Inflammatory Bowel Diseases

Dr. Nematollah AhangarAssistant 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 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