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Methotrexate

Methotrexate is a versatile medication with applications in oncology and autoimmune diseases. As a folate antagonist, it inhibits DNA synthesis and modulates immune responses, making it a cornerstone in treating conditions such as cancer, rheumatoid arthritis (RA), and psoriasis. This article synthesizes information from the British National Formulary (BNF)Lippincott Textbook of Pharmacology, and Lange Basic & Clinical Pharmacology to detail methotrexate’s mechanism, uses, dosing, side effects, precautions, and interactions.

Methotrexate acts as a competitive inhibitor of dihydrofolate reductase (DHFR), an enzyme required to convert folate into tetrahydrofolate, a critical cofactor in DNA and RNA synthesis. By depleting intracellular folate stores, methotrexate:

  1. Impairs cell division: Blocks thymidine and purine synthesis, particularly in rapidly dividing cells (e.g., cancer cells, immune cells).
  2. Modulates inflammation: At low doses, promotes adenosine release, which exerts anti-inflammatory effects in autoimmune diseases (LippincottLange).

In oncology, high-dose methotrexate directly targets proliferating malignant cells. In autoimmune conditions, its immunomodulatory effects reduce inflammation and tissue damage (BNF).

  1. Oncology:
    • Acute lymphoblastic leukemia, non-Hodgkin’s lymphoma, breast cancer, and choriocarcinoma (BNF).
  2. Autoimmune Diseases:
    • Rheumatoid arthritis, psoriasis, psoriatic arthritis, and juvenile idiopathic arthritis (Lippincott).
  3. Ectopic Pregnancy and Medical Abortion:
    • Used in gestational trophoblastic disease and early pregnancy termination (Lange).
  • Oncology:
    • High-dose regimens10–12 g/m² intravenously over 24 hours, followed by leucovorin rescue to mitigate toxicity (BNF).
    • Low-dose protocols15–30 mg/m² weekly for maintenance therapy (Lippincott).
  • Rheumatoid Arthritis/Psoriasis:
    • 7.5–25 mg orally or subcutaneously once weekly, adjusted based on response and tolerance (Lange).
  • Medical Abortion:
    • 50 mg/m² intramuscularly as a single dose (BNF).

Administration:

  • Oral, intramuscular, intravenous, or subcutaneous routes.
  • Folate supplementation (e.g., folic acid 1–5 mg daily) reduces toxicity without compromising efficacy (Lippincott).
  • Common: Mucositis, nausea, fatigue, and elevated liver enzymes (Lippincott).
  • Serious:
    • Myelosuppression: Leukopenia, thrombocytopenia, and anemia (Lange).
    • Hepatotoxicity: Fibrosis or cirrhosis with long-term use (BNF).
    • Pulmonary Toxicity: Interstitial pneumonitis or fibrosis (Lippincott).
    • Teratogenicity: Contraindicated in pregnancy due to fetal malformations (Lange).
  • Pregnancy: Strictly contraindicated; effective contraception required during and for 6 months after treatment (BNF).
  • Renal/Hepatic Impairment: Dose reduction necessary; avoid if severe dysfunction (Lippincott).
  • Monitoring: Regular full blood counts, liver function tests (LFTs), and renal function tests (Lange).
  • Hypersensitivity: Rare but severe reactions, including Stevens-Johnson syndrome (BNF).
  • NSAIDs (e.g., ibuprofen): Reduce renal excretion, increasing methotrexate toxicity (Lippincott).
  • Proton Pump Inhibitors (e.g., omeprazole): May impair renal clearance (Lange).
  • Trimethoprim/Sulfonamides: Synergistic folate antagonism, raising myelosuppression risk (BNF).
  • Live Vaccines: Avoid due to immunosuppression (Lippincott).

Methotrexate is the generic name. Brand names include Trexall®Rheumatrex®, and Otrexup®. Available as tablets (2.5 mg, 5 mg, 10 mg), injectable solutions, and auto-injectors for subcutaneous use.

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