Chemistry - An aminpyrimidine agent structurally related to trimethoprim, pyrimethamine occurs as an odorless, white, or almost white, crystalline powder or crystals. It is practically insoluble in water and slightly soluble in alcohol.
Storage/Stability/Compatibility - Pyrimethamine tablets should be stored in tight, light-resistant containers. Pyrimethamine tablets may be crushed to make oral suspensions of the drug. Although stable in an aqueous solution, sugars tend to adversely affect the stability of pyrimethamine. If cherry syrup, corn syrup, or sucrose-containing liquids are used in the preparation of the suspension, it is recommended to store the suspension at room temperature and discard after 7 days.
Pharmacology - Pyrimethamine is a folic acid antagonist similar to trimethoprim. It acts by inhibiting the enzyme, dihydrofolate reductase that catalyzes the conversion of dihydrofolic acid to tetrahydrofolic acid.
Uses/Indications - In veterinary medicine, pyrimethamine is used to treat (often in combination with sulfonamides) toxoplasmosis in small animals. In horses, it is used to treat equine protozoal myeloencephalitis, sometimes called equine toxoplasmosis.
In humans, pyrimethamine is used for the treatment of toxoplasmosis and as a prophylactic agent for malaria.
Pharmacokinetics - No pharmacokinetic data was located for veterinary species. In humans, pyrimethamine is well absorbed from the gut after oral administration. It is distributed primarily to the kidneys, liver, spleen and lungs, but does cross the blood-brain barrier. It has a volume of distribution of about 3 L/kg and is 80% bound to plasma proteins. Pyrimethamine enters milk in levels greater than those found in serum and is detected in milk for up to 48 hours after dosing.
In humans, the plasma half-life is approximately 3-5 days. It is unknown how or where the drug is metabolized, but metabolites are found in the urine.
Contraindications/Precautions/Reproductive Safety - Pyrimethamine is contraindicated in patients hypersensitive to it and should be used cautiously in patients with preexisting hematologic disorders. Pyrimethamine has been demonstrated to be teratogenic in rats. However, it has been used in treating women with toxoplasmosis during pregnancy. Clearly, the risks associated with therapy must be weighed against the potential for toxicity, the severity of the disease, and any alternative therapies available (e.g., clindamycin in small animals). Concomitant administration of folinic acid has been recommended if the drug is to be used during pregnancy.
Adverse Effects/Warnings - In small animals, anorexia, malaise, vomiting, depression and bone marrow depression (anemia, thrombocytopenia, leukopenia) have been seen. Adverse effects may be more prominent in cats and may be noted 4-6 days after starting combination therapy. Hematologic effects can develop rapidly and frequent monitoring is recommended, particularly if therapy persists longer than 2 weeks. Oral administration of folinic acid at 1 mg/kg PO, folic acid 5 mg/day, or Brewer’s yeast 100 mg/kg/day have been suggested to alleviate adverse effects.
The drug is unpalatable to cats when mixed with food and the 25 mg tablet dosage size makes successful dosing a challenge.
In horses, pyrimethamine when used in combination with sulfonamides has caused leukopenias, thrombocytopenia and anemias. Baker’s yeast or folinic acid have been suggested to be used to antagonize these adverse effects.
Overdosage/Acute Toxicity - Reports of acute overdosage of pyrimethamine in animals was not located. In humans, vomiting, nausea, anorexia, CNS stimulation (including seizures) and hematologic effects can be seen. Recommendations for treatment include: standard procedures in emptying the gut or preventing absorption, parenteral barbiturates for seizures, folinic acid for hematologic effects and long-term monitoring (at least 1 month) of renal and hematopoietic systems.
Drug Interactions - Pyrimethamine is synergistic with sulfonamides in activity against toxoplasmosis (and malaria). p-aminobenzoic acid (PABA) is reportedly antagonistic towards the activity of pyrimethamine; clinical significance is unclear. Use of pyrimethamine with trimethoprim/sulfa is not recommended (in humans) as adverse effects may be additive, but this combination has been used clinically in horses.
For equine protozoal myeloencephalitis:
a) Pyrimethamine 0.1 - 0.2 mg/kg PO once daily, with trimethoprim/sulfadiazine 15 mg/kg PO bid. Dosage may be continued for up to 2 months. Reinstitute therapy if animal is stressed; long-term intermittent therapy may be rational. Guarded prognosis; relapses are not uncommon. (Brewer 1987) (NOTE: Since this reference was published, pyrimethamine dosage is now more commonly given at 1 mg/kg PO once daily—Plumb; March 1999)
Monitoring Parameters -
1)See adverse effects; CBC with platelet count 2)Clinical efficacy
Client Information - Clients should he instructed to monitor for symptoms of abnormal bleeding, lassitude, etc. that may signal development of hematologic disorders. Accurate dosing of the tablets in cats may be very difficult as only 25 mg tablets are commercially available. Preferably, custom prepared capsules containing the accurate dosage should be prepared.
Dosage Forms/Preparations/FDA Approval Status -
Veterinary-Approved Products: None
Pyrimethamine Tablets 25 mg; Daraprim® (Glaxo Wellcome); (Rx)
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