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

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Leflunomide

Leflunomide is a prodrug that is converted to an active malonitrilamide metabolite, A77 1726 (M1).

Leflunomide

Leflunomide (Arava) is an isoxazole derivative ap-proved for the treatment of rheumatoid arthritis in 1998. Limited data suggest that it is comparable in effi-cacy to sulfasalazine and produces fewer adverse ef-fects. It has a faster onset of action (4 weeks) than other DMARDs.

Basic Pharmacology

Leflunomide is a prodrug that is converted to an active malonitrilamide metabolite, A77 1726 (M1). inhibits T-cell proliferation by blocking de novo pyrimidine syn-thesis and inhibiting the tyrosine kinases that are associ-ated with certain cytokine and growth factor receptors.

Adverse Effects

Diarrhea occurs in approximately one-third of patients taking this drug; indigestion, nausea, and vomiting occur in about 10%. Other common adverse effects include weight changes, headache, skin rashes, pruritus, and re-versible alopecia and hepatic enzyme elevation.Although leflunomide acts as an immunosuppressive, it does not ap-pear to cause significant bone marrow depression.

Contraindications and Drug Interactions

Leflunomide is teratogenic in animal models; it is ab-solutely contraindicated in pregnancy, in women who may become pregnant, and in breast-feeding women. Because of its long half-life, the M1 metabolite of leflunomide may remain in the body for up to 2 years; therefore, a drug elimination procedure using choles-tyramine should be used before any attempt at preg-nancy. This drug is not recommended for use in chil-dren. Caution should be used when administering this drug to individuals with renal or hepatic disease, heavy alcohol use, or immunosuppression.

The long half-life of leflunomide must be taken into account to prevent drug interactions. Hepatotoxicity is possible if leflunomide is given in conjunction with a he-patotoxic agent such as methotrexate or certain NSAIDs. Leflunomide inhibits CYP2C9, the enzyme responsible for the metabolism of numerous drugs. Rifampin induces the P450 enzyme responsible for converting leflunomide to its M1 metabolite. Cholestyramine enhances the clear-ance of leflunomide and its M1 metabolite.

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