a synergistic effect and overcome resistance, pyrimethamine is frequently combined with sulfonamides (which block folic acid synthesis at an earlier step).
Key combinations include:
- Sulfadoxine + pyrimethamine (known commercially as Fansidar).
- Sulfalene + pyrimethamine.
Side Effects and Toxicity
Because the drug is a folic acid antagonist, it can disrupt folate metabolism and DNA synthesis in the patient's own cells. The primary complication is iatrogenic megaloblastic anemia (macrocytic hyperchromic).
Managing Toxicity: To treat the anemia, folic acid is administered orally at 5 mg/day for 20–30 days (allergic reactions may occur). Important rule: In pernicious anemia, isolated folic acid supplementation is contraindicated; it must be administered only together with vitamin B12 (otherwise neurological deficits will progress).
Contraindications: Due to the high risk of antifolate teratogenicity, pyrimethamine (and its combination with sulfadiazine) is contraindicated in pregnancy.
Dosage and Administration
Administered orally. Standard reference dosing regimen: 10 mg 3 times daily for 3 days.
Prescription example: `Rp.: Tab. Pyrimethamini 0.01` `D.t.d. N. 10` `S. Take orally 1 tablet 3 times a day for 3 days.`