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Chapter: Modern Pharmacology with Clinical Applications: Drugs Used in Gastrointestinal Disorders

Treatment of Inflammatory Bowel Disease

Inflammatory bowel disease mainly refers to ulcerative colitis and Crohn’s disease.




Inflammatory bowel disease mainly refers to ulcerative colitis and Crohn’s disease. Ulcerative colitis is charac-terized by a relapsing inflammatory condition involving the mucosa of variable lengths of the colon resulting in bleeding, urgency, diarrhea, and tenesmus. The endo-scopic and radiographic appearance may demonstrate multiple diffuse erosions or ulcerations. Biopsy reveals distorted crypt abscesses and diminished goblet cells. When involvement is limited to the rectum, it is termed ulcerative proctitis. Crohn’s disease may involve the gut from esophagus to anus; however, the small bowel or colon or both are the major areas of involvement. Inflammation is transmural. If the colon is predomi-nantly involved, the symptoms and presentation are quite similar to those of ulcerative colitis. Small bowel involvement may result in large-volume bloodless diar-rhea or obstruction. Normal areas of gut may be found between areas of inflamed mucosa. Fistulas, strictures, and abscess formation are fairly common in Crohn’s disease.


The present primary mode of therapy for these dis-eases involves the use 5-amino-salicylate (5-ASA) products. Often patients require additional medications, including corticosteroids, to help induce remission and various immune modulators, such as azathioprine, 6-mercaptopurine or methotrexate, to maintain remis-sion. In Crohn’s disease certain antibiotics, such as metronidazole and ciprofloxacin, and infliximab (Remi-cade), an anti–tumor necrosis factor- (TNF ) antibody, also have been used.





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 symp-toms, 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 in-stillation 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 reac-tions. 5-ASA, the active metabolite, may inhibit the syn-thesis 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 fe-cal 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 in-volved colonic mucosa, although remission of ileal dis-ease 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 dis-ease. Since sulfasalazine does not prevent relapse of Crohn’s disease once remission is achieved, mainte-nance 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 im-prove. Fever, rash, aplastic anemia, and autoimmune hemolysis are hypersensitivity reactions to the medica-tion. These occur less commonly and are not dose re-lated. 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 admin-istered 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 re-mission of ulcerative colitis, but a commonly reported side effect is a paradoxical increase in diarrhea. The U. S. Food and Drug Administration (FDA) has ap-proved 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- -alanine; the latter compound is only minimally absorbed and is largely inert.





TNF-α is an inflammatory cytokine thought to have a contributory role in producing chronic inflammation in various diseases, including Crohn’s disease and rheuma-toid arthritis . Infliximab (Remicade) is a mouse–human chimeric monoclonal neutralizing anti-body to human TNF-α and is considered a biological drug. Specific indications are for the reduction of signs and symptoms in patients with moderately to severely active Crohn’s disease who have had an inadequate re-sponse to conventional therapies (single infusion) and for reduction of the number of draining enterocuta-neous fistulas in patients with fistulizing Crohn’s disease (three-infusion regimen). Responses occur within 2 weeks of an infusion, and significant clinical responses were reported in 50 to 80% of patients in initial trials with infliximab. This antibody is being studied as main-tenance therapy for Crohn’s disease and to determine the best induction regimen to achieve remission.


The most common side effects, which are related to the intravenous infusion itself, include rash, low blood pressure, chills, and chest pain. These symptoms are generally temporary and often respond to a decrease in infusion rate. In addition, some patients develop anti-bodies, which have been associated in rare cases with symptoms similar to those of patients with systemic lu-pus erythematosus. These symptoms were also tempo-rary. Another side effect is increased risk of infections. Fatal cases of tuberculosis have been reported follow-ing infliximab therapy. Another potential side effect is an increased risk of lymphoma. Its occurrence remains controversial.




Recently, budesonide (Entecort EC) has been approved for the treatment of mildly to moderately active Crohn’s disease involving the ileum and/or ascending colon. Budesonide is a synthetic corticosteroid having a potent glucocorticoid and weak mineralocorticoid ac-tivity. In standard in vitro and animal models, budes-onide has an approximately 200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher top-ical antiinflammatory potency than cortisol. While budesonide is well absorbed from the GI tract, its oral bioavailability is low (about 10%), primarily because of extensive first-pass metabolism in the liver. Two ma-jor metabolites (16 -hydroxyprednisolone and 6 - hydroxybudesonide) are formed via the cytochrome P450 3A enzyme. In vitro studies on the binding of the two primary metabolites to the corticosteroid receptor indicate that their affinity for the receptor is less than 1% of that of the parent compound. It is hoped that use of this drug will avoid the long-term adverse reactions seen with systemically active corticosteroids.



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