Drugs Used To Treat Inflammatory Bowel Disease

Inflammatory Bowel Disease

• Includes:
• Ulcerative Colitis
• Crohn's disease

• Pathogenesis is unknown.
• Drugs chosen depend on:
• Severity
• Responsiveness
• Drug toxicity.

Therapeutic Pyramid Approach

Retrac
to

Mib Respon
d šve
Olsease
Responsiveness
severity Therapy to ther

Surgery
Natalizumab
Severe Cyclospo•ina
TNF antagonists

O ids
 TNF antagonists
Oral corticosteroids
MOdetate
Methötrexate
Azathioprine / 5-
Mercaptopurine

Budesonide (ileitis)
Topical corticosteroids
(proctitis) Antibiotics
S. Am inosalicylates
Aminosalicylates
Introduction

• Contain 5-Aminosalicylic Acid (5-ASA)

• Work topically in diseased Gl mucosa
• 80% rapidly absorbed from proximal small intestine
• Formulations allow drug to reach ileum, colon:
• Azo Compounds: Sulfasalazine, Olsalazine, Balsalazide
• Mesalamine Compounds: Pentasa, Asacol, Lialdat Rowasa, Canasa
Azo Compounds

• Markedly reduce absorption from small intestine

• In colon, resident bacteria cleave azo bond (azoreductase) releasing active 5-ASA
• High concentrations in terminal ileum, colon.

sulfasalazine Olsalazinebasalazide

sullapyridinemesalamine (5•ASA)
(metabolite)(the active drug) (metabolite)

N.acetvl-S.ASA
(metabolite)
Source: gruntan Chabner LA. KnollmSnn Goðdmap•

ownu.accessrnedic•rie.cørn
 Copyright The MCGraeo-tOl' Inc. All rights reserved.
Metabolic fates of the different formulations meggamjne IS-ASA), Chemical structures are in Figure 47—

Sites of Action

Pharmacokinetics

• Absorbed 5-ASA undergoes N-acety/ation in gut, liver

• Metabolite excreted by kidneys
• Sulfasalazine:
• >85% of sulfapyridine is absorbed from colon
• Undergoes hepatic metabolism
• Renally excreted

• Balsalazide:
• 70% of carrier peptide is excreted intact in feces.
Mechanism of Action

• Modulation of inflammatory mediators {cyclooxygenase, lipoxygenase)

• Reduced production of inflammatory cytokines
• Inhibition of natural killer cells, mucosal lymphocytes, macrophages
• Scavenge reactive oxygen metabolites.
Clinical Indïcations

• 1st line agents for mild - moderate active IBD of colon, distal ileum
Adverse Effects Sulfasalazine

• Common in slow acetylators

• Nausea
• Headaches
• Arthralgias
• Myalgias
• Bone marrow suppression
Adverse Effects - Sulfasalazine

• Hypersensitivity reactions:
• Exfoliative dermatitis
• Hemolytic anemia

• Pericarditis
• Hepatitis

• Oligospermia.
• Impaired folate absorption (supplement folic acid)
Glucocorticoids
Clinical Use

• Treatment of moderate - severe IBD

• IV in severely il
• Rectal suppositories for rectal disease

• Useful for induction (not maintenance)

 Purine Analogs Azath ioprine
6 Mercaptopurine
Overview

• Bioavailability:
• Azathioprine (80%)
• 6-MP (50%)

• Azathioprine is rapidly converted to 6-MP (non-enzymatic)

• 6-MP is metabolized by xanthine oxidase
• Therapeutic benefit after 17 weeks
Clinical Use

• Induction and maintenance of IBD

Adverse Effects

• Nausea, vomiting
• Bone marrow depression
• Hepatotoxicity
• Hypersensitivity: (fever, rash, pancreatitis, diarrhea, hepatitis)
Drug Interactions

• Allopurinol:
• Inhibits xanthine oxidase
• Reduces 6 MP metabolism
• Increaased bone marrow suppression,
Methotrexate
Overview

• Antimetabolite

• Given:
• PO (70% bioavailability)
• SC, 1M (100% bioavailability)

• Induce and maintain remission in Crohn's disease

Adverse Effects

• Bone marrow depression

• Megaloblastic anemia
• Alopecia
• Mucositis
• Folate supplementation reduces the risk without impairing anti-inflammatory
action.
Antibiotics

• Colonic bacteria initiate or perpetuate inflammation . Uses:

• Adjunctive
• Treatment of Crohns Disease complication (Intra abdominal, peri anal abscesses

• Metronidazole, ciprofloxacin, clarithromycin are most commonly used,

Anti-TNF AgentsInfliximab
AdalimumabCertolizumab
Overview

• TNF is a pro-inflammatory cytokine

• Monoclonal antibodies used for treatment of IBD:
• Infliximab (IV)
• Adalimumab (subQ)
• Certolizumab (subQ)
Overview

• All bind to TNF with high affinity

• Prevent cytokine from binding to receptors
• Treatment of refractory severe IBD
Adverse Effects

• Infection (suppression of THI response):

' Bacterial sepsis
• Reactivation of hepatitis B
• Invasive fungal infections
Adverse Effects

• Acute infusion reactions (Infliximab)

• Delayed serum-sickness like reaction
• Acute hepatic failure
• Increased risk of lymphoma.
Anti Integrin Therapy
Natalizumab
Natalizumab

• Monoclonal antibody against integrin (adhesion molecule)

• Prevents binding of leukocytes to vascular endothelium and subsequent migration
• Treatment of refractory Crohn's disease
• Adverse effects:
• Reactivation of JC virus infection (Progressive multifocal leukoencephalopathy)
Irritable Bowel Syndrome