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Pharmacotherapy ofInflammatory Bowel disease
(IBD)Melinda C. Tagle, M.D.
November 17, 2011
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Objectives
1. Review the pathologenesis ofinflammatory bowel disease.
2. Discuss the drugs used in thetreatment of IBD, their
pharmacokinetics,pharmacodynamics, adverse effectsand toxicity.
3. Discuss the novel drugs used forIBD.
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Inflammatory Bowel Disease(IBD)Chronic,IdiopathicInflammatory intestinal conditions
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Gastrointestinal symptoms
DiarrheaAbdominal painBleeing
AnemiaWeight loss
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Extraintestinal symptoms
ArthritisAnkylosing spondylitisSclerosing cholangitis
UveitisIritisPyoderma gangrenosum
Erythema nodosum
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Major Subtypes
Ulcerative colitisCrohns disease or regional enteritis
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Ulcerative Colitis
Characterized by confluent mucosalinflammation of the colon
Starts at anus and spreads proximally
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Crohns disease
Characterized by transmuralinflammation of any part of GI
Most common area - ileocecal valve
Non-confluent area of inflammationskip areasLead to fibrosis ,strictures and fistula
formation
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Goals for Therapy
Control acute exacerbationMaintain remissionTreat specific complication like fistula
Glucocorticoids remain the treatmentof choice for moderate-to-severe flaresbut inappropriate for long-term usebecause of side effects and inability tomaintain remission
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Mainstay before were glucocorticoidsand sulfasalazine
Now: azathioprine, cycloporine
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Pathogenesis of IBD
Crohns disease -
Transmural
marked infiltration of lymphocyes,macrophages,granuloma formation, andsubmucosal fibrosis
Cytokine profile: increase interleukins 12,interferon Y, tumor necrosis factor
T-helper mediated inflammatory process
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Ulcerative colitis
Superficial
lymphocytic and neutrohilic infiltrates
Mediated by T2 pathway
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Mesalamine (5-ASA) basedtherapy
First-line therapy for mild to moderateulcerative colitis
Archetype is sulfasalazine (Azulfidine)which is 5-ASA linked to sulfapyridine withan azo bond
Azo bond prevents absorption of drug in upperGI
Although a salicylate, does not produce
cyclooxygenase inhibition as aspirin
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Sulfapyridine is responsible to side-effects of sulfasalazine
Advantage of 2nd generation drugs -1. Not linked to sulfapyridineOlsalazine ( Dipentum)
Balsalazide ( Colazide)
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2. Delayed release mechanism-decreased side effects
Pentasa
Asacol
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Pharmacokinetics
20-30% absorbed in sm intestine70% in colon
Sites of release of mesalamine in GIT
Colon: sulfazalazineolsalazine
Ileum, colon: Asacol - mesalamine pHsensitive release tablets
Stomach, jejunum, ileum, colon: Pentasa
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Adverse Effects
Headache, nausea, fatigueAllergic reactionsInhibits folate absorption
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Glucocorticoids
Effective in acute exacerbationsResponse divided in 3 classes:
Steroid responsive
Steroid dependentSteroid unresponsive
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Steroid responsiveImproves clinically within 1-2 weeks
and remains in remission as the
steroids are taperedSteroid dependent - response to
steroids but experience a relapse ofsymptoms as the steroid dose is
tapered
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Steroid unresponsive - patients do notimprove even with prolonged high-dose glucocorticoids
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Glucocorticoids are not effective inmaintaining remission in IBDs
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Immunosuppresive Agents
Thiopurine derivativesMercaptopurine (6-MP Purinethol)Azathioprine (Imuran)
Used to treat severe IBD or those whoare steroid-resistant or steroid-dependent
Impair purine biosynthesis and inhibitcell proliferation
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MethotrexateInduces and maintains remission, with
more rapid response
Higher doses compared toautoimmune disease
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CyclosporineFor severe ulcerative colitisLong-term therapy NEORAL , a
microemulsion form with increasedoral bioavailabilityUsed to treat fistula complications
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Anti-TNF Therapy
Infliximab (Remicade), a chimericimmunoglobulin (25% mouse, 75%human) binds and neutralize TNF-a,one of the principal cytokinesmediating the T1 immune response inCrohns
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Antibiotics
May either initiate or perpetuate theinflammation of IBD
Used as adjunctive treatment
Treatment of specific complication ofCrohns diseaseProphylaxis for recurrence in
postoperative Crohns disease
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MetronidazoleCiprofloxacinClarithromycin
Effective for complications like intra-abdominal abscesses, infections likeC. deficile
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Supportive Therapy in IBD
AnalgesicsAnticholinergics- DicyclomineAntidiarrheal- Loperamide,
DiphenoxylateCholestyramineOral iron, folates, Vit B12
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Therapy of IBD in Pregnancy
Category B - used frequently inpregnancy and considered safe
Mesalamine
Glucocorticoids
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END
GOOD AFTERNOON!