Chronic inflammatory Bowel Diseases By Prof. Abdulqader Alhaider 1434H

Chronic inflammatory bowel diseases (IBD) IBD is a group of auto-immune disorders in which the intestines become inflamed. are chronic inflammatory bowel disease which have relapsing and limiting course. The major types of IBD are Crohn's disease and ulcerative colitis (UC).Crohn's diseaseulcerative colitis

Differences between Crohn's disease and UC Ulcerative colitis Crohn's disease Restricted to colon & rectum affect any part of the GIT, from mouth to anusmouthanus Location Continuous area of inflammation Patchy areas of inflammation (Skip lesions) Distribution Shallow, mucosalMay be transmural, deep into tissues Depth of inflammation Toxic megacolon Strictures, Obstruction Abscess, Fistula Complications

Ulcerative colitis Crohn’s disease Limited to colonic mucosa and may reach proximal part of the colon.Bloody diarrhea Effect the entire thickness of the wall and involve any part of GIT. No blood

Symptoms of UC : - Abdominal pain; Diarrhea and bleeding. Complications: Anemia ; megacolon, fever, abdominal pain, dehydration, colon cancer.

Treatment of IBD 1. 5-amino salicylic acid compounds (5- ASA). 2. Glucocorticoids 3. Immunomodulators 4. Biological therapy (TNF-α inhibitors). 5. Surgery in severe condition

Drugs Used for Rx and maintenance of I.B.D I) Anti-inflammatory Drugs 1) A. 5-Aminosalicylic Acid: MOA: inhibit prostaglandins and leukotriens synthesis; decreases neutrophil chemotaxis and decreases free radicles production. scavenging free radical production Note: since it is irritant to GIT, this drug should not be given orally as such. Formulations: a)Sulpha containing 5-Aminosalicylic Acid (e.g: Sulphasalazine ) Sulphasalazine is a Prodrug (20-30 %) absorbed by intestine, secreted in the bile and hydrolysed in ileum and colon by isoreductase. Sulfapyridine + 5- ASA Hydrolysed in bacteria in ileum Linked by Azo group and colon Which part is active and is it absorbed?

Sulphasalazine (Continue…) Prodrug used in maintenance therapy less effective in acute attack; Use for U.colitis; Crohn’s colitis but not Crohn’s of small intestine Why?. Note: Nowadays it is seldom to be used for Crohn’s disease (new 5-ASA are preferred but still use for UC).

- Side Effects : - Muscular pain 29%, N/V, Diarrhea - Crystalluria and interstitial nephritis Hypersensitivity reactions as: skin rash, fever, aplastic anemia. Why? Inhibit absorption of folic acid ` (megaloplastic anemia)  Infertility in man (decrease sperm counts). However, it is save in pregnancy.

B. Non-sulpha containing 5- Aminosalicylic Acid 1. Mesalamines Compounds  Formulations that have been designed to deliver 5-ASA in small & large colon.  e.g. pentasa (orally): time release microgranules that release 5-ASA through the small intestine e.g. Asacol 5-ASA coated in pH sensitive resin that dissolved at pH 7  e.g. Rowasa (enema) or Canasa (suppositories)  Treat and maintain remission in mild to moderate ulcerative colitis.  Well tolerated, less side effects (sulfa free).

2. Azo compounds Compounds contain 5-ASA and connected by azo bond to another molecule of 5-ASA or to inert compound Azo structure (N=N) reduces absorption in small intestine Bacteria cleave the azo dye and release 5-ASA in terminal ileum and colon Examples: Olsalazine (Two molecules (dimer) of 5-ASA linked together by diazo bond which pass small intestine to ilium and colon)) Balsalazide 5-ASA + inert carrier (Colazal).

Stomach Small Intestine Large Intestine Azo Compounds Mesalamine in microgranules Mesalamine w/ eudragit-S Oral 5-ASA Release Sites Block PGs, LTs & cytokine production / NF-kB activation Inhibit bacterial peptide–induced neutrophil chemotaxis & adenosine-induced secretion, Scavenge reactive oxygen metabolites Mechanism of action AMINOSALICYLATES [5-ASA]

Clinical uses of 5-amino salicylic acid compounds  Induction and maintenance of remission in mild to moderate ulcerative colitis & Crohn’s disease (First line of treatment).  Are NOT USEFUL in actual attack or severe forms of IBD.  Rheumatoid arthritis (Sulfasalazine only)  Rectal formulations are used in ulcerative proctitis and proctosigmoiditis.

2. Corticosteroid MOA: Inhibits phospholipase A2, inhibit gene expression of NO synthase, COX-2 Inhibit inflammatory cytokines (TNF-a) Indications: Treat moderate – severe ulcerative colitis (prednisone P.O mg/day for 2 weeks Less effective as prophylactic (maintaining remission). Budesonide as controlled release oral (9 mg/day) formulation (Entocort). Hydrocortisone enema or suppository for rectum or sigmiod colon used also for extracolonic manifestations such as ocular lesion, skin disease and peripheral arthritis ;

II. Immunomodulators Are used to induce remission in IBD in active or severe conditions or steroid dependent or steroid resistant patients. Immunomodulators include: Methotrexate Purine analogs: (azathioprine & 6-mercaptopurine).

II) Immunomosuppressive Agents : 1) Azathioprine; is pro-drug of 6- mercaptopurine that Inhibit purine synthesis M.O.A.: Suppress the body’s immune system Clinical indications: for Rx and maintenance of remission of severe conditions and steroids dependent or resistant (ulcerative and Cronn’s disease) Side Effects: - N/V and bone marrow depression; LFT changes - Hypersensitivity reactions Why?

2. Methotrexate: MOA: dihydrofolate reductase inhibitor works as antimetabolite.  Uses: Cronn’s disease (to induce and maintain remission); Rheumatoid Arthratis and cancer. Side effects: Bone marrow suppresion.

Monoclonal antibodies used in IBD (TNF-α inhibitors) Infliximab Adalimumab Certolizumab

Infliximab  Is a monoclonal IgG antibodies.  25% murine – 75% human.  Anti-TNF-α: Inhibits soluble or membrane –bound TNF-α located on activated T lymphocytes and  Given as infusion (5-10 mg/kg).  has long half life (8-10 days)  2 weeks to give clinical response Uses  Severe crohn’s disease.  Patients not responding to Immunomodulators or glucocorticoids.  Treatment of rheumatoid arthritis  Psoriasis

Side effects  Acute or early adverse infusion reactions (Allergic reactions or anaphylaxis in 10% of patients).  Delayed infusion reaction (serum sickness- like reaction, in 5% of patients).  Pretreatment with diphenhydramine, acetaminophen, corticosteroids is recommended.

Side effects (Cont.)  Infection complication (Latent tuberculosis, sepsis, hepatitis B).  Loss of response to infliximab over time due to the development of antibodies to infliximab  Severe hepatic failure.  Rare risk of lymphoma.

Adalimumab (HUMIRA) Fully humanized IgG antibody to TNF-α Adalimumab is TNFα inhibitorTNFα It binds to TNFα, preventing it from activating TNF receptorsTNFα Has an advantage that it is given by subcutaneous injection injection is approved for treatment of, moderate to severe Crohn’s disease, rheumatoid arthritis, psoriasis.Crohn’s disease

Certolizumab pegol (Cimzia) Fab fragment of a humanized antibody directed against TNF-α Certolizumab is attached to polyethylene glycol to increase its half-life in circulation.polyethylene glycolhalf-life Given subcutaneously for the treatment of Crohn's disease & rheumatoid arthritis Crohn's diseaserheumatoid arthritis

Summary for drugs used in IBD 5-aminosalicylic acid compounds Azo compounds: sulfasalazine, olsalazine, balsalazide Mesalamines: Pentasa, Asacol, Rowasa, Canasa Glucocorticoids prednisone, prednisolone, hydrocortisone, budesonide Immunomodulators Methotrexate Purine analogues: Azathioprine&6mercaptopurine TNF-alpha inhibitors (monoclonal antibodies) Infliximab – Adalimumab - Cetrolizumab

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