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The mechanism of action in cancer: Methotrexate is an antimetabolite and antifolate drug. Methotrexate acts by inhibiting the metabolism of folic acid. Folic acid is needed for the synthesis of the nucleoside thymidine, required for DNA synthesis. Methotrexate acts specifically by inhibiting dihydrofolic acid reductase (DHFR). Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis and cellular replication. Actively proliferating tissues such as malignant cells are in general more sensitive to this effect of methotrexate. When cellular proliferation in malignant tissues is greater than in most normal tissues, methotrexate may impair malignant growth without irreversible damage to normal tissues.

The mechanism of action in rheumatoid arthritis: For the treatment of rheumatoid arthritis multiple mechanisms appear to be involved including: inhibition of purine and pyrimidine synthesis, suppression of methyltransferase activity with accumulation of polyamines, inhibition of T cell activation, and promotion of adenosine release. It is possible that a combination of these mechanisms is responsible for the antiinflammatory effects of methotrexate.


  • Neoplastic Diseases: Methotrexate is indicated in the treatment of a number of cancers including: breast cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides (cutaneous T cell lymphoma), and lung cancer, particularly squamous cell and small cell types. Methotrexate is also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin’s lymphomas.
  • Psoriasis: Methotrexate is indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy
  • Rheumatoid Arthritis in adults and Juvenile Rheumatoid Arthritis: Methotrexate is now considered the first-line Disease-modifying antirheumatic drugs (DMARD) agent for most patients with Rheumatoid Arthritis. It is usually used in patients who have had an insufficient therapeutic response to, or are intolerant to the first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs).
  • Induction of medical abortions: Methotrexate is an abortifacient and is commonly used to terminate pregnancies during the early stages, generally in combination with misoprostol
  • Ectopic Pregnancy: In early treatment of an ectopic pregnancy, methotrexate terminates the growth of the developing embryo; this may cause an abortion, or the developing embryo may then be either resorbed by the woman's body or pass with a menstrual period. Contraindications include liver, kidney, or blood disease, as well as an ectopic embryonic mass > 3.5 cm.

[edit] DOSAGE

Cancer: The dose of methotrexate varies depending on the type of cancer being treated and body weight or size.

Oral administration

  • Rheumatoid Arthritis in adults: Starting dose is 7.5 mg taken as one dose once weekly by mouth or 2.5 mg taken every 12 hours for 3 doses once weekly. The dose may be increased to 20-25 mg a week over time if needed. The benefits of treatment usually appear about 3 to 6 weeks after starting the medication.
  • Juvenile Rheumatoid Arthritis: The recommended starting dose is 10 mg/m2 given once weekly.
  • Psoriasis: The usual adult starting dose of methotrexate is 10 mg to 25 mg per week in one dose or 2.5 mg taken every 12 hours for 3 doses once weekly. Doses can be adjusted gradually but don't usually exceed 30 mg weekly.


  • Pregnancy: Methotrexate can cause fetal death or teratogenic effects. Pregnancy should be avoided if either partner is receiving methotrexate; during and for a minimum of three months after therapy for male patients, and during and for at least one ovulatory cycle after therapy for female patients.
  • Nursing mothers: Because of the potential for serious adverse reactions from methotrexate in breast fed infants, it is contraindicated in nursing mothers.
  • Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver disease should not receive methotrexate.
  • Patients with psoriasis or rheumatoid arthritis who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anemia, should not receive methotrexate.
  • Patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence of immunodeficiency syndromes should not receive methotrexate.


Patients starting methotrexate should be carefully evaluated for renal insufficiency, acute or chronic liver disease, significant alcohol intake or alcohol abuse, leukopenia (low white blood cell counts), thrombocytopenia (low platelet counts), or untreated folate deficiency.


NSAIDs and the antibiotic trimethoprim block the renal excretion of methotrexate and increase serum levels with an increased risk of toxicity:

  • Caution should be used when NSAIDs and salicylates are administered concomitantly. The coadministration of NSAIDS with methotrexate is routine in patients with rheumatoid arthritis and is considered safe by rheumatologists as long as liver function tests and blood counts are closely monitored.
  • Concomitant use of methotrexate and trimethoprim should be avoided.


Pregnancy Category X (US). Methotrexate is teratogenic (harmful to fetus) and hence not used in pregnant patients with Psoriasis and rheumatoid arthritis

  • Nursing mothers: contraindicated


The most frequently reported adverse reactions include ulcerative stomatitis (mouth ulcers, or sores), leukopenia (low white blood cell count) and thus predisposition to infection, nausea, and abdominal distress. Other frequently reported adverse effects are malaise, headaches, undue fatigue, chills, fever and dizziness.

Hair loss is a relatively uncommon at the dosage used for Rheumatoid Arthritis.

Stomatitis , mild alopecia and hair thinning, and GI upset (nausea) can be improved with 1mg daily folic acid supplementation without diminishing the efficacy of methotrexate

Most serious complications of methotrexate therapy: hepatic cirrhosis, interstitial pneumonitis, and severe myelosuppression are quite rare


Methotrexate description
Methotrexate metabolism & MOA
Methotrexate for Rheumatoid Arthritis