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Saturday, August 16, 2025

Methotrexate


Executive Overview

Methotrexate (MTX) is a folate antagonist with cytotoxic, immunosuppressive, and anti-inflammatory properties. First introduced as an antineoplastic agent in the 1940s, it is now a cornerstone in oncology, autoimmune disease management, and dermatology. At high doses, it is a cytotoxic drug used in malignancies; at low weekly doses, it is a disease-modifying antirheumatic drug (DMARD) in conditions like rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Its dual clinical identity reflects dose-dependent mechanisms of action.

Methotrexate requires careful dosing, strict avoidance of daily use in autoimmune disease, and monitoring for hepatic, hematologic, renal, and pulmonary toxicity. Folic acid supplementation is standard in chronic therapy to reduce adverse effects.

Pharmacological Class

  • Class: Antimetabolite; folate analogue; antineoplastic and immunosuppressant

  • ATC Code: L01BA01

  • Formulations:

    • Oral tablets (2.5 mg, 5 mg, 10 mg)

    • Oral solution (rare, pediatric use)

    • Parenteral solutions for subcutaneous, intramuscular, intravenous, or intrathecal administration (various strengths: 25 mg/mL, 50 mg/2 mL, 500 mg/20 mL, high-dose infusion bags)

Mechanism of Action

  1. High-dose (oncology)

    • Inhibits dihydrofolate reductase (DHFR) → blocks tetrahydrofolate production → inhibits thymidylate and purine synthesis → prevents DNA replication and cell division.

    • Particularly cytotoxic to rapidly dividing malignant cells.

  2. Low-dose (autoimmune/anti-inflammatory)

    • Effects are less about cytotoxicity and more about adenosine accumulation (anti-inflammatory mediator) and suppression of T-cell activation and cytokine release.

    • Inhibits enzymes involved in purine metabolism, leading to anti-inflammatory effects without full cytotoxicity.

Pharmacokinetics

  • Absorption: Oral bioavailability is dose-dependent: ~70% at low doses, but reduced at doses >25 mg. Subcutaneous administration improves consistency.

  • Distribution: Widely distributed; accumulates in liver and kidneys. Crosses placenta.

  • Metabolism: Hepatic metabolism to active polyglutamate forms; some intestinal bacterial metabolism.

  • Elimination: Renal excretion (glomerular filtration and tubular secretion).

  • Half-life: Biphasic, ~3–10 h at low doses; 8–15 h at high doses.

Clinical Indications

Oncological Uses

  • Acute lymphoblastic leukemia (ALL)

  • Non-Hodgkin’s lymphoma, primary CNS lymphoma

  • Osteosarcoma

  • Choriocarcinoma and gestational trophoblastic disease

  • Head and neck cancers

  • Bladder, breast, and other solid tumors (in regimens)

Non-Oncological Uses (low-dose, once weekly)

  • Rheumatoid arthritis (RA) — anchor DMARD

  • Psoriasis and psoriatic arthritis — effective in skin and joint involvement

  • Juvenile idiopathic arthritis (JIA)

  • Inflammatory bowel disease (Crohn’s disease, off-label in some regions)

  • Vasculitides (e.g., giant cell arteritis, granulomatosis with polyangiitis)

Contraindications

  • Hypersensitivity to methotrexate

  • Pregnancy and breastfeeding (teratogenic, abortifacient)

  • Severe hepatic or renal impairment

  • Alcoholism or chronic liver disease (cirrhosis, hepatitis)

  • Pre-existing significant blood dyscrasias (bone marrow suppression, anemia, leukopenia, thrombocytopenia)

  • Immunodeficiency syndromes

  • Active serious infections

Precautions

  • Strict once-weekly dosing in autoimmune disease — fatal errors occur with daily administration.

  • Folic acid supplementation: 1–5 mg daily (not on same day as methotrexate) reduces stomatitis, GI upset, and cytopenias.

  • Liver toxicity: monitor LFTs; avoid in significant hepatic disease and caution with alcohol.

  • Renal impairment: accumulation increases risk of toxicity; hydration and alkalinization required with high doses.

  • Pulmonary toxicity: interstitial pneumonitis and pulmonary fibrosis possible, even at low doses.

  • Myelosuppression: risk of leukopenia, anemia, thrombocytopenia.

  • Infections: immunosuppressive; screen for TB and hepatitis prior to long-term therapy.

  • Vaccinations: avoid live vaccines during treatment.

  • Drug rescue: High-dose regimens require leucovorin (folinic acid) rescue to prevent severe toxicity.

Adverse Effects

Common

  • Nausea, vomiting, anorexia

  • Oral ulcers, stomatitis

  • Fatigue, malaise

  • Alopecia (mild, reversible)

Hematological

  • Leukopenia, thrombocytopenia, anemia

  • Pancytopenia in overdose

Hepatic

  • Elevated transaminases

  • Chronic hepatotoxicity, fibrosis, cirrhosis with long-term use

Pulmonary

  • Acute pneumonitis (non-dose-related)

  • Chronic interstitial fibrosis

Dermatological

  • Rash, photosensitivity

  • Rare: Stevens-Johnson syndrome, toxic epidermal necrolysis

Reproductive

  • Teratogenicity (neural tube defects, skeletal abnormalities)

  • Oligospermia, menstrual irregularities (reversible)

Drug Interactions

  • NSAIDs, penicillins, sulfonamides: reduce renal clearance → increased toxicity

  • Trimethoprim-sulfamethoxazole: risk of severe bone marrow suppression (avoid)

  • Alcohol: additive hepatotoxicity

  • Live vaccines: risk of disseminated infection

  • Other hepatotoxic or nephrotoxic drugs: increased risk of organ damage

  • Leucovorin/folic acid: counteracts toxicity but reduces anti-tumor efficacy if misused in oncology dosing

Dosage

Low-Dose (Autoimmune, Weekly)

  • Rheumatoid arthritis, psoriasis, JIA:

    • Oral/subcutaneous: 7.5–15 mg once weekly, titrated up to 20–25 mg once weekly (maximum 30 mg).

    • Always prescribe with folic acid supplementation (at least 5 mg weekly, or 1 mg daily except on MTX day).

High-Dose (Oncology, Daily or Cyclical)

  • Acute lymphoblastic leukemia (maintenance/consolidation): 15–30 mg/m² weekly or high-dose IV (1–5 g/m²) with leucovorin rescue.

  • Osteosarcoma: 12 g/m² IV infusion over 4 hours, with hydration, urine alkalinization, and leucovorin rescue.

  • Lymphomas and solid tumors: doses vary widely depending on regimen.

Intrathecal Use

  • For prophylaxis or treatment of meningeal leukemia or lymphoma: 12 mg intrathecal injection (dose adjusted by age/weight in pediatrics).

Monitoring

  • Baseline: CBC, LFTs, renal function, chest X-ray, hepatitis and TB screen, pregnancy test (in women of childbearing potential).

  • During therapy:

    • CBC, LFTs, creatinine every 2–4 weeks initially, then every 1–3 months.

    • Monitor for pulmonary symptoms (dry cough, dyspnea).

    • Assess for stomatitis, GI upset, rash.

  • High-dose regimens: monitor serum methotrexate levels and adjust leucovorin rescue accordingly.

Patient Counseling Points

  • Take methotrexate once weekly, never daily (for non-oncologic use).

  • Take folic acid supplements as prescribed.

  • Avoid alcohol and limit hepatotoxic medications.

  • Report mouth ulcers, unusual bleeding, persistent cough, shortness of breath, or signs of infection immediately.

  • Contraception is essential (men and women) during therapy and for at least 3 months after stopping (some guidelines recommend 6 months).

  • Do not receive live vaccines while on treatment.





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