Methotrexate: Drug Effects, Side Effects, Dosage and Uses

Products

Methotrexate is commercially available as a solution for parenteral use and in tablet form. See also under methotrexate prefilled syringe (low-dose).

Structure and properties

Methotrexate (C20H22N8O5, Mr = 454.44 g/mol) is a dicarboxylic acid that exists as a yellow to orange crystalline powder that is virtually insoluble in water. Methotrexate was developed as a folic acid analog.

Effects

Methotrexate (ATC L01BA01, ATC L04AX03) has antineoplastic, immunosuppressive, and anti-inflammatory effects. It was originally developed as a folic acid antagonist for cancer therapy but is now used in paxis mainly for inflammatory rheumatic diseases. The cytostatic effect is due to the inhibition of various folic acid-dependent enzymes in the synthesis of purines and pyrimidines, thereby inhibiting DNA synthesis and thus tumor cell proliferation.

Mechanism of action

The action of methotrexate is based on inhibition of dihydrofolic acid reductase, a key enzyme in the folic acid biosynthetic pathway. It catalyzes the reduction of folic acid to dihydrofolic acid and further to tetrahydrofolic acid, which is required for the synthesis of purine nucleotides. Methotrexate also inhibits other enzymes in the folic acid biosynthesis pathway such as thymidylate synthetase, which is responsible for pyrimidine synthesis. Blocking these folate-dependent steps inhibits the synthesis of AMP, GMP, the DNA and RNA, resulting in cell cycle arrest and thus inhibition of tumor cell proliferation. The immunosuppressive or anti-inflammatory mode of action of methotrexate has not been fully elucidated (see literature).

Indications

Methotrexate as a cytostatic agent (high-dose therapy):

  • Acute lymphocytic and myeloid leukemia.
  • Non-Hodgkin’s lymphomas, especially CNS lymphomas.
  • Solid tumors such as breast, lung, and bladder cancers, as well as malignant head and neck tumors and choriocarcinomas
  • Osteosarcoma in children and adolescents

Methotrexate as an immunosuppressant (deep-dose therapy) is suitable for the treatment of certain autoimmune diseases such as:

  • Rheumatoid arthritis, juvenile idiopathic arthritis.
  • Severe forms of psoriasis
  • Rarer today: Crohn’s disease and multiple sclerosis

See also under methotrexate pre-filled injection (low-dose).

Dosage

According to the drug label. In cancer therapy, methotrexate is dosed significantly higher than in immunosuppressive therapy (high dose up to 12′ 000 mg/m2, low dose 5-15 mg per week). In high-dose therapy, the effect of methotrexate is antagonized by the additional administration of folic acid to prevent severe side effects caused by damage to rapidly dividing cells.

Contraindications

Methotrexate is contraindicated in hypersensitivity, during pregnancy and lactation, in patients with renal dysfunction, hepatic impairment, preexisting diseases of the hematopoietic system, immunodeficiency, gastrointestinal ulcers, and severe or existing infections and excessive alcohol consumption. Particular emphasis should be placed on renal dysfunction. Full details of precautions and interactions can be found in the Drug Information Leaflet.

Interactions

Interactions with NSAIDs, glucocorticoids, antibiotics, allopurinol, theophylline, and oral anticoagulants are of primary concern. Elimination of methotrexate occurs almost entirely via the kidneys by glomerular filtration and active tubular secretion. Only a small fraction is excreted via the bile. Agents that reduce the clearance of methotrexate cause toxicity. An important interaction occurs when probenecid is taken concomitantly. It inhibits both renal tubular secretion and biliary excretion of organic anions, resulting in a reduction in the elimination of methotrexate. However, probenecid is rarely used in practice today. Colestyramine has the opposite effect. It increases biliary excretion and thus the elimination of methotrexate. Therefore, it can be used in cases of methotrexate overdose or renal dysfunction. Colestyramine is also rarely used today. NSAIDs are also organic anions and can lead to interactions, which is particularly significant in cancer therapy with high MTX doses.Literature reports that displacement of methotrexate from protein binding greatly increases blood levels. This results in severe hematologic and gastrointestinal toxicity, which can lead to death. Other interactions have been described with glucocorticoids, antibiotics such as trimethoprim and trimethoprim combined with sulfamethoxazole, allopurinol, theophylline, and oral anticoagulants, among others.

Adverse effects

Gastrointestinal symptoms such as oral mucositis, diarrhea, nausea, abdominal discomfort are among the most common adverse reactions. Bone marrow depression is also frequently observed, depending on dose or renal function and possible accumulation. Methotrexate and its main metabolite 7-hydroxymethroxate are bound to polyglutamate in cells. These methotrexate polyglutamates accumulate in tissues and especially in the small intestinal epithelium. Another very common adverse side effect is an increase in liver enzymes (transaminases); severe liver damage can occur. In contrast to the gastrointestinal side effects, the transaminase increase can be prevented by substituting folic acid to methothrexate therapy. Other side effects: Renal dysfunction, skin rash, rarely hair loss, pneumonitis, and allergic reactions. Regular laboratory monitoring of renal and hepatic function is therefore essential because of the side effect profile.