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

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

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

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

fibrosis and strictures or, alternatively, fistula formation in CD

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

Aminosalicylates Sulfasalazine Olsalazine Balsalazide Various forms of mesalamine

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

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

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)

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

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

Corticosteroids have been widely used for the treatment of ulcerative colitis and Crohn’s disease For moderate to severe disease Prednisolone is 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) Budesonide controlled-release formulation

Ulcerative Colitis First line mild to moderate colitis is oral sulfasalazine or an oral mesalamine derivative 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 Transdermal nicotine improved symptoms of patients with mild to moderate active ulcerative colitis

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

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

Crohn’s Disease The goal of treatment for active Crohn’s disease is to achieve remission sulfasalazine, mesalamine derivatives, 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

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

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

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

Anti-Integrin Therapy Natalizumab humanized IgG 4 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