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
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•
•
•
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