Pyrimethamine
Pyrimethamine is a potent **antiprotozoal** agent primarily used in veterinary medicine to treat severe protozoal infections such as **toxoplasmosis**, **neosporosis**, and ***Hepatozoon americanum*** in small animals, as well as **Equine Protozoal Myeloencephalitis (EPM)** in horses. It is almost always used in combination with sulfonamides to achieve a synergistic blockade of folic acid synthesis. **Clinical Pearl:** Because it targets folate metabolism, host bone marrow suppression is a significant risk, particularly in cats. Supplementation with folinic acid (not folic acid, which the protozoa can sometimes utilize) or Baker's yeast is often recommended to mitigate hematologic toxicity.
Mechanism: Pyrimethamine is a **folic acid antagonist**. It competitively inhibits the enzyme **dihydrofolate reductase (DHFR)** โ blocks the reduction of **dihydrofolic acid** to **tetrahydrofolic acid** (the active form of folate) โ depletes folate reserves essential for purine and pyrimidine synthesis โ halts protozoal DNA and RNA synthesis. When combined with sulfonamides (which inhibit **dihydropteroate synthase** earlier in the pathway), it produces a synergistic, sequential blockade of the folate synthesis pathway.
Dosing by species
- Toxoplasmosis ยท 0.5-1 mg/kg PO once daily for 2 days, then 0.25 mg/kg PO once daily for 2 weeks ยท PO ยท once daily ยท 2 days, then 2 weeks ยท Given with sulfadiazine at 30-50 mg/kg PO divided two to four times a day for 1-2 weeks
- Toxoplasmosis (enteroepithelial cycle) ยท 2 mg/kg, PO once daily ยท PO ยท once daily
- Toxoplasmosis (extraintestinal cycle) ยท 0.5-1 mg/kg PO divided two to three times daily ยท PO ยท divided two to three times daily ยท Combined with sulfonamides (e.g., triple sulfa, sulfadiazine) at 60 mg/kg PO or IM divided two to three times daily
- Protozoal myocarditis ยท 1 mg/kg PO once daily for 3 days, then decrease dose to 0.5 mg/kg PO once a day ยท PO ยท once daily ยท 3 days, then ongoing ยท Given with sulfadimethoxine 25 mg/kg PO, IV, or IM once a day
- Toxoplasmosis ยท 0.5 mg/kg PO per day ยท PO ยท per day ยท 7-10 days ยท Given with sulfadiazine at 30 mg/kg, PO q12h. Do not use continuously for longer than 2 weeks. Supplementation with folic acid 5 mg/day or folinic acid 1 mg/kg/day may alleviate toxicity.
- Equine protozoal myeloencephalitis ยท 1 mg/kg PO once a day for 90-120 days (or longer) ยท PO ยท once a day ยท 90-120 days (or longer) ยท Given with a sulfa or potentiated sulfa (sulfadiazine 20 mg/kg PO once or twice a day). Monitor CBC's.
- Coccidian organisms in raptors (Toxoplasmosis, Atoxoplasmosis, Sarcocystis) ยท 0.5 mg/kg PO twice daily for 14-28 days ยท PO ยท twice daily ยท 14-28 days
Routes of administration
Contraindications
- Known hypersensitivity to pyrimethamine
- Preexisting hematologic disorders (use with extreme caution)
- Pregnancy (potentially teratogenic, weigh risks vs. benefits)
- Pregnancy (teratogenic)
- Pre-existing bone marrow suppression
- Hypersensitivity to pyrimethamine
Adverse effects
- Small animals: Anorexia, malaise, vomiting, depression
- Small animals: Bone marrow depression (anemia, thrombocytopenia, leukopenia)
- Cats: Highly susceptible to adverse reactions (noted 4-6 days after starting combination therapy)
- Horses: Leukopenias, thrombocytopenia, and anemias
- Bone marrow suppression (anemia, leukopenia, thrombocytopenia)
- Anorexia
- Vomiting
- Lethargy
- Depression
Drug interactions
- p-Aminobenzoic acid (PABA) ยท Reportedly antagonistic towards the activity of pyrimethamine; clinical significance is unclear.
- Sulfonamides ยท Synergistic with pyrimethamine in activity against toxoplasmosis and malaria. ยท moderate
- Trimethoprim ยท Use with pyrimethamine/sulfa is not recommended in humans as adverse effects may be additive, however, this combination has been used clinically in horses. ยท major
- Phenobarbital ยท May increase folate deficiency ยท moderate
- Phenytoin ยท May increase folate deficiency ยท moderate
Monitoring
- CBC with platelet count (frequent monitoring recommended)
- Clinical efficacy
- Signs of abnormal bleeding or lassitude
- Complete Blood Count (CBC) every 1-2 weeks
- Appetite and body weight
- Signs of bleeding, bruising, or lethargy
Overdose
Reports of acute overdosage in animals were not located. In humans, signs include **vomiting, nausea, anorexia, CNS stimulation (including seizures), and hematologic effects**. **Treatment recommendations:** - Standard procedures to empty the gut or prevent absorption. - Parenteral barbiturates for seizures. - Folinic acid for hematologic effects. - Long-term monitoring (at least 1 month) of renal and hematopoietic systems.
VetSheet drug reference is intended for licensed veterinary professionals as a clinical decision-support aid, not a substitute for professional judgement or the manufacturerโs current label.