A 22-year-old man presents for the evaluation of abdominal pain and diarrhea. He states that for approximately a month he has had progressively worsening cramping pains. He has had watery diarrhea and, from time to time, has noted blood mixed in with his stool. He has lost approximately 5 lb. He has tried over-the-counter antidiarrheal medications without relief. He is on no medication regularly and has no significant medical history. Examination of his abdomen reveals it to be distended and to have hyperactive bowel sounds. It is diffusely tender with no palpable masses. Rectal examination is very painful and reveals heme-positive watery stool. A blood count shows that he has iron deficiency anemia and an erythrocyte sedimentation rate that is markedly elevated. An office sigmoidoscopy reveals changes consistent with ulcerative colitis. You start him on a short course of corticosteroids and plan to place him on long-term sulfasalazine.
What is the mechanism of action of sulfasalazine?
Sulfasalazine cannot be used by persons allergic to which class of antibiotics?
Answers to case: agents for lower GI disorders
Summary: A 22-year-old man with ulcerative colitis is started on a short course of corticosteroids and long-term sulfasalazine.
Mechanism of action of sulfasalazine: 5-aminosalicylic acid (5-ASA) component of sulfasalazine inhibits leukotriene and prostaglandin production in the colon.
Sulfasalazine cannot be used by persons allergic to: Sulfonamides.
Sulfasalazine is used to achieve and maintain remission in persons with inflammatory bowel disease (IBD: ulcerative colitis and Crohn’s disease). It is composed of two constituents — 5-ASA bound by an AZO bond (N=N) to sul-fapyridine. The AZO bond limits the gastrointestinal (GI) absorption of the inactive, parent compound. However, in the terminal ileum and colon, bacteria break down sulfasalazine into its two components. 5-ASA is the active anti-inflammatory component. Its mechanism of action, while not entirely known, is thought to involve inhibition of the production of inflammatory leukotrienes and prostaglandins in the colon. Its activity is terminated by hepatic acetylation. Sulfapyridine, which is also acetylated, does not appear to play an active role in the reduction of inflammation in the colon. Sulfapyridine mediates the allergic cross-reaction with sulfonamide drugs. 5-ASA can also be administered as mesalamine, balsalazide, and olsalazine, which do not have a sulfa component. Sulfasalazine, balsalazide, and olsalazine are administered orally. Mesalamine has oral, suppository, and enema formulations. The many adverse effects of sulfasalazine, attributable primarily to the systemic actions of sulfapyridine, which for many patients is not tolerated, and which is more common in slow acetylators than fast acetylators, includes severe GI discomfort with nausea, headache, myalgia, bone marrow suppression, possible oligospermia that is reversible, and a hypersensitivity with numerous attendant serious sequelae.
Approach to pharmacology of agents that act on the lower GI tract
1. List drugs used as antidiarrheal agents and describe their mechanisms of action, therapeutic uses, and adverse effects.
2. List drugs used as laxatives and describe their mechanisms of action and adverse effects.
3. List drugs used to treat irritable bowel syndrome (IBS) and IBD.
Ulcerative colitis: Inflammatory disease of gastrointestinal (GI) mucosa that is localized in the large intestine.
Crohn’s disease: Inflammatory disease of the GI tract that can occur anywhere from the mouth to the anus.
Irritable Bowel Syndrome (IBS): Recurrent abdominal pain with altered bowel movements (constipation or diarrhea), among other symptoms, that is due to alterations in motor and sensory function.
Inflammatory Bowel Disease: Condition with symptoms of chronic GI inflammation.