Chapter: Modern Pharmacology with Clinical Applications: Antiinflammatory and Antirheumatic Drugs


Of the DMARDs, methotrexate (Rheumatrex) is the most widely prescribed.


Of the DMARDs, methotrexate (Rheumatrex) is the most widely prescribed. It is indicated for the treatment of rheumatoid arthritis and psoriasis; it is also used for psoriatic arthritis, systemic lupus erythematosus, andsarcoidosis. It is generally as efficacious as the other agents, with a low incidence of serious side effects when prescribed on a low-dose weekly schedule.

Basic Pharmacology

Methotrexate is a folate antimetabolite that inhibits di-hydrofolate reductase and other folate-dependent en-zymes in cells. When given in high doses, methotrexate exerts potent suppressing action on cellular and humoral immunity . At the low doses used in the therapy of rheumatoid arthritis, methotrexate appears to be act-ing more as an antiinflammatory agent than as an im-munosuppressant. Methotrexate inhibits folate-depend-ent enzymes involved in adenosine degradation, increasing concentrations of extracellular adenosine. Adenosine acts via cell surface receptors to inhibit the production of inflammatory cytokines such as TNF-αand IFN- . Methotrexate also decreases the production of inflammatory prostaglandins and proteases, though a direct action on the COX enzymes has not been noted.

Adverse Effects

In the low-dose regimen used for rheumatoid arthritis, most side effects of methotrexate are mild and can be managed by temporarily stopping the drug or reducing the dose. These include nausea, stomatitis, GI discom-fort, rash, diarrhea, and headaches. Changes in liver aminotransferases and mild to moderate immunosup-pression have been reported in rheumatoid arthritis pa-tients taking methotrexate. Severe toxicity is possible but rare and may be a function of drug accumulation. These effects include hepatotoxicity progressing to cir-rhosis, pneumonitis progressing to pulmonary fibrosis, and bone marrow depression with anemia, leukopenia, and thrombocytopenia. Folic acid supplementation is of-ten used to alleviate certain side effects of methotrexate therapy (stomatitis, GI irritation, hematopoietic effects) but may also contribute to resistance to this therapy.

Contraindications and Drug Interactions

Methotrexate is teratogenic and is contraindicated dur-ing pregnancy and breast-feeding. Prior to attempting pregnancy, women should wait at least one menstrual cycle and men at least 3 months after discontinuing this drug. Additional contraindications to methotrexate ad-ministration include kidney, liver, and lung disease; moderate to high alcohol use; immunodeficiency; blood dyscrasias; and hypersensitivity. Elderly persons may be at increased risk for toxicity because of decreased renal and hepatic function.

Methotrexate clearance can be decreased by the coadministration of NSAIDs; however, this not usually a problem with the low doses of methotrexate used to treat arthritis. Methotrexate can be displaced from plasma protein binding sites by phenylbutazone, pheny-toin, sulfonylureas, and sulfonamides and certain other antibiotics. The antifolate effects of methotrexate are additive with those of other folate-inhibitory drugs, such as trimethoprim.

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Modern Pharmacology with Clinical Applications: Antiinflammatory and Antirheumatic Drugs : Methotrexate |

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