Chrones disease and IBD

First line Agents - Aminosalicylates

MOA: 5-ASA inhibits leukotriene production, reduces interleukin-1 and TN Fα signaling & has antiproliferative effects

Aminosalicylates structures

Glucocorticoids- Budesonide - Entocort EC

• relieve inflammation

• Indications: Treatment of Crohn's disease

• Capsules with once-a-day dosing, CYP3A4 substrate

• Advantage: 80-90% first-pass effect metabolism which limits systemic availability

• Uceris - extendedrelease tablet for induction of remission of mild to moderate ulcerative colitis

• Before introduced other glucocorticoids used as enemas, foams

Budesonide - Entocort EC structure

TNF⍺ inhibitors: Infliximab - Remicade®

• - The first monoclonal chimeric lgG1 antibody that targets the high affinity soluble and transmembrane forms of tumor necrosis factor alpha

• - Inhibition of TNF⍺ prevents the cascade release of many pro￾inflammatory cytokines that lead to severe inflammation

• - Others with same mechanism and indications: Certolizumab Cimzia® (PEG modified) and Adalimumab-Humira®

• Indications: IV administration

  • • Crohn's disease - inflammation of the intestinal tract

  • • Rheumatoid arthritis (new indication)

    • - For Crohn's disease a single dose can give relief for up to 12 weeks

    • - For rheumatoid arthritis used in combination with methotrexate

integrin receptor antagonist: Natalizumab - Tysabri®

• - Initially marketed for multiple sclerosis

• - Approved for Crohn's for induction and maintenance treatment when the disease does not respond to conventional treatments and TNFα inhibitors

• - Conventional treatments: mesalamine, ciprofloxacin, metronidazole, mercaptopurine, azathioprine, steroids

• - TNF⍺ inhibitors previous mentioned

• - Restricted distribution program

• MOA: monoclonal antibody that targets integrin receptors on leukocytes, preventing binding to gut vascular receptors andleukocyte migration inhibiting the inflammatory cascade

• Use caution with other immunomodulators and watch for serioushepatic toxicity

integrin receptor antagonist: Vedolizumab - Entyvio®

• - Approved for Adult Crohn's and Ulcerative Colitis when the disease does not respond to conventional corticosteroid treatments

• MOA: an integrin receptor antagonist, is a humanized lgG1 monoclonal antibody produced in Chinese hamster ovary cells that binds to the human ⍺4β7 integrin

• The ⍺4β7 integrin is expressed on the surface of a discrete subset of memory T-lymphocytes that preferentially migrate into the gastrointestinal tract. MAdCAM-1 (mucosal vascular addressin cell adhesion molecule 1)is mainly expressed on gut endothelial cells and plays a critical role in the homing of T-lymphocytes to gut lymph tissue. The interaction of the ⍺4β7 integrin with MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of ulcerative colitis and Crohn's disease.

• Intravenous administration with a 25-day half-life

lmmunosuppression therapy

Immunosuppressi:on therapy relieves the inflammation in

Inflammatory bowel diseases: Azathioprine -lmuran® and Azasan® Mercaptopurine - Purinethol®

• Covered under antineoplastic agents - inhibit purine synthesis and stop T-cells Methotrexate

• Covered under antineoplastic agents: inhibits dihydrofolate reductase: Cyclosporine - Sandimmune® & Tacrolimus - Prograf®

• Covered under allotransplant agents to prevent rejection, inhibits with lymphocyte activation