Inflammatory bowel disease/ Irritable bowel syndrome Dr. Syed Md. Basheeruddin Asdaq

Learning outcomes At the end of lecture, student should be able to: Discuss the pharmacology of drugs used in inflammatory bowel diseases Outline main therapeutic uses of the drugs of each class

Inflammatory bowel disease (IBD) IBD refers to the bowel disorders, ulcerative colitis and Crohn's disease. The etiology is unknown. IBD has a prevalence of 0.3% to 0.5% in the adult U.S. population with a slight female preponderance. It is most commonly seen in young patients. Approximately 15% of patients with IBD have close relatives who also have IBD.

Ulcerative colitis It is an inflammatory disorder of the mucosa of the rectum and colon. The rectum is virtually always involved, and if any portion of the remaining colon is involved, it is in a contiguous manner extending proximally from the rectum.

Crohn's disease It typically affects all layers of the bowel wall and may do so usually in a patchy distribution throughout the entire gastrointestinal (GI) tract. Crohn's disease may involve any part of the GI tract from the mouth to the anus, but most frequently involves the terminal ileum.

Approximately one third of cases involve the small bowel only, one third involve the colon only, and one third involve both the colon and the small bowel. The rectum may be spared. Crohn's disease in the elderly usually involves only the colon. Crohn's disease of the esophagus, stomach, and duodenum is rare, but may present alone or in combination with involvement of the segments of the GI tract.

IMMUNOSUPPRESSIVE DRUGS  Glucocorticoids are used both systemically and topically (given by enema). They are often able to induce clinical remission, but are less valuable in maintaining remission.  Cytotoxic agents (azathioprine, mercaptopurine) can be beneficial in patients who do not respond to glucocorticoids.  They are superior to glucocorticoids in maintaining remission but they have a slow onset of action (sometimes 1-2 months).

Methotrexate has a more rapid onset of action and is effective in Crohn’s disease but not in ulcerative colitis. Infliximab is a monoclonal antibody to TNF-alpha. TNF-alpha is believed to play a role in the pathogenesis of Crohn’s disease. A single IV infusion is effective in inducing clinical remission of the disease.

5-aminosalicylates Unabsorbed 5-aminosalicylic acid (5-ASA) is an active anti-inflammatory drug in IBS. Mesalamine (5-ASA)  It is administered rectally or as a delayed-release oral tablet.  About 20-30% is absorbed and metabolized rapidly by intestinal cells and liver.  Half life is 5-7 hours. Systemic effects are rare.

Sulfasalazine combines sulfapyridine with 5-ASA. Taken orally, it is poorly absorbed and is broken down in the colon by bacteria to release 5-ASA and sulfapyridine. Half life is 5-10 hours. Its use has declined because sulfapyridine may cause agranulocytosis.

Olsalazine was synthesized to prevent the side effects of sulfapyridine. It combines two 5-ASA molecules. It releases 5-ASA molecules in the large intestine by action of colonic bacteria. Half life of Olsalazine is 1 hour. Less than 1 percent of Olsalazine is absorbed into systemic circulation.

Mechanism of action 5-ASA likely acts by multiple mechanisms including: a) Inhibition of PGs and leukotriene biosynthesis (likely the main mechanism) b) Scavenging of reactive oxygen metabolites c) Reduction of macrophage chemotaxis and phagocytosis d) Inhibition of cytokine production by intestinal cells

Adverse effects Sulfasalazine has a high incidence of adverse effects, mainly related to hypersensitivity reactions to the sulfa moiety. They include, hepatitis, pancreatitis, exfoliative dermatitis, hemolytic anemia, bone marrow suppression. 5-ASA is well tolerated. It can cause nausea and vomiting, abdominal discomfort and (rarely) nephrotoxicity.

Clinical uses:  5-aminosalicylates are effective in mild or moderate ulcerative colitis, but less so in severe colitis and in Crohn’s disease.  They are more effective in maintaining than in achieving clinical remission.

Irritable bowel syndrome (IBS, or spastic colon) It is a symptom-based diagnosis characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits. Diarrhea or constipation may predominate, or they may alternate (classified as IBS-D, IBS- C or IBS-A, respectively).

Historically a diagnosis of exclusion, a diagnosis of IBS can now be made on the basis of symptoms alone, in the absence of alarm features Alarm features: – age of onset greater than 50 years, – weight loss – gross hematochezia – systemic signs of infection or colitis – family history of inflammatory bowel disease.

Onset of IBS is more likely to occur after an infection (post-infectious, IBS-PI), a stressful life event, or onset of maturity. Although there is no cure for IBS, there are treatments that attempt to relieve symptoms, including dietary adjustments, medication and psychological interventions. Patient education and a good doctor-patient relationship are also important.

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