Sulfasalazine

SULFASALAZINE

Mechanism of Action

Sulfasalazine, a synthetic DMARD, is metabolized to sulfapyri-dine and 5-aminosalicylic acid. The sulfapyridine is probably the active moiety when treating rheumatoid arthritis (unlike inflam-matory bowel disease). Some authorities believe that the parent compound, sulfasalazine, also has an effect. In treated arthritis patients, IgA and IgM rheumatoid factor produc-tion are decreased. Suppression of T-cell responses to concanavalin and inhibition of in vitro B-cell proliferation have also been docu-mented. In vitro, sulfasalazine or its metabolites inhibit the release of inflammatory cytokines, including those produced by mono-cytes or macrophages, eg, interleukins-1, -6, and -12, and TNF-α. These findings suggest a possible mechanism for the clinical efficacy of sulfasalazine in rheumatoid arthritis.

Pharmacokinetics

Only 10–20% of orally administered sulfasalazine is absorbed, although a fraction undergoes enterohepatic recirculation into the bowel where it is reduced by intestinal bacteria to liberate sulfapyridine and 5-aminosalicylic acid (see Figure 62–8). Sulfapyridine is well absorbed while 5-aminosalicylic acid remains unabsorbed. Some sulfasalazine is excreted unchanged in the urine whereas sulfapyridine is excreted after hepatic acetylation and hydroxylation. Sulfasalazine’s half-life is 6–17 hours.

Indications

Sulfasalazine is effective in rheumatoid arthritis and reduces radio-logic disease progression. It has also been used in juvenile chronic arthritis and in ankylosing spondylitis and its associated uveitis. The usual regimen is 2–3 g/d.

Adverse Effects

Approximately 30% of patients using sulfasalazine discontinue the drug because of toxicity. Common adverse effects include nausea, vomiting, headache, and rash. Hemolytic anemia and methemo-globinemia also occur, but rarely. Neutropenia occurs in 1–5% of patients, while thrombocytopenia is very rare. Pulmonary toxicity and positive double-stranded DNA (dsDNA) are occasionally seen, but drug-induced lupus is rare. Reversible infertility occurs in men, but sulfasalazine does not affect fertility in women. The drug does not appear to be teratogenic.