Inflammatory Bowel Diseases

1. Inflammatory Bowel Diseases Dr. Nematollah Ahangar Assistant Prof. of Pharmacology

2. Definition • Two idiopathic forms • ulcerative colitis: • mucosal inflammatory condition • confined to the rectum and colon • Crohn’s disease: • transmuralinflammation of GI mucosa • may occur in any part of the GI tract • The etiologies: unknown, but may have a common pathogenetic mechanism

3. PATHOPHYSIOLOGY • combination of infectious, genetic, and immunologic causes • Microflora of the GI tract may provide a trigger to activate inflammation • Crohn’s disease may involve a T lymphocyte disorder that arises in genetically susceptible individuals • Smoking appears to be protective for ulcerative colitis but associated with increased frequency of Crohn’s disease

5. Ulcerative colitis and Crohn’s disease differ in two general respects: anatomic sites and depth of involvement within the bowel wall

10. fibrosis and strictures or, alternatively, fistula formation in CD

11. Comparisons • CD: marked infiltration of lymphocytes and macrophages, granuloma formation, and submucosal fibrosis • UC: lymphocytic and neutrophilic infiltrates • CD: interleukin-12 (IL-12), interferon-γ, and tumor necrosis factor-a (TNF-α), and T-helper 1 (TH1) • UC: T-helper 2

13. Aminosalicylates • Sulfasalazine • Olsalazine • Balsalazide • Various forms of mesalamine

15. Mesalamine Compounds • To deliver it to different segments of the small or large bowel • Pentasa • Asacol • Rowasa • Canasa

17. Pharmacokinetics & Pharmacodynamics • 5-ASA is readily absorbed from the small intestine • Absorption of 5-ASA from the colon is extremely low • 10% of sulfasalazine and less than 1% of balsalazide are absorbed • Sulfapyridine is absorbed from the colon • Mechanisms

18. Clinical Uses • Induce and maintain remission in ulcerative colitis • considered to be the first-line agents for treatment of mild to moderate active ulcerative colitis • Efficacy in Crohn's disease is unproven • Effectiveness : depends in part on achieving high drug concentration at the site of active disease • suppositories or enemas are useful in patients with ulcerative colitis or Crohn's disease confined to the rectum (proctitis)

20. Adverse Effects • Sulfasalazine: systemic effects of the sulfapyridine molecule • Individual differences of sulfasalazine AEs • nausea, gastrointestinal upset, headaches, arthralgias, myalgias, bone marrow suppression, and malaise • Hypersensitivity to sulfapyridine • Oligospermia • Impairs folate absorption and processing • Dietary supplementation with 1 mg/d folic acid is recommended

21. Adverse Effects • Other aminosalicylate formulations are well tolerated • Olsalazine :a secretory diarrhea in 10% of patients • Rare cases of interstitial nephritis • Rarely cause worsening of colitis

22. Corticosteroids • have been widely used for the treatment of ulcerative colitis and Crohn’sdisease • For moderate to severe disease • Prednisoloneis most commonly used • once-daily dosing • 40–60 mg/d • After 1–2 weeks, the dosage is tapered to minimize development of adverse effects • In severely ill patients, the drugs are usually administered intravenously • Hydrocortisone enemas, foam, or suppositories (15–30% of the administered dosage is still absorbed) • Budesonidecontrolled-release formulation

23. Ulcerative Colitis • First line • mild to moderate colitis is oral sulfasalazine • or an oral mesalaminederivative • or topical mesalamine • or steroids for distal disease • Prednisone up to 1 mg/kg/day or 40 to 60 mg daily • Steroids and sulfasalazine appear to be equally efficacious • Choice of formulation • Transdermalnicotine improved symptoms of patients with mild to moderate active ulcerative colitis

24. Severe or Intractable Disease • Requiring hospitalization • parenteral steroids and surgical procedures • Colectomy • Continuous IV infusion of cyclosporine (4 mg/kg/day) is recommended for patients with acute severe ulcerative colitis refractory to steroids

25. Maintenance of Remission • The major agents: sulfasalazine (2g/day) and the mesalamine derivatives • Steroids do not have a role in the maintenance of remission • Azathioprine is effective in preventing relapse of ulcerative colitis for periods exceeding 4 years

26. Crohn’s Disease • The goal of treatment for active Crohn’s disease is to achieve remission • sulfasalazine, mesalaminederivatives, or steroids, azathioprine, mercaptopurine, methotrexate, infliximab, and metronidazole • Steroids are frequently used • Metronidazole (given orally up to 20 mg/kg/day) in some patients with colonic or ileocolonic involvement • Combination of metronidazole with ciprofloxacin

28. Other drugs • Cyclosporine: not recommended except for patients with symptomatic and severe perianal or cutaneous fistulas • Methotrexate: given as a weekly injection of 5 to 25 mg

29. Anti- TNFs • Infliximab, adalimumab, and certolizumab • Infliximab: IV • adalimumab, and certolizumab: SC • Injections: weekly • For the acute and chronic treatment of patients with moderate to severe Crohn's disease • Infliximab: also for UC • The median time to clinical response is 2 weeks

31. Adverse Effects • in up to 6% of patients • infection due to suppression of the TH1 inflammatory response • Antibodies to the antibody • Acute adverse infusion reactions • myalgia, arthralgia, jaw tightness, fever, rash, urticaria, and edema • Lymphoma

32. Anti-Integrin Therapy • Natalizumab • humanized IgG4 monoclonal antibody targeted against the α4 subunit of integrins • significant efficacy for a subset of patients with moderate to severe Crohn's disease And multiple sclerosis • 300 mg every 4 weeks by intravenous infusion • 50% of patients respond to initial therapy with natalizumab • infusion reactions and a small risk of opportunistic infections • multifocal leukoencephalopathy due to reactivation of a human polyomavirus

33. Thanks for your attention