Aminosalicylates

Sulfasalazine (Azulfidine) was first introduced in 1940 as a treatment for rheumatoid arthritis. It was found that a number of patients with coexistent inflammatory bowel disease showed improvement of their GI symptoms, and the drug has subsequently been used for the treatment of patients with inflammatory bowel disease.

Sulfasalazine is composed of sulfapyridine and 5-ASA molecules linked by an azo bond. Sulfapyridine has no effect on the inflammatory bowel disease, and instillation of this agent into the colon does not heal colonic mucosa. It is, however, responsible for most of sulfasalazine's side effects, including sulfa allergic reactions. 5-ASA, the active metabolite, may inhibit the synthesis of mediators of inflammation.

Following oral administration, 30% of the sul-fasalazine is absorbed from the small intestine. Because most of the compound that is absorbed is later excreted into the bowel, 75 to 85% of the administered oral dose eventually reaches the colon intact. Bacteria in the colon then split the azo linkage, liberating sulfapyridine and 5-ASA. The sulfapyridine is absorbed, acetylated, hydroxylated, and conjugated to glucuronic acid in the liver. The major portion of the sulfapyridine molecule and its metabolites are excreted in the urine. The 5-ASA remains in the colon, eventually reaching high fecal levels.

Sulfasalazine treatment results in an 85% remission rate in mild to moderate ulcerative colitis. Termination of therapy leads to an 80% relapse within the next year. In Crohn's disease, sulfasalazine acts primarily on involved colonic mucosa, although remission of ileal disease also has been reported. The National Cooperative Crohn's Disease Study found sulfasalazine to be better in the treatment of colonic disease, while corticosteroids were judged better in the treatment of small bowel disease. Since sulfasalazine does not prevent relapse of Crohn's disease once remission is achieved, maintenance therapy is not characteristically used.

Nausea, vomiting, and headaches, the most common side effects, are related to the blood level of sulfapyri-dine. If the dose is reduced, symptoms frequently improve. Fever, rash, aplastic anemia, and autoimmune hemolysis are hypersensitivity reactions to the medication. These occur less commonly and are not dose related. Sulfasalazine should not be used in patients with hypersensitivity agranulocytosis or aplastic anemia.

Since sulfasalazine inhibits the absorption of folic acid, patients may become folate deficient during long-term therapy. Sulfasalazine decreases the bioavailability of digoxin. Cholestyramine reduces the metabolism of sulfasalazine. Sulfasalazine causes a reversible decrease in sperm counts. Sulfasalazine is safe in pregnancy.

To avoid the side effects of sulfapyridine, various preparations to target 5-ASA directly to sites of disease have been formulated. Also known as mesalamine, 5-ASA has been formulated in oral forms (Pentasa, Asacol). Pentasa is a time-release capsule that releases the drug throughout the GI tract. Asacol is a pH-dependent-release preparation that delivers drug to the distal small bowel and colon. The response of ulcerative colitis to this formulation appears to be identical to that seen with sulfasalazine. Mesalamine can also be administered as a suppository (Canasa) or enema (Rowasa) for distal colonic disease.

Olsalazine sodium (Dipentum) links two 5-ASA molecules with an azo linkage. Following cleavage of the azo linkage in the colon, two 5-ASA molecules are released. Olsalazine is approved for maintenance of remission of ulcerative colitis, but a commonly reported side effect is a paradoxical increase in diarrhea. The U. S. Food and Drug Administration (FDA) has approved balsalazide disodium (Colazal) as a treatment of mild to moderately active ulcerative colitis. Balsalazide disodium is delivered intact to the colon, where it is cleaved by bacterial azoreduction to release equimolar quantities of mesalamine, the therapeutically active portion of the molecule, and 4-aminobenzoyl-p-alanine; the latter compound is only minimally absorbed and is largely inert.

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