1. DRUG TREATMENT OF INFLAMMATORY BOWEL DISEASE

2. Objectives Describe the mechanism of action, pharmacokinetics and adverse effects of drugs in IBD

3. INFLAMMATORY BOWEL DISEASE Ulcerative Colitis Crohn ’ s disease

4. Inflammatory bowel disease Inappropriate inflammatory response to intestinal microbes in a genetically susceptible host

5. Ulcerative colitis - diffuse mucosal inflammation - limited to colon - defined by location (eg proctitis;pancolitis)

7. Crohn’s disease - patchy transmural inflammation - fistulae, strictures - any part of GI tract

8. AIMS OF THERAPY Suppress inflammatory response Suppress the immune reaction

9. Aminosalicylates corticosteroids Acute maintenance acute

10. Aminosalicylates precise MOA unknown act on epithelial cells anti-inflammatory modulate release of cytokines and reactive oxygen species

11. Aminosalicylates Local effect on mucosa in reducing inflammation

12. Sulfasalazine Mesalamine Olsalazine Aminosalicylates

13. Sulfasalazine Mesalamine Olsalazine Aminosalicylates

14. Sulphasalazine Broken down by gut bacterial azoreductase to 5- aminosalicylate & sulphapyridine

15. SULFASALAZINE Bacterial Flora (Colon) Bacterial azoreductase Sulfapyridine5-aminosalicylic Acid Absorbed Acts through the lumen Systemic Adverse Effect Anti-inflammatory Effect

16. Aminosalicylates 5-ASA absorbed in small intestine Acetylated by N- acetyltransferase-1 Excreted in urine

17. Indications Maintaining remission in UC Reduce risk of colorectal cancer by 75% (long term Rx for extensive disease) Less effective for maintenance in CD Inducing remission in mild UC/CD (higher doses)

18. Contraindications /cautions 5-ASA - Salicylate hypersensitivity Sulfapyridine - G6PD deficiency (haemolysis) - Slow acetylator status (  risk of hepatic and blood disorders)

19. Adverse effects Dose-related Idiosyncratic (rare) - blood disorders - skin reactions – lupus like syndrome; Stevens-Johnson syndrome; alopecia

20. Blood disorders Agranulocytosis; aplastic anaemia; leucopenia; neutropenia; thrombocytopenia; methaemoglobinemia Patients should advised to report any unexplained bleeding; bruising; purpura; sore throat; fever or malaise

21. Steven’s Johnson syndrome immune-complex– mediated hypersensitivity erythema multiforme target lesions, mucosal involvement

22. Newer formulations Mesalazine (5-ASA) Balsalazide (a prodrug of 5-ASA) Olsalazine (5-ASA dimer)

23. Mesalazine Available as Enteric-coated tablets (for ileal Crohn’s disease) Slow release tablets (for proximal bowel Crohn’s) Enemas, suppositories (for distal colonic disease) Used when sulphasalazine can not be tolerated

24. Sulfasalazine  Oral use Mesalamine (5-aminosalicylic acid). Oral delayed release capsules Enema Olsalazine. 5-ASA-n=n-5-ASA Bacterial flora breaks it into 5-ASA Aminosalicylates

25. Anti-inflammatory & Immunosuppressive Drugs Corticosteroids Prednisolone Hydrocortisone

26. Corticosteroids USES Remission Induction Route of Administration Oral Intravenous Topical (Enema)

27. Indications Moderate to severe relapse UC & CD No role in maintenance therapy Combination oral and rectal Indications

28. Immunomodulators Azathioprine Cyclosporine Infliximab (Anti-TNF-  )

29. Thiopurines Azathioprine MOA: inhibit ribonucleotide synthesis; induce T cell apoptosis by modulating cell (Rac1) signalling

30. Indications Steroid sparing agents Active disease CD/UC Maintenance of remission CD/UC Generally continue treatment x 3-4years

31. Ciclosporin MOA:inhibitor of calcineurin preventing clonal expansion of T cells Indicated in Severe UC No value in CD

32. Methotrexate MOA: inhibitor of dihyrofolate reductase; anti-inflammatory Inducing remission/preventing relapse in CD Refractory to or intolerant of Azathioprine

33. Infliximab Indicated active and fistulating CD - in severe CD refractory or intolerant of steroids & immunosupressants - for whom surgery is inappropriate MOA: anti-TNF monoclonal antibody Potent anti-inflammatory

34. Antibiotics Metronidazole Ciprofloxacin Clarithromycin “Probiotics” (administration of “healthy” bacteria)

35. Summary

36. Drugs for IBD Aminosalicylates Glucocorticoids Immunosuppressives Cytokine modulators Antibiotics

37. Management of UC to induce remission 1. oral +- topical 5-ASA 2. +- oral corticosteroids 3. Azathioprine 4. iv steroids/Colectomy/ ciclosporin (severe)

38. Maintaining remission 1. oral +- topical 5-ASA 2. +- Azathioprine (frequent relapses)

39. Management of CD to induce remission 1. oral high dose of 5-ASA 1. +- oral corticosteroids reducing over 8/52 2. Azathioprine 3. iv steroids/ metronidazole/elemental diet/surgery/infliximab

40. Maintaining remission +- Azathioprine (frequent relapses) Methotrexate (intolerant of azathioprine) Infliximab infusions (8 weekly )