Usage
- Pyrimethamine is prescribed for the treatment and prevention of toxoplasmosis, a parasitic infection caused by Toxoplasma gondii. It is also used, in combination with other medications, for the treatment of malaria caused by susceptible strains of Plasmodium falciparum. It’s important to note that for malaria treatment, pyrimethamine is not recommended as a monotherapy for acute infections. Fast-acting schizonticides are preferred for acute malaria.
- Pharmacological Classification: Antiparasitic, Antimalarial, Dihydrofolate reductase inhibitor
- Mechanism of Action: Pyrimethamine inhibits dihydrofolate reductase (DHFR), an enzyme crucial for the synthesis of tetrahydrofolic acid in parasites. This inhibition disrupts DNA and RNA synthesis, ultimately leading to parasite death.
Alternate Names
How It Works
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Pharmacodynamics: Pyrimethamine selectively inhibits parasitic DHFR, disrupting folic acid metabolism and nucleic acid synthesis, which is essential for parasite growth and replication. Human cells are less sensitive to its effects.
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Pharmacokinetics:
- Absorption: Well-absorbed orally. Taking it with food can reduce nausea and vomiting.
- Metabolism: Hepatic metabolism.
- Elimination: Renal excretion, with a half-life of approximately 80-100 hours.
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Mode of Action: Pyrimethamine competitively binds to and inhibits the enzyme dihydrofolate reductase (DHFR) in parasites. DHFR catalyzes the conversion of dihydrofolate to tetrahydrofolate, a crucial cofactor in the synthesis of purines and pyrimidines, the building blocks of DNA and RNA. By inhibiting DHFR, pyrimethamine disrupts nucleic acid synthesis, ultimately leading to parasite death. This inhibition is selective for parasitic DHFR, sparing human DHFR to a greater extent.
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Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Enzyme inhibition (DHFR).
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Elimination Pathways: Primarily renal excretion.
Dosage
Standard Dosage
Adults:
- Toxoplasmosis Treatment: 50–75 mg pyrimethamine once daily with 1–4 g of a sulfapyrimidine-type sulfonamide (e.g., sulfadiazine), such as 3 tablets of Fansidar. This regimen is usually continued for 1 to 3 weeks, followed by a reduced dose for 4 to 5 weeks. Concomitant administration of folinic acid (leucovorin) is recommended to mitigate hematological side effects.
- Malaria Treatment (only in combination and with other fast-acting agents): 25 mg pyrimethamine daily for two days. Usually given with other, fast-acting schizonticides.
- Malaria Chemoprophylaxis (when resistance patterns allow): 25 mg pyrimethamine weekly. This is not suitable for most travelers due to widespread resistance.
Children:
- Toxoplasmosis Treatment: 1 mg/kg/day divided into two equal doses for two days, then 1 mg/kg/day once daily for 2-6 months (duration depending on severity), followed by 1 mg/kg thrice weekly for another 6 months. Administer with sulfadiazine and calcium folinate.
- Malaria Treatment (only in combination and with other fast-acting agents): Refer to adult dosing, adjust according to weight if necessary.
- Malaria Chemoprophylaxis (when resistance patterns allow): Refer to adult dosing, adjust according to weight if necessary.
Special Cases:
- Elderly Patients: Start with the lower end of the dosing range and monitor closely due to increased risk of adverse effects.
- Patients with Renal Impairment: Dose adjustments may be necessary. Monitor renal function.
- Patients with Hepatic Dysfunction: Dose adjustments may be necessary. Monitor hepatic function.
- Patients with Comorbid Conditions: Caution is advised for patients with pre-existing hematological disorders or folate deficiency.
Clinical Use Cases
Pyrimethamine is not typically used in the context of intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like status epilepticus or cardiac arrest. Its primary role is in treating specific parasitic infections, not for these acute care scenarios.
Dosage Adjustments
Dosage adjustments may be necessary in patients with renal or hepatic impairment. Monitor blood counts, especially during high-dose therapy, to detect potential hematological side effects.
Side Effects
Common Side Effects
- Nausea
- Vomiting
- Loss of appetite
- Insomnia
- Headache
- Lightheadedness
- Dry mouth
Rare but Serious Side Effects
- Severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis)
- Blood disorders (anemia, leukopenia, thrombocytopenia, pancytopenia)
- Seizures
- Hypersensitivity reactions (including anaphylaxis)
Long-Term Effects
- Potential for folate deficiency with prolonged use. Supplementation with folinic acid is recommended.
Adverse Drug Reactions (ADR)
- Severe skin reactions
- Blood disorders
- Hypersensitivity reactions
Contraindications
- Known hypersensitivity to pyrimethamine
- Megaloblastic anemia due to folate deficiency
Drug Interactions
- Other antifolate drugs (e.g., methotrexate, trimethoprim): Increased risk of bone marrow suppression.
- Drugs that lower blood counts (e.g., zidovudine, proguanil): Increased risk of myelosuppression.
- CYP450 interactions: May interact with drugs metabolized by CYP enzymes. Specific interactions should be checked.
- Lorazepam: May increase the risk of hepatotoxicity.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: C
- Fetal Risks: Potential for teratogenicity, especially in the first trimester. Folic acid supplementation is crucial if pyrimethamine is used during pregnancy.
- Breastfeeding: Pyrimethamine is excreted in breast milk. While generally considered compatible with breastfeeding by some authorities, caution is advised, and the infant should be monitored for potential side effects. Decisions about breastfeeding during pyrimethamine therapy should consider the risk to the infant and the importance of the drug to the mother.
Drug Profile Summary
- Mechanism of Action: Inhibits dihydrofolate reductase (DHFR), disrupting parasite growth.
- Side Effects: Nausea, vomiting, anorexia, blood disorders, skin reactions, hypersensitivity reactions.
- Contraindications: Hypersensitivity to pyrimethamine, megaloblastic anemia due to folate deficiency.
- Drug Interactions: Antifolate drugs, drugs that lower blood counts, lorazepam.
- Pregnancy & Breastfeeding: Category C, caution advised. Folinic acid supplementation in pregnancy.
- Dosage: Varies depending on indication and patient factors. See dosage section.
- Monitoring Parameters: Complete blood counts, liver function tests, renal function tests.
Popular Combinations
- Sulfadoxine-pyrimethamine (Fansidar): Used for malaria and toxoplasmosis.
- Sulfadiazine-pyrimethamine: Used for toxoplasmosis.
- Clindamycin-pyrimethamine: Used for toxoplasmosis.
- Dapsone-pyrimethamine: Used for toxoplasmosis prophylaxis.
Precautions
- General Precautions: Monitor for blood disorders, especially with high doses. Folinic acid supplementation is often recommended. Closely monitor patients with renal or hepatic impairment.
- Specific Populations (See “Special Cases” under Dosage for more details): Pregnant women, breastfeeding mothers, children, elderly.
- Lifestyle Considerations: No specific lifestyle considerations are typically associated with pyrimethamine use, aside from dietary advice related to taking the drug with food to reduce nausea and vomiting.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Pyrimethamine?
A: The dosage varies depending on the indication and patient factors. Refer to the detailed dosage section above for specific recommendations.
Q2: What are the common side effects of Pyrimethamine?
A: Common side effects include nausea, vomiting, loss of appetite, insomnia, headache, lightheadedness, and dry mouth.
Q3: What are the serious side effects of Pyrimethamine?
A: Serious side effects include severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), blood disorders (anemia, leukopenia, thrombocytopenia), seizures, and hypersensitivity reactions.
Q4: What are the contraindications for Pyrimethamine use?
A: Pyrimethamine is contraindicated in patients with known hypersensitivity to the drug and in patients with megaloblastic anemia due to folate deficiency.
Q5: Can Pyrimethamine be used during pregnancy?
A: Pyrimethamine is a pregnancy category C drug, meaning that it should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. Folinic acid supplementation is recommended during pregnancy to prevent folate deficiency.
Q6: Can Pyrimethamine be used during breastfeeding?
A: Pyrimethamine is excreted in breast milk. While considered compatible with breastfeeding by some, caution is advised. The decision to breastfeed during treatment should consider the risks and benefits for both the mother and infant.
Q7: What are the important drug interactions with Pyrimethamine?
A: Significant drug interactions can occur with other antifolate medications, drugs that lower blood counts, and some other medications like lorazepam. Consult the drug interactions section for more details.
Q8: How does Pyrimethamine work against Toxoplasmosis?
A: Pyrimethamine, often used in combination with sulfadiazine for toxoplasmosis, inhibits the parasitic enzyme dihydrofolate reductase, interfering with the parasite’s ability to synthesize DNA and RNA, thus limiting its growth and replication.
Q9: What is the role of folinic acid with Pyrimethamine therapy?
A: Folinic acid (leucovorin) is often given alongside pyrimethamine to reduce the risk of hematological side effects like bone marrow suppression, which can lead to anemia, leukopenia, and thrombocytopenia. Folinic acid helps “rescue” human cells from the antifolate effects of pyrimethamine.
