Pyrimethamine — Veterinary Vademecum Drug Reference

Dosage & Administration Guidelines

Species	Route	Dose	Frequency	Duration & Clinical Notes
Dog	PO	1 mg/kg	q24h	Duration: 4-6 weeks Notes: For toxoplasmosis, often combined with sulfadiazine (20-30 mg/kg q12h). For neosporosis, use 1 mg/kg q24h for 4-6 weeks.
Cat	PO	0.5-1 mg/kg	q24h	Duration: 4-6 weeks Notes: For toxoplasmosis, combine with sulfadiazine (20-30 mg/kg q12h). Monitor for bone marrow suppression.
Horse	PO	1 mg/kg	q24h	Duration: 90-120 days Notes: For EPM, combine with sulfadiazine (20 mg/kg q12h). Treatment may be prolonged.
Cattle	PO	1-2 mg/kg	q24h	Duration: 3-5 days Notes: For coccidiosis, often combined with sulfonamides. Withdrawal times must be observed.
Small Ruminants	PO	1-2 mg/kg	q24h	Duration: 3-5 days Notes: For coccidiosis, use in combination with sulfonamides. Adjust dose based on response.
Rabbit	PO	1 mg/kg	q24h	Duration: 4-6 weeks Notes: For encephalitozoonosis, combine with sulfadiazine. Monitor renal function.
Bird/Poultry	PO	1-2 mg/kg	q24h	Duration: 3-5 days Notes: For coccidiosis, use in combination with sulfonamides. Ensure adequate water intake.

Clinical Indications & Species Uses

General Indications

Treatment of protozoal infections caused by susceptible organisms

Dog (Canine)

Treatment of toxoplasmosis
Treatment of neosporosis
Treatment of coccidiosis (in combination with sulfonamides)

Cat (Feline)

Treatment of toxoplasmosis
Treatment of coccidiosis (in combination with sulfonamides)

Horse (Equine)

Treatment of equine protozoal myeloencephalitis (EPM) caused by Sarcocystis neurona (in combination with sulfadiazine)

Cattle (Bovine)

Treatment of coccidiosis (in combination with sulfonamides)

Small Ruminants (Sheep / Goat)

Treatment of coccidiosis (in combination with sulfonamides)

Rabbit & Small Mammals

Treatment of encephalitozoonosis (Encephalitozoon cuniculi) (in combination with sulfonamides)

Avian & Poultry

Treatment of coccidiosis (in combination with sulfonamides)

Exotic & Other Species

Treatment of toxoplasmosis in various exotic species
Treatment of neosporosis in exotic species

Pharmacology & Mechanism of Action

Drug Class: Antiprotozoal | Pharmacological Group: Diaminopyrimidine

Mechanism of Action: Pyrimethamine is a folic acid antagonist that selectively inhibits the protozoal enzyme dihydrofolate reductase (DHFR), which is essential for the reduction of dihydrofolate to tetrahydrofolate. This inhibition disrupts the synthesis of tetrahydrofolate, a cofactor required for the synthesis of nucleic acids and amino acids. Consequently, the drug interferes with the production of DNA and RNA in susceptible protozoa, leading to their death. The selectivity of pyrimethamine for protozoal DHFR over the mammalian enzyme is due to differences in the binding affinity, allowing therapeutic use in animals with relatively low toxicity to the host.

Pharmacodynamics: Pyrimethamine exhibits a slow onset of action, typically requiring several days to achieve maximal antiprotozoal effect. It is primarily coccidiocidal and is effective against a range of protozoal parasites, including Toxoplasma gondii, Neospora caninum, and some species of Eimeria. The drug is often used in combination with sulfonamides (e.g., sulfadiazine) to provide synergistic inhibition of the folate pathway, as sulfonamides inhibit dihydropteroate synthase, an enzyme upstream of DHFR. This combination enhances the antiprotozoal spectrum and reduces the likelihood of resistance development. The pharmacodynamic effects are dose-dependent, with higher doses achieving more rapid parasite clearance but also increasing the risk of host toxicity.

⚡ Pharmacokinetics Summary

Absorption: Pyrimethamine is well absorbed after oral administration in most species. In dogs and cats, oral bioavailability is high, with peak plasma concentrations occurring within 2-4 hours. In horses, absorption is also good, but the rate may be slightly slower. Food can affect absorption, with a high-fat meal potentially increasing the extent of absorption.

Distribution: Pyrimethamine is widely distributed throughout the body, including the central nervous system, due to its lipophilic nature. It crosses the blood-brain barrier and achieves therapeutic concentrations in the cerebrospinal fluid, which is important for treating toxoplasmosis and neosporosis. It also distributes into tissues such as the liver, kidneys, and lungs. The volume of distribution is large, and the drug accumulates in red blood cells and other cells.

Metabolism: Pyrimethamine is extensively metabolized in the liver, primarily by oxidative pathways. The major metabolites are hydroxylated derivatives, which are less active than the parent compound. The metabolism is mediated by cytochrome P450 enzymes, and there is potential for drug interactions with inhibitors or inducers of these enzymes.

Excretion: The drug and its metabolites are excreted primarily in the urine, with a smaller portion eliminated in the feces. Renal excretion involves both glomerular filtration and tubular secretion. In animals with renal impairment, the elimination half-life may be prolonged, requiring dose adjustment.

Half-Life: The elimination half-life of pyrimethamine varies by species: approximately 10-14 hours in dogs, 24-36 hours in cats, 10-12 hours in horses, and 4-6 hours in cattle. In rabbits, the half-life is around 8-10 hours.

Bioavailability: Oral bioavailability is high, typically greater than 75% in dogs and cats. In horses, bioavailability is approximately 60-80%. The presence of food may increase bioavailability slightly.

Protein Binding: Pyrimethamine is approximately 80-90% bound to plasma proteins, primarily albumin. This high protein binding can influence drug interactions and the free concentration available for pharmacological activity.

Available Formulations & Strengths

Oral Tablet 25 mg, 50 mg (PO)

Oral Suspension 2 mg/mL (compounded) (PO)

Contraindications & Clinical Warnings

Contraindications:

Hypersensitivity to pyrimethamine or any component of the formulation
Severe hepatic or renal impairment
Pregnancy (especially in the first trimester) unless the benefit outweighs the risk
Lactation (use with caution)
Concurrent use with other folic acid antagonists (e.g., methotrexate) without careful monitoring
Use in animals with pre-existing bone marrow suppression

Warnings & Clinical Precautions:

Use with caution in animals with folate deficiency or those on a folate-restricted diet
Monitor complete blood count (CBC) regularly during prolonged therapy due to risk of bone marrow suppression
In cats, use with caution as they are more sensitive to the hematologic effects
In horses, prolonged treatment may require monitoring for anemia and leukopenia
In food animals, observe withdrawal times to prevent drug residues in meat and milk
Avoid use in animals with known glucose-6-phosphate dehydrogenase (G6PD) deficiency (rare in animals)
Use with caution in animals with renal or hepatic disease; dose adjustment may be necessary
May cause teratogenic effects; avoid use in pregnant animals unless absolutely necessary

Adverse Effects & Reactions

Common:

Anorexia
Vomiting
Diarrhea
Lethargy
Megaloblastic anemia
Leukopenia
Thrombocytopenia

Serious / Severe:

Severe bone marrow suppression (pancytopenia)
Hepatotoxicity
Renal toxicity
Teratogenicity
Neurological signs (ataxia, seizures) at high doses

Rare:

Hypersensitivity reactions (skin rash, urticaria)
Photosensitivity
Pulmonary fibrosis (with prolonged use)

Key Drug Interactions

Interacting Drug / Class	Clinical Effect & Mechanism	Severity
Sulfonamides (e.g., sulfadiazine)	Synergistic antiprotozoal effect; increased risk of bone marrow suppression and crystalluria	Moderate
Folic acid or folinic acid (leucovorin)	May reduce the antiprotozoal efficacy; used to mitigate hematologic toxicity	Moderate
Methotrexate	Additive antifolate effects; increased risk of severe bone marrow suppression	High
Phenytoin	May increase phenytoin levels due to inhibition of metabolism	Moderate
Chloramphenicol	May antagonize the antiprotozoal effect; avoid concurrent use	Moderate
Trimethoprim	Additive antifolate effects; increased risk of hematologic toxicity	Moderate

Overdose & Toxicity Management

Signs of Toxicity:

Vomiting
Diarrhea
Anorexia
Tremors
Seizures
Bone marrow suppression (anemia, leukopenia, thrombocytopenia)
Hepatotoxicity
Renal failure

Emergency Treatment Protocol: Treatment is primarily symptomatic and supportive. Induce emesis if ingestion is recent and the animal is conscious. Administer activated charcoal to reduce absorption. Provide intravenous fluids to maintain hydration and promote excretion. Monitor CBC, liver enzymes, and renal parameters. Administer folinic acid (leucovorin) at a dose of 1-5 mg/kg IV or IM every 6 hours to counteract the antifolate effects. In severe cases, blood transfusions may be necessary for anemia. Seizures may be controlled with diazepam or barbiturates. There is no specific antidote.

Food Animal Withdrawal Times

🥩 Meat: 21 days🥛 Milk: 7 days🥚 Eggs: 14 days

Withdrawal times are estimates and may vary by country and formulation. Always consult the label and local regulations. For cattle, sheep, goats, and poultry, ensure compliance with withdrawal periods to avoid drug residues.

Storage, Handling & Regulatory Information

Storage Temperature: Store at controlled room temperature (20-25°C, 68-77°F).

Light Sensitivity: Light-sensitive — protect from direct exposure.

Handling & Special Conditions: Protect from light and moisture. Keep in a tightly closed container. Compounded suspensions should be stored according to the compounding pharmacy's instructions, typically refrigerated and used within a specified period.

Dispensing Status: Prescription Required (Rx Only)

Approval Status: Pyrimethamine is FDA-approved for human use (Daraprim) but not for veterinary use. However, it is commonly used in veterinary medicine as an extra-label drug.

Extra-Label (Off-Label) Use: In the United States, pyrimethamine is not FDA-approved for veterinary use in most species, but it can be used legally under the Animal Medicinal Drug Use Clarification Act (AMDUCA) for extra-label use in animals, provided a valid veterinarian-client-patient relationship exists. For food animals, extra-label use requires a withdrawal period established by the veterinarian, and the drug must not be used in an extra-label manner that results in violative residues.

Clinical Pearls & Practice Notes

💡 Clinical Insights: Pyrimethamine is a valuable antiprotozoal agent in veterinary medicine, particularly for treating toxoplasmosis, neosporosis, and equine protozoal myeloencephalitis. It is almost always used in combination with a sulfonamide to enhance efficacy and reduce the risk of resistance. Due to its potential for bone marrow suppression, especially in cats, it is essential to monitor complete blood counts regularly during therapy. Folic acid supplementation may be considered to mitigate hematologic toxicity, but it may also reduce efficacy; therefore, folinic acid (leucovorin) is preferred if needed. In food animals, strict adherence to withdrawal times is critical. The drug is contraindicated in pregnant animals unless the benefits clearly outweigh the risks, as it is teratogenic. Clinical response should be monitored, and treatment should be continued for the full duration to prevent relapse. Always consider the species-specific pharmacokinetics and adjust dosing accordingly.

References & Literature

📚 Plumb's Veterinary Drug Handbook
📚 Papich Veterinary Pharmacology and Therapeutics
📚 Compendium of Veterinary Products (CVP)