1. “Drugs used in IBD and biological and immune therapy of IBD ”
PHARMACOLOGY
GIT Block
2018/ 2019
Mrs.Sandra Hababeh
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5/3/2019

2. 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

3. 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)
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5/3/2019

4. 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

5. 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

6. (Ulcerative colitis) Vs (Crohn's disease)
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5/3/2019

7. 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

8. Stepwise therapy of IBD
5-amino salicylic acid compounds (5-ASA) or aminosalicylates.
Glucocorticoids
Immunomodulators
Biological therapy (TNF-α inhibitors).
Surgery in severe condition.
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5/3/2019

9. IBD Step Up Therapy:
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10. STEPWISE Treatment of IBD:
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11. 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
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5/3/2019

12. Mechanism of action of 5-Aminosalicylates
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13. 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.
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14. 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: ASA + 5-ASA
Balsalazide: 5-ASA + inert carrier

15. 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.
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5/3/2019

16. 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)
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17. 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

18. 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

19. 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)

20. 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

21. 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).

22. 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

23. 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

24. 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 .

25. 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

26. 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.

27. 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)

28. 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

29. Good luck 