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Inflammatory bowel disease (IBD) is a spectrum of chronic, idiopathic, inflammatory intestinal conditions. IBD causes significant gastrointestinal (GI) symptoms that include diarrhea, abdominal pain, bleeding, anemia, and weight loss. IBD also is associated with a variety of extraintestinal manifestations, including arthritis, ankylosing spondylitis, sclerosing cholangitis, uveitis, iritis, pyoderma gangrenosum, and erythema nodosum
IBD conventionally is divided into two major subtypes: ulcerative colitis and Crohn's disease. Ulcerative colitis is characterized by confluent mucosal inflammation of the colon starting at the anal verge and extending proximally for a variable extent (e.g., proctitis, left-sided colitis, or pancolitis). Crohn's disease, by contrast, is characterized by transmural inflammation of any part of the GI tract but most commonly the area adjacent to the ileocecal valve. The inflammation in Crohn's disease is not necessarily confluent, frequently leaving "skip areas" of relatively normal mucosa. The transmural nature of the inflammation may lead to fibrosis and strictures or, alternatively, fistula formation.
Recently, this relatively simplistic classification has been revised in the light of the description of regulatory T cells and pro-inflammatory TH17 cells, a novel T-cell population that expresses IL-23 receptor as a surface marker and produces, among others, the pro-inflammatory cytokines IL-17, IL-21, IL-22, and IL-26. Several studies have demonstrated an important role of TH17 cells in intestinal inflammation, particularly in Crohn's disease
Shown are the interactions among bacterial antigens in the intestinal lumen and immune cells in the intestinal wall. If the epithelial barrier is impaired, bacterial antigens can gain access to antigenpresenting cells (APC) such as dendritic cells in the lamina propria. These cells then present the antigen(s) to CD4+ lymphocytes and also such interleukin (IL)-12 and IL-18, thereby inducing the differentiation of T H1 cells in Crohn's disease (or, under the control of IL-4, type 2 helper T cells [TH2] in ulcerative colitis). The balance of pro-inflammatory and anti-inflammatory events is also governed by regulatory TH17 and TReg cells, both of twhhei cehx psearnvseio tno olifm thite i mremguulnaeto arny dT incefllal msumbasetotsry. Trehsep Tonses in the GI tract. Transforming growth factor (TGF) and IL-6 are important cytokines that drive H1 cells produce a characteristic array of cytokines, including interferon (IFN) and TNF , which in turn activate macrophages. Macrophages positively regulate TH1 cells by secreting additional cytokines, including IFN and TNF . Recruitment of a variety of leukocytes is mediated by activation of resident immune cells including neutrophils. Cell adhesion molecules such as integrins are important in the infiltration of leukocytes and novel biological therapeutic strategies aimed at blocking leukocyte recruitment are effective at reducing inflammation. General immunosuppressants (e.g., glucocorticoids, thioguanine derivatives, methotrexate, and cyclosporine) affect multiple sites of inflammation. More sitespecific intervention involve intestinal bacteria (antibiotics, prebiotics, and probiotics) and therapy directed at TNF or IL-12
IBD also is associated with a variety of extraintestinal manifestations, including arthritis, ankylosing spondylitis, sclerosing cholangitis, uveitis, iritis, pyoderma gangrenosum, and erythema nodosum
Idiosyncratic effects include skin rash, hepatitis, pancreatitis, pneumonitis, agranulocytosis, and aplastic anemia.
INFLAMMATORY BOWEL DISEASE IBD
Dr. MOHD ASHRAF ALAM
Inflammatory Bowel Disease
• Inflammatory bowel disease (IBD) is a
spectrum of chronic, idiopathic, inflammatory
• Two major types of IBD:
– Ulcerative colitis (UC)
– Crohn's disease (CD)
PATHOGENESIS OF INFLAMMATORY BOWEL
• Crohn's disease and ulcerative colitis are chronic
idiopathic inflammatory disorders of the GI tract.
• Although Crohn's disease and ulcerative colitis share a
number of GI and extra intestinal manifestations and can
respond to a similar array of drugs, emerging evidence
suggests that they result from fundamentally distinct
• Histologically, transmural lesions in CD exhibit
marked infiltration of lymphocytes &
macrophages, granuloma formation, &
submucosal fibrosis, whereas superficial lesions
in UC have lymphocytic & neutrophilic infiltrates.
• The diseased bowel in CD, includes increased
levels of IL-12, IFN-ϒ, & TNF- α, findings
characteristic of T-helper 1 (TH1)-mediated
• In contrast, the inflammatory response in UC
resembles more closely that mediated by TH2
• Genetic analyses of CD, mutations in a gene
called nucleotide-binding oligomerization
domain-2 (NOD2, also called CARD15) associated
with both familial & sporadic CD in Caucasians
• NOD2 is expressed in monocytes, granulocytes,
dendritic cells, and intestinal epithelial cells
• It is proposed to function as an intracellular
sensor for bacterial infection by recognizing
peptidoglycans, thereby playing an important role
in the natural immunity to bacterial pathogens.
DRUG THERAPY FOR IBD
• Mainstay of therapy for mild to moderate UC
& CD is sulfasalazine & other 5-ASA agents.
• Effective at inducing remission in both UC &
CD & in maintaining remission in UC.
• whether they have a role in maintaining
remission in CD?
Mechanism of Action & Pharmacological
• Prototype for this class of medications is
sulfasalazine, consists of 5-ASA linked to
sulfapyridine by an azo bond.
• Drug developed originally for rheumatoid arthritis,
clinical trials demonstrated a beneficial effect on GI
sym. of subjects with concomitant UC.
• It is one of first example. of an oral drug delivered
effectively to distal GI tract.
• Given individually, as 5-ASA or sulfapyridine
absorbed in upper GI tract; azo linkage in
sulfasalazine prevents absorption in stomach &
small intestine, & individual components not
liberated for absorption until colonic bacteria cleave
• 5-ASA regarded as therapeutic moiety, with little, if
any, contribution by sulfapyridine.
• Many potential sites of action demonstrated by in vitro
studies for either sulfasalazine or mesalamine are:
– inhibition of prod. of IL-1 & TNF-α,
– inhibition of lipoxygenase pathway,
– scavenging of free radicals & oxidants
– inhibition of NF-kB (a transcription factor pivotal to production
of infl. mediators)
• Specific mechanisms of action of these drugs have not
• Sulfapyridine causes many of side effects in
patients taking sulphasalazine.
• To preserve therapeutic. effect of 5-ASA without
side effects of sulfapyridine, several second-
generation 5-ASA compounds have been
• They are divided into two groups:
– Prodrugs: contain same azo bond as sulfasalazine but
replace linked sulfapyridine with either another 5-ASA
(olsalazine) or an inert comp.(balsalazide).
– Coated drugs: delayed-release formulation or a pH-
• Oral sulfasalazine is of proven value in pts with
mild or mod. active UC, with response rates in
• Usual dose: 4 g/day in four divided doses with
food; to avoid Adverse Effects, dose increased
grad. From initial dose of 500 mg BD.
• Doses as high as 6 g/day can be used.
Oral 5-ASA Preparations
PREPARATION FORMULATION DELIVERY DOSING PER DAY
Sulfasalazine (500mg) Sulfapyridine-5-ASA Colon 3-6 g (acute)
2-4 g (main.)
Olsalazine(250mg) 5ASA-5-ASA Colon 1-3 g
Colon 6.75-9 g
Eudragit S (pH 7) Distal ileum-colon 2.4-4.8 g(acute)
Eudragit L (pH 6) Ileum-colon 1.5-3 g(acute)
Mesalamine (250, 500,
1000 mg) (Pentasa)
Stomach-colon 2–4 g (acute)
1.5–4 g (main)
1.5 g (main)
• Mesalamine suspended in wax matrix
suppository or in suspension enema are
effective in active proctitis & distal UC.
• Mesalamine enemas (4 g/60 ml) to be used at
bedtime & retained for at least 8 hours &
suppository (500 mg) to be used 2-3 times a
day with retaining it for at least 3 hr.
• Occur in 10-45% of pts. & related primarily to sulfa moiety.
• Some are dose-related:
– fatigue, which can be minimized by giving med. with meals or by decreasing
• Allergic reactions:
– Stevens-Johnson syndrome,
– hemolytic anemia
– bone marrow suppression.
• Also inhibits intestinal folate absorption
• Newer mesalamine form. are well tolerated &
side effects are relatively infrequent & minor.
• Headache, dyspepsia & skin rash are the most
• Diarrhea particularly common with olsalazine
• Nephrotoxicity, although rare, is a more serious
concern, Mesalamine has been associated with
• Both sulfasalazine & its met. cross placenta but
have not been shown to harm fetus, newer form.
appear to be safe in pregnancy.
• Effects of glucocorticoids on inflammatory
response are numerous & well documented.
• Although glucocorticoids are universally
recognized as effective in acute exacerbations,
their use in either UC or CD are indicated only
for moderate to severe conditions.
• Response to steroids in individual pts. with IBD divides them
into three general classes:
– steroid-responsive (40%): pts. improve clinically, within 1-2
wk. & remain in remission as steroids tapered &
– steroid-dependent (30-40%): pts. also respond but then
experience a relapse of symptoms as dose tapered.
– steroid-unresponsive (15-20%): pts. do not improve even
with prolonged high-dose.
• Steroids not effective in maintaining remission in either UC or
DOSE & FORMULATIONS
• Initial doses between 40-60 mg prednisone per day orally
preferred; higher doses generally are no more effective.
• Dose tapered over wks. to months.
• Even with these slow tapers, efforts should made to minimize
duration of steroid therapy.
• Induce remission in majority of patients with either UC or CD.
• Most pts. improved within 5 days
• For more severe cases, steroids given iv, generally
methylprednisolone (40-60mg/day) or hydrocortisone
• Steroid enemas useful in pts. whose disease limited to rectum
(proctitis) & left colon.
– Hydrocortisone available as enema (100 mg/60 ml), &
usual dose is one 60-ml enema per night for 2 or 3 weeks.
• Once clinical remission induced, should be tapered according
to clinical activity, normally at a rate of no more than 5
• Usually tapered to 20 mg/d within 4–5 weeks but often take
several months to be discontinued altogether
• The side effects are :
– fluid retention,
– fat redistribution,
– subcapsular cataracts,
– emotional disturbances, and
– withdrawal symptoms.
• Several drugs developed for cancer
chemotherapy or as immunosuppressive agents
in organ transplants adapted for Tt. of IBD.
• Use in IBD based on immunosuppressive effects,
specific mechanisms of action are unknown.
• Increasing clinical experience has defined specific
roles for each of these medicines as mainstays in
pharmacotherapy of IBD
• Cytotoxic thiopurine derivatives azathioprine & mercaptopurine (6MP)
used to treat pts.with severe IBD or those steroid-resistant or steroid-
• Thiopurine antimetabolites impair purine biosynthesis & inhibit cell
• Both are prodrugs: Azathioprine is converted to mercaptopurine,
subequently. metabolized to 6-thioguanine nucleotides, presumed active
• DOSE: typically azathioprine (2 to 3 mg/kg/d) or 6-MP (1.5 mg/kg/d).
• Effectively maintain remission in both diseases
• Immunosuppressive may be viewed as steroid-sparing agents.
• It inhibits dihydrofolate reductase, thereby blocking DNA
synthesis & causing cell death.
• Also decreases IL-1 production.
• Reserved for pts. whose IBD is either steroid-resistant or
• In Crohn's disease, it both induces & maintains remission,
generally with a more rapid response than that seen with
mercaptopurine or azathioprine.
• Only limited studies examined its role in UC.
• DOSE: higher doses (15-25 mg/wk) given IM/SC.
• ADRs- leukopenia , hepatic fibrosis
• Cyclosporine (calcineurin inhibitor) effective in
severe UC that failed to respond adequately to
• It blocks the production of IL-2 by T- helper cells.
• 50-80% of severely ill pts. improve significantly
(within 7 days) in response to iv (2-4 mg/kg/d).
• Careful monitoring levels is necessary to maintain
a therapeutic level in whole blood between 300-
• Renal function impairment
• Gingival hyperplasia
• Electrolyte abnormalities
• Opportunistic infections, most notably
Pneumocystis carinii pneumonia.
• TNF- α- key inflammatory cytokine & mediator of intestinal inflammation.
• Although a great many of both pro- & anti-inflammatory cytokines
generated in inflamed gut in IBD , there is some rationale for targeting
TNF- α because it is one of the principal cytokines mediating TH1 immune
response characteristic of CD.
• Infliximab is a chimeric monoclonal Ab. against TNF- α is effective in CD.
• MOA: It blocks TNF- α in serum & at cell surface & probably lyses TNF- α
producing macrophages & T cells through complement fixation &
• Of active CD pts. refractory to steroids, 6-MP or 5-ASA, 65% respond to iv
infliximab (5 mg/kg).
– serum sickness-like
• Increased incidence of resp. infections; potential
reactivation of tuberculosis or other granulomatous
infections with subsequent dissemination.
• Possible increased incidence of non-Hodgkin's
• Is a functional bowel disorder characterized by
abdominal pain or discomfort & altered bowel habits in
absence of detectable structural abnormalities.
• No clear diagnostic markers exist for IBS, thus
diagnosis of disorder is based on clinical presentation.
• IBS symptoms tend to come & go over time & often
overlap with other functional disorders such as
fibromyalgia, headache, backache & genitourinary
Diagnostic Criteria for Irritable Bowel
Recurrent abdominal pain or discomfortat
least 3 days per month in last 3 months
associated with two or more of following:
1. Improvement with defecation
2. Onset associated with a change in frequency of
3. Onset associated with a change in form
(appearance) of stool
• Pathogenesis of IBS is poorly understood,
although roles of:
– abnormal gut motor and sensory activity
– central neural dysfunction
– psychological disturbances
– luminal factors
• Abnormal gut motor & sensory activity:
• IBS pts. may exhibit increased rectosigmoid motor activity for up to 3 h
• IBS pts. frequently exhibit exaggerated sensory responses to visceral
• Mech. responsible for visceral hypersensitivity are still
under investigation, which may be:
– increased end-organ sensitivity with recruitment of "silent" nociceptors
– spinal hyperexcitability with activation of nitric oxide and possibly other
– endogenous (cortical and brainstem) modulation of caudad nociceptive
– over time, possible development of long-term hyperalgesia due to
development of neuroplasticity, resulting in permanent or
semipermanent changes in neural responses to chronic or recurrent
• Central neural dysfunction: strongly suggested by clinical
association of emotional disorders & stress with symptom
exacerbation & therapeutic response to therapies that act on
cerebral cortical sites
DRUG THERAPY FOR IBS
Patient Counseling and Dietary
• Reassurance & careful explanation of
functional nature of disorder & of how to
avoid obvious food precipitants are important
first steps in pts. counseling & dietary change.
• High-fiber diets & bulking agents, such as bran or hydrophilic
• Most gastroenterologists consider stool-bulking agents worth
trying in pts. with IBS-C.
– water-holding action of fibers may contribute to increased stool bulk
– speeds up colonic transit
– because of their hydrophilic properties, stool-bulking agents bind water &
thus prevent both excessive hydration or dehydration of stool
– fiber supplementation with psyllium shown to reduce perception of rectal
distention, indicating that fiber may have positive affect on visceral
• Anticholinergic drugs may provide temporary relief for symptoms
such as painful cramps related to intestinal spasm.
• Most effective when prescribed in anticipation of predictable pain.
• Most anticholinergics contain natural belladonna alkaloids, which
may cause xerostomia, urinary hesitancy & retention, blurred
vision, & drowsiness.
• Synthetic anticholinergics such as dicyclomine have less effect on
mucous membrane secretions & produce fewer undesirable side
• Peripherally acting opiate-based agents are initial therapy of choice
– increases in segmenting colonic contractions,
– delays in fecal transit,
– increases in anal pressures,
– reductions in rectal perception
• When diarrhea is severe, esp. in painless diarrhea variant of IBS,
small doses of loperamide, 2–4 mg every 4–6 h up to a maximum of
12 g/d, can be prescribed
• Another anti-diarrhea agent that may be used in IBS pts. Is bile acid
binder cholestyramine resin.
• In addition to their mood-elevating effects, antidepressant
medications have several physiologic effects
• Tricyclic antidepressant (imipramine) slows jejunal migrating motor
complex transit propagation & delays orocecal & whole-gut transit,
indicative of a motor inhibitory effect, may alter visceral afferent
• Beneficial effects of tricyclic comp. in Tt. of IBS appear to be
independent of their effects on depression
• Therapeutic benefits for bowel symptoms occur faster & at a lower
• SSRI paroxetine accelerates orocecal transit, raising possibility that
this drug class may be useful in IBS-C pts.
• Pts. should be advised to eat slowly & not chew gum or
drink carbonated beverages.
• Beano, an over-the-counter oral-glycosidase sol., may
reduce rectal passage of gas.
• Pancreatic enzymes reduce bloating, gas, & fullness
during & after high-calorie, high-fat meal ingestion
Serotonin Receptor Agonist and
• Serotonin rec. antagonists have been evaluated as
therapies for IBS-D.
• In humans, a 5-HT3rec. antagonist such as Alosetron
reduces perception of painful visceral stimulation in IBS.
• It is currently is approved for Tt. of women with severe IBS
in whom diarrhea is predominant symptom.
• Dosa: 1 mg once or twice daily, it reduces IBS-related lower
abdominal pain, cramps, urgency, & diarrhea.
• Novel 5-HT4 rec. agonists such as Tegaserod exhibit
prokinetic activity by stimulating peristalsis.
• MOA: Tegaserod stimulation of 5-HT4 rec. on mucosal
afferent nerve fibers triggers release of
neurotransmitters from submucosal & myenteric
plexuses, including calcitonin gene-related peptide,
that stimulate peristaltic reflex.
• These neurotransmitters stimulate proximal bowel
contraction (via acetylcholine & substance P) & distal
bowel relaxation (via nitric oxide & vasoactive
• DOSE: 6 mg/d
Chloride Channel Activators
• Lubiprostone is a bicyclic fatty acid that stimulates chloride
channels in apical membrane of intestinal epithelial cells.
• A new class of comp. for Tt. of chronic constipation with or
• Chloride secretion induces passive movement of sodium &
water into bowel lumen & improves bowel function.
• Major side effects are nausea & diarrhea.
Possible Drugs for a Dominant Symptom in IBS
SYMPTOM DRUG DOSE
Diarrhea Loperamide 2–4 mg when
necessary/maximum 12 g/d
Cholestyramine resin 4 g with meals
Alosetron 0.5–1 mg bid (for severe IBS,
Constipation Psyllium husk 3-4 g BID with meals, than
Methylcellulose 2 g BID with meals, than
Calcium polycarbophil 1 g QID
Lactulose syrup 10-20 g BID
70% sorbitol 15 ml BID
Polyethylene glycol 3350 17 g in 250 ml water QID
Lubiprostone 24 mg BID
Magnesium hydroxide 30-60 ml QID
Abdominal pain Smooth muscle relaxant QID
Tricyclic antidepressant Start 25-50 mg HS, than adjust
Selective serotonin reuptake
Begin small dose, increase as