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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!