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Inflammatory Bowel Disease

Inflammatory Bowel Disease. Inflammatory bowel disease. Ulcerative colitis - diffuse mucosal inflammation - limited to colon - defined by location (eg proctitis;pancolitis) Crohn’s disease - patchy transmural inflammation - fistulae; strictures - any part of GI tract

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Inflammatory Bowel Disease

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  1. Inflammatory Bowel Disease

  2. Inflammatory bowel disease • Ulcerative colitis - diffuse mucosal inflammation - limited to colon - defined by location (eg proctitis;pancolitis) • Crohn’s disease - patchy transmural inflammation - fistulae; strictures - any part of GI tract - defined by location or pattern

  3. Treatment options • Aminosalicylates • Corticosteroids • Thiopurines • Ciclosporin • Methotrexate • Infliximab • Surgery

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

  5. Sulphasalazine • Sulfapyridine + 5-aminosalicylic acid • Cleaved in colon by bacterial action • 5-ASA poorly absorbed active moiety • Sulfapyridine absorbed side effects

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

  7. Pharmacological properties • Oral; enema; suppositories • PH dependent release/resin coated (eg Asacol; caution with lactulose Ph) • Time controlled release (eg Pentasa) • Delivery by carrier molecules (eg Sulphasalazine;olsalazine;balsalazide)

  8. 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)

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

  10. Adverse effects - 5-ASA • Dose-related (10-45%) - headache, nausea, epigastric pain, diarrhoea* • Idiosyncratic (rare) - acute pancreatitis; hepatitis; myocarditis; pericarditis; eosinophilia; fibrosing alveolitis; interstitial nephritis; nephrotic syndrome - peripheral neuropathy - blood disorders - skin reactions – lupus like syndrome; Stevens-Johnson syndrome; alopecia

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

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

  13. Adverse effects - sulfapyridine • Heinz body anaemia; Megaloblastic anaemia • Hypersensitivity reactions • Orbital oedema • Renal reactions • Neurological reactions • Oligospermia • Orange coloured urine & tears

  14. Sulfasalazine • Modest therapeutic advantage in maintaining remission • Overall newer agents have comparable efficacy and better tolerability • Prescribing usually confined to selected cases • eg concomitant arthritis

  15. Corticosteroids • MOA: enter cells and bind to and activate specific cytoplasmic receptors • Steroid-receptor dimers enter cell nucleus • Activate steroid-responsive elements in DNA • Gene repression or induction  anti-inflammatory effects • Anti-inflammatory effects take several hours

  16. Pharmacological properties • Prednisolone oral/ enema • Hydrocortisone iv • Budesonide (poorly absorbed – used for iliocaecal CD/ UC)

  17. Indications • Moderate to severe relapse UC & CD • No role in maintenance therapy • Combination oral and rectal • No added benefit over 40mg /day • <15mg ineffective • Rapid reduction a/w relapse

  18. Corticosteroids •  inflammation •  healing • Na retention/ K loss / Ca loss •  gluconeogenesis – diabetogenic •  catabolism • Redistribution of fat – Cushingoid appearance • Reduced endogenous steroids – withdrawal a/w acute adrenal insufficiency

  19. Downloaded from: StudentConsult (on 24 October 2005 02:39 PM) © 2005 Elsevier

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

  21. Indications • Unlicensed indication (specialist supervision) • Steroid sparing agents  two courses of steroids in 1 year Relapse at steroid dose < 15mg Relapse within 6 weeks of stopping Post-op for complicated CD • Active disease CD/UC • Maintenance of remission CD/UC • Generally continue treatment x 3-4years

  22. Adverse effects • Flu-like symptoms (20%) - occur at 2-3 weeks; cease on withdrawal • Hepatotoxicity; pancreatitis (<5%) • Leucopenia (3%) – myelotoxicity - determined by TPMT activity - weekly FBC x 8 weeks - 3 monthly thereafter - warn patients re: sore throat/fever

  23. Ciclosporin • Indicated in Severe UC (Unlicensed) • No value in CD • Controversial • MOA:inhibitor of calcineurin preventing clonal expansion of T cells • S/E dose dependent nephrotoxicity;hepatotoxicity;hypertension; hypertrichosis; gingival hypertrophy etc. • Need to monitor BP; FBC/ RF and levels

  24. Methotrexate • Inducing remission/preventing relapse in CD (Unlicensed indication) • Refractory to or intolerant of Azathioprine • MOA: inhibitor of dihyrofolate reductase; anti-inflammatory • S/E: myelosupression*;mucositis;GI; hepatotoxicity; pneumonitis • Co-administration of folinic acid reduces myelosupression;mucositis

  25. 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 • S/E: infusion reactions/anaphylaxis; infection (TB reactivation; overwhelming sepsis) ?malignancy

  26. Management of UC • Acute to induce remission • oral +- topical 5-ASA • +- oral corticosteroids eg 40mg prednisolone • Azathioprine (Chronic active) • iv steroids/Colectomy/ ciclosporin (severe) • Maintaining remission • oral +- topical 5-ASA • +- Azathioprine (frequent relapses)

  27. Management of CD • Acute to induce remission • oral high dose5-ASA • +- oral corticosteroids reducing over 8/52 • Azathioprine (Chronic active) • Methotrexate (intolerant of azathioprine) • iv steroids/ metronidazole/elemental diet/surgery/infliximab • Maintaining remission • Smoking cessation • oral 5-ASA limited role • +- Azathioprine (frequent relapses) • Methotrexate (intolerant of azathioprine) • Infliximab infusions (8 weekly)

  28. Biliary disease

  29. Gallstones • Laparoscopic cholecystectomy • ERCP • Bile acids • Ursodeoxycholic acid • Chenodeoxycholic acid • MOA: dissolve non-calcified cholesterol gallstones

  30. Ursodeoxycholic acid • Indications 1. Gallstones - unimpaired gallbladder function - small radioleucent stones - mild symptoms unamenable surgery - recur in 25% 2. Primary biliary cirrhosis • S/E diarhoea

  31. Colestyramine • Anion exchange resin • MOA: Non-absorbed, forms insoluble complex with bile acids • Ind: pruritis of primary biliary cirrhosis; diarrhoea in Crohn’s disease; hyperlipidaemia • S/E: hyperchloraemic acidosis • Int: impairs drug absorption

  32. Pancreatic supplements • Pancreatin – porcine pancreatin • Ind: cystic fibrosis; chronic pancreatitis • Inactivated by gastric acid • S/E GI; hypersensitivity

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