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Inflammatory Bowel Disease. Inflammatory bowel disease Ulcerative colitis Ulcerative colitis - diffuse mucosal inflammation - diffuse mucosal inflammation.

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Presentation on theme: "Inflammatory Bowel Disease. Inflammatory bowel disease Ulcerative colitis Ulcerative colitis - diffuse mucosal inflammation - diffuse mucosal inflammation."— Presentation transcript:

1 Inflammatory Bowel Disease

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

3 Treatment options 1. Aminosalicylates 2. Corticosteroids 3. Thiopurines 4. Ciclosporin 5. Methotrexate 6. Infliximab 7. 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 Sulfapyridine + 5-aminosalicylic acid Cleaved in colon by bacterial action Cleaved in colon by bacterial action 5-ASA poorly absorbed active moiety 5-ASA poorly absorbed active moiety Sulfapyridine absorbed  side effects Sulfapyridine absorbed  side effects

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

25 Infliximab Indicated active and fistulating CD Indicated active and fistulating CD - in severe CD refractory or intolerant - in severe CD refractory or intolerant of steroids & immunosupressants of steroids & immunosupressants - for whom surgery is inappropriate - for whom surgery is inappropriate MOA: anti-TNF monoclonal antibody MOA: anti-TNF monoclonal antibody Potent anti-inflammatory Potent anti-inflammatory S/E: infusion reactions/anaphylaxis; infection (TB reactivation; overwhelming sepsis) ?malignancy S/E: infusion reactions/anaphylaxis; infection (TB reactivation; overwhelming sepsis) ?malignancy

26 Management of UC Acute to induce remission Acute to induce remission 1. oral +- topical 5-ASA oral corticosteroids eg 40mg prednisolone 3. Azathioprine (Chronic active) 4. iv steroids/Colectomy/ ciclosporin (severe) Maintaining remission Maintaining remission 1. oral +- topical 5-ASA Azathioprine (frequent relapses)

27 Management of CD Acute to induce remission Acute to induce remission 1. oral high dose5-ASA oral corticosteroids reducing over 8/52 3. Azathioprine (Chronic active) 4. Methotrexate (intolerant of azathioprine) 5. iv steroids/ metronidazole/elemental diet/surgery/infliximab Maintaining remission Maintaining remission 1. Smoking cessation 2. oral 5-ASA limited role Azathioprine (frequent relapses) 4. Methotrexate (intolerant of azathioprine) 5. Infliximab infusions (8 weekly)

28 Biliary disease

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

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

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

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


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