Pharmacotherapy of Inflammatory Bowel disease (IBD)

Melinda C. Tagle, M.D. November 17, 2011

Objectives
1.

Review the pathologenesis of inflammatory bowel disease. 2. Discuss the drugs used in the treatment of IBD, their pharmacokinetics, pharmacodynamics, adverse effects and toxicity. 3. Discuss the novel drugs used for IBD.

Inflammatory Bowel Disease (IBD)

Chronic, Idiopathic Inflammatory

intestinal conditions

Gastrointestinal symptoms
Diarrhea Abdominal Bleeing Anemia Weight

pain

loss

Extraintestinal symptoms
Arthritis Ankylosing

spondylitis Sclerosing cholangitis Uveitis Iritis Pyoderma gangrenosum Erythema nodosum

Major Subtypes
Ulcerative

colitis Crohns disease or regional enteritis

Ulcerative Colitis
Characterized

by confluent mucosal inflammation of the colon Starts at anus and spreads proximally

Crohns disease
Characterized

by transmural inflammation of any part of GI Most common area - ileocecal valve Non-confluent area of inflammation skip areas Lead to fibrosis ,strictures and fistula formation

Goals for Therapy

Control

acute exacerbation Maintain remission Treat specific complication like fistula Glucocorticoids remain the treatment of choice for moderate-to-severe flares but inappropriate for long-term use because of side effects and inability to maintain remission

 Mainstay

before were glucocorticoids and sulfasalazine Now: azathioprine, cycloporine

Pathogenesis of IBD
Crohns

disease -

Transmural

marked infiltration of lymphocyes, macrophages,granuloma formation, and submucosal fibrosis profile: increase interleukins 12, interferon Y, tumor necrosis factor mediated inflammatory process

Cytokine

T-helper

 Ulcerative Superficial

colitis

lymphocytic and neutrohilic infiltrates by T2 pathway

Mediated

Mesalamine (5-ASA) based therapy

First-line

therapy for mild to moderate ulcerative colitis is sulfasalazine (Azulfidine) which is 5-ASA linked to sulfapyridine with an azo bond

Archetype

Azo bond prevents absorption of drug in upper GI Although a salicylate, does not produce cyclooxygenase inhibition as aspirin

 Sulfapyridine

is responsible to sideeffects of sulfasalazine

Advantage

of 2nd generation drugs 1. Not linked to sulfapyridine Olsalazine ( Dipentum) Balsalazide ( Colazide)

 2.

Delayed release mechanismdecreased side effects Pentasa Asacol

Pharmacokinetics
20-30%

absorbed in sm intestine 70% in colon

Sites

of release of mesalamine in GIT Colon: sulfazalazine olsalazine Ileum, colon: Asacol - mesalamine pH sensitive release tablets Stomach, jejunum, ileum, colon: Pentasa

Adverse Effects
Headache,

nausea, fatigue Allergic reactions Inhibits folate absorption

Glucocorticoids
Effective

in acute exacerbations Response divided in 3 classes: Steroid responsive Steroid dependent Steroid unresponsive

 Steroid

responsive Improves clinically within 1-2 weeks and remains in remission as the steroids are tapered Steroid dependent - response to steroids but experience a relapse of symptoms as the steroid dose is tapered

 Steroid

unresponsive - patients do not improve even with prolonged highdose glucocorticoids

 Glucocorticoids

are not effective in maintaining remission in IBDs

Immunosuppresive Agents
Thiopurine derivatives Mercaptopurine (6-MP Purinethol) Azathioprine (Imuran) Used to treat severe IBD or those who are steroid-resistant or steroiddependent Impair purine biosynthesis and inhibit cell proliferation

 Methotrexate Induces

and maintains remission, with more rapid response Higher doses compared to autoimmune disease

 Cyclosporine For

severe ulcerative colitis Long-term therapy NEORAL , a microemulsion form with increased oral bioavailability Used to treat fistula complications

Anti-TNF Therapy
Infliximab

(Remicade), a chimeric immunoglobulin (25% mouse, 75% human) binds and neutralize TNF-a, one of the principal cytokines mediating the T1 immune response in Crohns

Antibiotics
May

either initiate or perpetuate the inflammation of IBD Used as adjunctive treatment Treatment of specific complication of Crohns disease Prophylaxis for recurrence in postoperative Crohns disease

 Metronidazole Ciprofloxacin Clarithromycin Effective

for complications like intraabdominal abscesses, infections like C. deficile

Supportive Therapy in IBD

Analgesics Anticholinergics-

Dicyclomine Antidiarrheal- Loperamide, Diphenoxylate Cholestyramine Oral iron, folates, Vit B12

Therapy of IBD in Pregnancy

Category

B - used frequently in pregnancy and considered safe Mesalamine Glucocorticoids

 END GOOD

AFTERNOON!