Describe methotrexate with its mechanism, uses, adverse effects and interactions.

Mechanism of Action

Dhfr normally converts dihydrofolate → tetrahydrofolate → Tetrahydrofolate carries one-carbon units for thymidylate and purine synthesis → Methotrexate binds dhfr with far greater affinity than the natural substrate → Tetrahydrofolate is depleted → DNA synthesis fails — the effect is S-phase specific and hits the most rapidly dividing cells → At the low doses used in rheumatology the mechanism is different — chiefly adenosine-mediated anti-inflammatory action

Uses

Adverse Effects

• Mucositis and stomatitis — often the first sign of toxicity
• Myelosuppression — dose-limiting; pancytopenia
• Hepatotoxicity — transaminase rise, and with long-term use fibrosis and cirrhosis; alcohol markedly increases the risk
• Pneumonitis — an idiosyncratic hypersensitivity reaction that may occur at any dose and is potentially fatal; any new dry cough or breathlessness must be taken seriously
• Nephrotoxicity — methotrexate precipitates in acid urine, so high-dose therapy requires hydration and urinary alkalinisation; renal impairment then reduces clearance and causes a self-reinforcing spiral of toxicity
• Neurotoxicity — with intrathecal or high-dose use: arachnoiditis, encephalopathy, leukoencephalopathy
• Teratogenic and abortifacient — absolutely contraindicated in pregnancy; effective contraception is required in both sexes, and the drug stopped some months before conception
• Others — alopecia, photosensitivity, and reactivation of latent infection

Interactions and Monitoring

• NSAIDs, aspirin, probenecid and penicillins reduce renal tubular secretion of methotrexate and raise its level — important because rheumatology patients are commonly on NSAIDs
• Trimethoprim and CO-trimoxazole are the dangerous ones: both are antifolates, and the combination has caused fatal pancytopenia. This is one of the interactions most worth knowing
• Proton pump inhibitors may reduce elimination of high-dose methotrexate
• Monitoring — full blood count, liver and renal function before starting, then every 2 to 4 weeks initially and 2 to 3 monthly once stable; chest radiograph at baseline
• Folic acid 5 mg weekly, on a different day from the methotrexate, markedly reduces mucositis, nausea and hepatotoxicity without reducing efficacy

Applied Aspects

• Write "once weekly" in words on every prescription and confirm the patient understands. Inadvertent daily dosing causes fatal marrow suppression and is a well-documented, recurring and entirely preventable prescribing error — in India as elsewhere
• Tell the patient to report mouth ulcers, sore throat, fever, bruising, cough or breathlessness immediately
• Folinic acid, not folic acid, is the antidote in overdose or severe toxicity, given urgently and repeatedly; glucarpidase cleaves methotrexate in severe renal impairment
• Avoid in significant renal impairment, and check renal function whenever the patient is dehydrated or acutely unwell
• Advise limiting alcohol, given the additive hepatotoxicity
• Never co-prescribe co-trimoxazole or trimethoprim — a rule worth holding absolutely, since the combination is prescribed by clinicians unaware the patient is on methotrexate