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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 defined by location or pattern Treatment options 1. 2. 3. 4. 5. 6. 7. Aminosalicylates Corticosteroids Thiopurines Ciclosporin Methotrexate Infliximab Surgery Aminosalicylates MOA: precise MOA unknown act on epithelial cells; anti-inflammatory modulate release of cytokines and reactive oxygen species Sulphasalazine Sulfapyridine + 5-aminosalicylic acid Cleaved in colon by bacterial action 5-ASA poorly absorbed active moiety Sulfapyridine absorbed side effects Newer formulations Mesalazine (5-ASA) Balsalazide (a prodrug of 5-ASA) Olsalazine (5-ASA dimer) 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) 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) Contraindications /cautions 5-ASA - Salicylate hypersensitivity Sulfapyridine - G6PD deficiency (haemolysis) - Slow acetylator status ( risk of hepatic and blood disorders) 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; StevensJohnson syndrome; alopecia Blood disorders Agranulocytosis; aplastic anaemia; leucopenia; neutropenia; thrombocytopenia; methaemoglobinemia Patients should advised to report any unexplained bleeding; bruising; purpura; sore throat; fever or malaise Steven’s Johnson syndrome immune-complex– mediated hypersensitivity erythema multiforme target lesions, mucosal involvement Adverse effects - sulfapyridine Heinz body anaemia; Megaloblastic anaemia Hypersensitivity reactions Orbital oedema Renal reactions Neurological reactions Oligospermia Orange coloured urine & tears 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 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 antiinflammatory effects Anti-inflammatory effects take several hours Pharmacological properties Prednisolone oral/ enema Hydrocortisone iv Budesonide (poorly absorbed – used for iliocaecal CD/ UC) 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 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 Downloaded from: StudentConsult (on 24 October 2005 02:39 PM) © 2005 Elsevier Thiopurines Azathioprine MOA: inhibit ribonucleotide synthesis; induce T cell apoptosis by modulating cell (Rac1) signalling Metabolised to mercaptopurine 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 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 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 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 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 Management of UC Acute to induce remission 4. oral +- topical 5-ASA +- oral corticosteroids eg 40mg prednisolone Azathioprine (Chronic active) iv steroids/Colectomy/ ciclosporin (severe) Maintaining remission 1. 2. 3. 1. 2. oral +- topical 5-ASA +- Azathioprine (frequent relapses) Management of CD 1. 2. 3. 4. 5. 1. 2. 3. 4. 5. 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) Biliary disease Gallstones Laparoscopic cholecystectomy ERCP Bile acids Ursodeoxycholic acid Chenodeoxycholic acid MOA: dissolve non-calcified cholesterol gallstones 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 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 Pancreatic supplements Pancreatin – porcine pancreatin Ind: cystic fibrosis; chronic pancreatitis Inactivated by gastric acid S/E GI; hypersensitivity