Pyrimethamine

Mechanism of action

By chemical structure, the drug is a diaminopyrimidine derivative. Its primary target in the parasite's organism is folate metabolism.

Pyrimethamine competitively inhibits the dihydrofolate reductase enzyme, making the conversion of folic acid into its active form impossible. As a result, nucleic acid synthesis (DNA and RNA) is disrupted, and pathogen replication halts.

Use in malaria

The drug has the broadest spectrum of activity among all antimalarial agents and affects several stages of the Plasmodium life cycle simultaneously:

• Erythrocytic stage (hematoschontropic action): inhibits the development of all Plasmodium species, alleviating clinical manifestations. However, the effect develops slowly, which is why pyrimethamine is not suitable for monotherapy of severe acute conditions (e.g., falciparum malaria). In such cases, the drug of choice is quinine (administered intravenously for a rapid effect).
• Tissue stage (histoschizontropic action): affects the hepatic cycle of parasite development and is used for relapse prevention.
• Sexual forms (gametocidal action): causes damage to gametocytes. This blocks the development of the pathogen in the mosquito's gut (disrupts sporogony). This effect is used for mass chemoprophylaxis to prevent vector infection and halt the spread of the infection in the population. The drug is also used for personal prophylaxis (when there is a risk of infection).

Use in toxoplasmosis

The causative agent of the disease is Toxoplasma gondii (the primary hosts are cats, which shed oocysts in their feces).

The "gold standard" of etiotropic pharmacotherapy is the combination of: pyrimethamine + sulfadiazine.

If the classical regimen is not feasible, alternative combinations are used:

• Pyrimethamine + clindamycin (an antibiotic that in high doses is active against toxoplasmas and plasmodia).
• Co-trimoxazole (sulfamethoxazole + trimethoprim).
• Macrolides (clarithromycin or azithromycin).

Combination antifolate drugs

To achieve a synergistic effect and overcome resistance, pyrimethamine is often combined with sulfonamides (folic acid synthesis blockers acting at an earlier stage).

Main combinations:

• Sulfadoxine + pyrimethamine (known brand-name drug — Fansidar).
• Sulfalene + pyrimethamine.

Side effects and toxicity

Since the drug is a folic acid antagonist, it can impair folate metabolism and DNA synthesis in the patient's own cells. The main complication is iatrogenic megaloblastic anemia (macrocytic hyperchromic).

Toxicity management: To treat the anemia, folic acid is prescribed orally at 0.005 g/day in a 20–30 day course (allergic reactions are possible). Important rule: in pernicious anemia, isolated use of folic acid is unacceptable; it must be prescribed only together with vitamin B12 (otherwise, neurological disorders will not resolve).

Contraindications: Due to the high risk of teratogenic effects from antifolates, pyrimethamine (and its combination with sulfadiazine) is contraindicated in pregnant women.

Prescription and dosage

The drug is administered orally. According to the reference book, the standard regimen is 0.01 g 3 times a day for 3 days.

Example of prescribing tablets: `Rp.: Tab. Pyrimethamini 0,01` `D.t.d. N. 10` `S. Take orally 1 tablet 3 times a day for 3 days.`

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Life cycle of the malaria parasite (sporogony, tissue and erythrocytic schizogony).
• Mechanism of action of sulfonamides and their synergy with dihydrofolate reductase inhibitors.
• Iatrogenic megaloblastic anemia: differential diagnosis and blood picture.
• Pharmacology of quinine and treatment protocols for severe falciparum malaria.
• Alternative drugs for the treatment of toxoplasmosis in pregnant women (macrolides).

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