PYRIMETHAMINE

Chemistry - An aminpyrimidine agent structurally related to trimethoprim, pyrimethamine occursas an odorless, white, or almost white, crystalline powder or crystals. It is practically insoluble inwater and slightly soluble in alcohol.

Storage, Stability, Compatibility

Pyrimethamine tablets should be stored in tight, light-resistantcontainers.
Pyrimethamine tablets may be crushed to make oral suspensions of the drug. Although stable inan 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 isrecommended to store the suspension at room temperature and discard after 7 days.

Pharmacology - PYRIMETHAMINE

Pyrimethamine is a folic acid antagonist similar to trimethoprim. It acts by inhibiting the enzyme, dihydrofolate reductase that catalyzes the conversion of dihydrofolic acid totetrahydrofolic acid.

Uses, Indications

In veterinary medicine, pyrimethamine is used to treat (often in combinationwith sulfonamides) toxoplasmosis in small animals. In horses, it is used to treat equine protozoalmyeloencephalitis, sometimes called equine toxoplasmosis.
In humans, pyrimethamine is used for the treatment of toxoplasmosis and as a prophylactic agentfor malaria.

Pharmacokinetics - PYRIMETHAMINE

No pharmacokinetic data was located for veterinary species. In humans, pyrimethamine is well absorbed from the gut after oral administration. It is distributed primarily tothe kidneys, liver, spleen and lungs, but does cross the blood-brain barrier. It has a volume ofdistribution of about 3 L/kg and is 80% bound to plasma proteins. Pyrimethamine enters milk inlevels 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 ismetabolized, but metabolites are found in the urine.

Contraindications, Precautions, Reproductive Safety

Pyrimethamine is contraindicated inpatients hypersensitive to it and should be used cautiously in patients with preexisting hematologicdisorders. Pyrimethamine has been demonstrated to be teratogenic in rats. However, it has beenused in treating women with toxoplasmosis during pregnancy. Clearly, the risks associated withtherapy must be weighed against the potential for toxicity, the severity of the disease, and anyalternative therapies available (e.g., clindamycin in small animals). Concomitant administration offolinic acid has been recommended if the drug is to be used during pregnancy.

Adverse Effects, Warnings

In small animals, anorexia, malaise, vomiting, depression and bonemarrow depression (anemia, thrombocytopenia, leukopenia) have been seen. Adverse effects may bemore prominent in cats and may be noted 4-6 days after starting combination therapy. Hematologiceffects can develop rapidly and frequent monitoring is recommended, particularly if therapy persistslonger 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 makessuccessful 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 toantagonize these adverse effects.

Overdosage, Acute Toxicity

Reports of acute overdosage of pyrimethamine in animals was notlocated. 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.