“Drugs used in IBD and biological and immune therapy of IBD ” PHARMACOLOGY GIT Block 2018/ 2019 Mrs.Sandra Hababeh اسم ورقم المقرر – Course Name and No. 5/3/2019

Learning Objectives: Define inflammatory bowel disease. Differentiate between ulcerative colitis and Crohn’ disease. Define the stepwise treatment of IBD. Discuss the pharmacokinetics, pharmacodynamics, uses and adverse effects of 5-amino salicylic acid compounds (5-ASA), glucocorticoids, immunomodulators and biological therapy (TNF-α inhibitors). Compare between drugs used for induction of remission and those used for maintenance of remission. اسم ورقم المقرر – Course Name and No. 5/3/2019

What Inflammatory Bowel Disease (IBD) “A chronic inflammation of the digestive tract in the small intestine and colon” It has two types: CD (Crohn's disease) UC (Ulcerative colitis) اسم ورقم المقرر – Course Name and No. 5/3/2019

Causes, Symptoms & Complications of IBD: Causes: (Not known) Auto-immune disorder due to abnormal activation of the immune system. The susceptibility is genetically inherited. Symptoms: Abdominal pain, Vomiting, Diarrhea, Rectal bleeding Complications: Anemia, Mega colon, dehydration, Colon cancer

What is the Difference between CD & UC? Ulcerative colitis Crohn's disease Restricted to colon & rectum affect any part of the GIT, from mouth to anus Location Continuous area of inflammation Patchy areas of inflammation (Skip lesions) Distribution Shallow, mucosal deep into tissues Depth of inflammation Toxic mega colon Colon cancer Strictures, Obstruction Abscess, Fistula Complications

(Ulcerative colitis) Vs (Crohn's disease) اسم ورقم المقرر – Course Name and No. 5/3/2019

Treatment of IBD There are two goals of therapy Achievement of remission (Induction). Prevention of disease flares (maintenance). IBD treatment usually involves either drug therapy or surgery or combination. IBD treatment follows a stepwise approach (step up therapy) اسم ورقم المقرر – Course Name and No. 5/3/2019

Stepwise therapy of IBD 5-amino salicylic acid compounds (5-ASA) or aminosalicylates. Glucocorticoids Immunomodulators Biological therapy (TNF-α inhibitors). Surgery in severe condition. اسم ورقم المقرر – Course Name and No. 5/3/2019

IBD Step Up Therapy: اسم ورقم المقرر – Course Name and No. 5/3/2019

STEPWISE Treatment of IBD: اسم ورقم المقرر – Course Name and No. 5/3/2019

1. 5-amino salicylic acid compounds (5-ASA) Aminosalicylates Aminosalicylates work topically (not systemically) in areas of diseased gastrointestinal mucosa. 5-ASA is absorbed from the small intestine and does not reach the distal small bowel or colon . To overcome this, a number of formulations have been designed to deliver 5-ASA to various distal segments. Use All amino salicylates are used for induction and maintenance of remission (First line of treatment). M.O.A: Blocking the production of prostaglandins and leukotrienes اسم ورقم المقرر – Course Name and No. 5/3/2019

Mechanism of action of 5-Aminosalicylates اسم ورقم المقرر – Course Name and No. 5/3/2019

Formulations of aminosalicylates: 1. Azo compounds Sulfasalazine Balsalazide Olsalazine 2. Mesalamines Asacol Pentasa Canasa Rowasa The major differences are in mechanism and site of delivery. اسم ورقم المقرر – Course Name and No. 5/3/2019

1. Azo compounds What are they? Compounds that contain the active ing. (5-ASA) bound by an azo (N=N) bond to an inert compound or to another 5- ASA molecule Examples? The azo structure markedly reduces absorption of the parent drug from the small intestine. In the terminal ileum and colon, resident bacteria cleave the azo bond by means of an azo reductase enzyme, releasing the active 5-ASA. So high concentrations of active drug are made available in the terminal ileum or colon. Sulfasalazine :5-ASA + sulphapyridine Olsalazine: 5-ASA + 5-ASA Balsalazide: 5-ASA + inert carrier

Azo compounds.. 5-ASA )not absorbed, active moiety acting locally). Sulphapyridine (absorbed, causes most of side effects). Side effects of sulfasalazine Crystalluria. Bone marrow depression Megaloblastic anemia. Folic acid deficiency (should be provided). Impairment of male fertility (Oligospermia). Interstitial nephritis due to 5-ASA. اسم ورقم المقرر – Course Name and No. 5/3/2019

2. Mesalamines (sulfur free drugs) Depending on pH changes these formulation deliver 5-ASA in terminal small bowel & large colon. Mesalamine oral formulations (5-ASA in the small intestine.) Pentasa: micro granules that release 5-ASA throughout the small intestine. Mesalamine rectal formulations (5-ASA in the distal colon) Canasa (suppositories) Rowasa (enema) اسم ورقم المقرر – Course Name and No. 5/3/2019

Clinical uses of 5-amino salicylic acid compounds Induction and maintenance of remission in mild to moderate IBD (First line of treatment). Rheumatoid arthritis (Sulfasalazine only). Rectal formulations are used in distal ulcerative colitis

2. Glucocorticoids They are used to induce remission They are not indicated for maintenance treatment of IBD due to their high risks of adverse effects. They should be used in short course and tapered after response is achieved Ex. Oral preparation: e.g. prednisone, prednisolone Parenteral preparation: e.g. hydrocortisone, methyl prednisolone Rectal preparation e.g. Hydrocortisone

Mechanism of action of glucocorticoids Inhibit gene transcription of nitric oxide synthase, phospholipase A 2, cyclooxygenase-2. They act by inhibition of production of inflammatory cytokines (TNF-α, IL-1)

Uses of glucocorticoids: Induction of remission in moderate & severe active IBD. Not used for maintaining remission. Oral glucocorticoids is commonly used in active condition. Rectal glucocorticoids are preferred in IBD involving rectum or sigmoid colon

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

A. Purine analogs (azathioprine & 6-mercaptopurine) Is a pro-drug of 6-mercaptopurine Inhibits purine synthesis and inhibits synthesis of DNA, RNA, and proteins. Induction and maintenance of remission in IBD Adverse effects : nausea, vomiting, bone marrow depression (leading to leukopenia, thrombocytopenia), and hepatic toxicity. Complete blood count & liver function tests are required in all patients

Methotrexate A folic acid antagonist M.O.A: Inhibits dihydrofolate reductase required for folic acid activation (tetrahydrofolate) Impairs DNA synthesis Orally, S.C., I.M. Used to induce and maintain remission. Uses Inflammatory bowel disease Rheumatoid arthritis Cancer Adverse effects Megaloblastic anemia Bone marrow depression

Monoclonal antibodies used in IBD (TNF-α inhibitors) New trend by using monoclonal antibody to modulate the functions of inflammatory mediators. MOA: TNF-a is an inflammatory cytokine which has a contributory role in producing chronic inflammation Those drugs act as inhibitors of TNF and promote the apoptosis of the mononuclear inflammatory cells a monoclonal IgG antibodies (anti TNF-monoclonal antibody) Used for induction and maintenance of remission in Crohn's disease and Rheumatoid arthritis .

Infliximab 25% murine – 75% human. Given as IV infusion Infliximab needs 2 weeks to give a response Uses: Severe Crohn’s disease Patients not responding to immunosuppressants or glucocorticoids

Adalimumab (HUMIRA) Fully humanized IgG antibody to TNF-α Adalimumab binds to TNF-α, preventing it from activating TNF receptors Has an advantage that it is given by subcutaneous injection , while infliximab is given by IV only.

Side effects of TNF-α inhibitors Infection Common (Bacterial i.e. UTIs, Tb) Opportunistic (fungal) Malignancy (lymphomas) Worsening CHF (decreased cardiac output due to low stroke volume)

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

Good luck 