1. Chronic inflammatory Bowel Diseases By Prof. Abdulqader Alhaider 1432 H

2. Ulcerative colitis Crohn’s disease Limited to the colonic mucosa and may reach the proximal part of the colon. UC is associated with bloody diarrhea. Effects the entire thickness of the wall and involves any part of the GIT with no bleeding per rectum.

3. Symptoms of UC : - Abdominal pain, diarrhea, and bleeding. Complications: anemia, megacolon, fever, abdominal pain, dehydration, and increased risk for developing colon cancer.

4. Drugs Used for Rx and maintenance of I.B.D I) Anti-inflammatory Drugs 1- 5-Aminosalicylic Acid: MOA: inhibits prostaglandin and leukotriene synthesis, decreases neutrophil chemotaxis, and decreases free radical production. Note: 5-ASA irritates the GIT. Therefore, this drug should not be given orally as such, and is predominantly given in specific formulations.

5. Common Formulations: A) Sulfur-containing 5-Aminosalicylic Acid e.g. Sulfasalazine Sulfasalazine is a prodrug combining sulfapyridine and 5-ASA by an azo group. Sulfapyridine works as a carrier functioning in decreasing the portion of 5-ASA being absorbed in the small intestine. At the distal ileum, normal flora reduce the azo group by the enzyme azoreductase releasing 5-ASA which then works locally. Are they both active and absorbed? 5-ASA is the pharmacological primary active form. 5-ASA is not absorbed any longer at the distal ileum (decreasing its irritation), but 85% of sulfapyridine is absorbed to be metabolized and ultimately excreted by the kidneys.

6. Cont’d Sulfasalazine is a prodrug used for induction and maintenance therapy, yet is considered less effective in acute attacks. It is more commonly used for ulcerative colitis and for Crohn’s colitis than for Crohn’s disease of the small intestine. Nowadays, sulfasalazine is considered to be the first line of treatment for UC, yet is seldom used for Crhon’s disease when other formulation of 5-ASA are preferred.

7. - Side Effects: - Muscular pain 29%, N/V, and diarrhea - Crystalluria and interstitial nephritis Hypersensitivity reactions as: skin rash, fever, aplastic anemia Inhibits the absorption of folic acid (megaloblastic anemia)  Infertility in men.  However, 5-ASA is considered to be safely used in pregnancy because it decreases the concentration of PGs (such as PGE 2 ) which might cause induction of labor. Folate is given prophylactically together with 5-ASA to decrease the aplastic anemia and male infertility.

8. B. Non-sulfur containing 5-Aminosalicylic Acid 1. Mesalamine, a pure 5-ASA drug which is dependent on the GI pH for releasing its microgranules. It is better given rectally. 2. Mesalazine ( Salofalk R ), an oral control release form of 5-ASA. It has less side effects than mesalamine, but is more expensive. Salofalk is present in the form of tablets, granules, suppositories, enemas, and rectal foam. All contain the active ingredient mesalazine. 3. Olsalazine (Two molecules (dimer) of 5-ASA linked together by diazo bond which passes through the small intestine to the ileum and colon. 4. Balsalazid: contains azo bond

9. Azo compounds Different combinations of azo groups: Sulfasalazine 5-ASA + sulfapyridine Olsalazine Two molecules of 5-ASA (Dipentum) Balsalazide 5-ASA + 4-aminobenzoyl-β- alanine(Colazal).

10. Mesalamines Compounds  Formulations that have been designed to deliver pure 5-ASA in the small and large colon.  1- Pentasa (PO): is a time-dependent microgranule releasing drug which releases 5-ASA gradually through the small intestine.  2- Asacol, a 5-ASA coated in pH-sensitive resin that readily dissolves at pH=7. (eudragit-s coating)  3- Rowasa (enema) or Canasa (suppositories) These compounds of mesalamine treat and maintain remission in mild to moderate ulcerative colitis. They are well tolerated with less side effects due to the absence of sulfur.

11. Stomach Small Intestine Large Intestine Azo Compounds Mesalamine in microgranules Mesalamine w/ eudragit-S Oral 5-ASA Release Sites Block the production of PGs, Leukotrienes, and cytokines such as the nuclear factor kappa-light-chain-enhancer of activated B cells Inhibit bacterial peptide–induced neutrophil chemotaxis and adenosine-induced secretion Scavenging reactive oxygen metabolites Mechanism of action: AMINOSALICYLATES [5-ASA]

12. Uses: They are used orally and rectally for the treatment of:  Mild to moderate ulcerative colitis for induction of remission and maintenance.  Crohn’s disease  Rheumatoid arthritis - Should be taken after meals - The dose should be reduced in patients with renal failure

13. 2. Corticosteroids MOA: Inhibition of phospholipase A2, gene expression of NO synthase, COX-2, and major inflammatory cytokines such as (TNF-a) Indications: They are mainly used for acute attacks of moderate-severe ulcerative colitis e.g. prednisone PO 40-60 mg/day for 2 weeks  Budesonide in controlled release oral (9 mg/day) formulation (Entocort).  Hydrocortisone enema or suppository for rectum or sigmiod colon  Corticosteroids are also used for systemic manifestations such as ocular lesion, skin diseases, and peripheral arthritis They’re not useful to maintain disease remission

14. II) Immunomosuppressive Agents: 1) Azathioprine and 6-Mercaptopurine; M.O.A: Systemic immunosuppression Clinical indications: for the treatment and maintenance of remission of severe conditions and steroids dependent and/or resistant ulcerative or Cronn’s disease. Side Effects: - N/V and bone marrow suppression; hepatotoxicity - Hypersensitivity reactions, Why? The thio group is replaced by sulfur which causes hypersensitivity.

15. 2. Methotrexate: MOA: dihydrofolate reductase inhibitor works as an antimetabolite. Uses: Crohn’s disease to induce and maintain remission and in rheumatoid arthritis Side effects: Bone marrow suppresion.

16. III) Biological therapy (Disease modifying Therapy): New trend by using monoclonal antibody to modulate the functions of various inflammatory mediators e.g: Infliximab (Cytokine inhibitor) MOA: TNF-  is an inflammatory cytokine which has a contributory role in producing chronic inflammation Infliximab (Remicade R ) neutralizes TNF effects by blocking soluble TNF and transmembrane TNF. Thus may promote apoptosis of the mononuclear inflammatory cells through complement. - is a monoclonal IgG antibodies (Tumor necrosis factor, anti TNF- monoclonal antibody). - used for induction and maintenance of remission in Crohn’a disesase and Rheumatoid arthritis. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn's disease. Gastroenterology

17. Infliximab  25% murine – 75% human.  Given as IV infusion (5-10 mg/kg).  Infliximab needs 2 weeks to give a response Uses:  Severe Crohn’s disease  Patients not responding to immunosuppressants or glucocorticoids improvement of symptoms in 65% 60% reduction in baseline endoscopic lesions 60% in fistulating crohn’s where antibiotics or immunosuppressive were disappointing. Maintenanc: repeat dose after 3 months.

18. Side effects and limitations: 1) Infusion related like hypersensitivity reaction which is temporary and responds to a decrease in the infusion rate. 2) One report of a case of infliximab-associated optic neuritis with favorable outcome after systemic steroid treatment. 3) An increased rate of infections (some of them severe), especially tuberculosis (mainly due reactivation). Other side effects that can be considered infrequent and are due to immune modulation include demyelinization, heart failure, blood dyscrasias and lymphomas indicating that a thorough knowledge of these drugs is necessary for their use.

19. Adalimumab (HUMIRA) Fully humanized IgG antibody to TNF-α Adalimumab binds to TNF-α, preventing it from activating TNF receptorsTNF-α Has an advantage that it is given by subcutaneous injection while infliximab is given by IV only.injection IV. Antibiotics: To prevent relapse V. Surgery

20. Inductive Therapies For UC Aminosalicylates Corticosteroids Cyclosporin > For CD Aminosalicylates Corticosteroids Antibiotics Infliximab > Immunosupressors Azathioprine 6-MP Methotrexate Aminosalicylates Infliximab NO corticosteroids Maintenance Therapies Severe Moderate Mild Systemic Corticosteroids Aminosalicylates Surgery Oral Steroids AZA/6-MP Cyclosporine Infliximab