Write a short note on methotrexate — mechanism, indications, adverse effects and monitoring.

Definition & Mechanism

Methotrexate (MTX) is a folate antimetabolite and the anchor drug of rheumatology. It competitively inhibits dihydrofolate reductase (DHFR), blocking the conversion of dihydrofolate to tetrahydrofolate, the carrier of one-carbon units required for thymidylate and purine synthesis. The result is impaired DNA synthesis, affecting rapidly dividing cells — malignant cells, and cells of the marrow, gut mucosa and skin.

Two distinct mechanisms by dose — a key examination point:

• High dose (oncology): cytotoxic, through DHFR inhibition and arrest of DNA synthesis.
• Low dose, once weekly (rheumatology and dermatology): anti-inflammatory and immunomodulatory, mediated largely by increased adenosine release, together with inhibition of lymphocyte proliferation and reduced cytokine production. This is why low-dose MTX is not simply "mild chemotherapy".

Indications

Dosing Principles

In rheumatology and dermatology, MTX is given once weekly — typically starting at 7.5–15 mg weekly and titrating upwards. Folic acid 5 mg weekly, given on a different day from the methotrexate, markedly reduces mucositis, nausea and hepatotoxicity without reducing efficacy.

Adverse Effects

• Hepatotoxicity — the most important long-term risk: transaminitis progressing to steatosis, fibrosis and cirrhosis. Avoid alcohol; monitor LFTs.
• Myelosuppression — leucopenia, thrombocytopenia, macrocytic anaemia; risk increased by renal impairment and drug interactions.
• Mucositis and stomatitis — painful oral ulceration, an early sign of toxicity; largely preventable with folic acid.
• Pulmonary toxicity — methotrexate pneumonitis, presenting with dry cough, dyspnoea and fever with ground-glass change on HRCT. It is idiosyncratic, may occur at any dose, and requires permanent discontinuation plus corticosteroids.
• Nephrotoxicity — MTX is renally excreted and crystallises in the tubules at high dose.
• Teratogenicity — an absolute contraindication in pregnancy; causes neural tube defects and fetal loss. Effective contraception is required, and the drug should be stopped for at least 3 months before conception.
• Others: alopecia, photosensitivity, accelerated rheumatoid nodulosis, and increased infection risk.

Monitoring

Baseline: CBC, LFT, renal function, chest X-ray, hepatitis B and C serology, and pregnancy test. During therapy: CBC, LFT and creatinine every 2–4 weeks initially, then every 2–3 months once stable.

Withhold the drug if: neutrophils fall below 1.5 × 10⁹/L, platelets below 100 × 10⁹/L, transaminases exceed three times the upper limit of normal, or new breathlessness or cough develops.

Folinic Acid Rescue

After high-dose methotrexate in oncology, folinic acid (leucovorin, a reduced folate that bypasses the DHFR block) is given 24 hours later to rescue normal cells while tumour cells remain affected. It is accompanied by vigorous hydration and urinary alkalinisation to prevent tubular crystallisation, and by serum methotrexate level monitoring to guide the duration of rescue. Glucarpidase is available for severe toxicity with renal failure.

Drug Interactions & Contraindications

NSAIDs, trimethoprim/co-trimoxazole, probenecid, penicillins and proton pump inhibitors reduce renal clearance or add antifolate effect, raising toxicity. Co-trimoxazole with methotrexate is a classic cause of fatal pancytopenia. Contraindications include pregnancy and breastfeeding, significant renal or hepatic impairment, active infection, marrow failure and heavy alcohol intake.