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DRUG TREATMENT OF INFLAMMATORY BOWEL DISEASE

DRUG TREATMENT OF INFLAMMATORY BOWEL DISEASE. Objectives. Describe the mechanism of action, pharmacokinetics and adverse effects of drugs in IBD. INFLAMMATORY BOWEL DISEASE. Ulcerative Colitis Crohn ’ s disease. Inflammatory bowel disease.

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DRUG TREATMENT OF INFLAMMATORY BOWEL DISEASE

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  1. DRUG TREATMENT OFINFLAMMATORY 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)

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

  7. AIMS OF THERAPY • Suppress inflammatory response • Suppress the immune reaction

  8. Aminosalicylates corticosteroids • Acute maintenance acute

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

  10. Aminosalicylates • Local effect on mucosa in reducing inflammation

  11. Aminosalicylates Sulfasalazine Mesalamine Olsalazine

  12. Aminosalicylates Sulfasalazine Mesalamine Olsalazine

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

  14. SULFASALAZINE Bacterial Flora (Colon) Bacterial azoreductase Sulfapyridine 5-aminosalicylic Acid Acts through the lumen Absorbed Anti-inflammatory Effect Systemic Adverse Effect

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

  16. 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)

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

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

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

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

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

  22. 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

  23. Aminosalicylates 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

  24. Anti-inflammatory &Immunosuppressive Drugs • Corticosteroids • Prednisolone • Hydrocortisone

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

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

  27. Immunomodulators • Azathioprine • Cyclosporine • Infliximab (Anti-TNF-)

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

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

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

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

  32. 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

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

  34. Summary

  35. Drugs for IBD • Aminosalicylates • Glucocorticoids • Immunosuppressives • Cytokine modulators • Antibiotics

  36. Management of UC to induce remission • oral +- topical 5-ASA • +- oral corticosteroids • Azathioprine • iv steroids/Colectomy/ ciclosporin (severe)

  37. Maintaining remission • oral +- topical 5-ASA • +- Azathioprine (frequent relapses)

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

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

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