Treatment of ibd

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  • As mentioned earlier, the majority of 6-MP is lost to first pass metabolism, largely via xanthine oxidase, producing 6-thiouric acid (6-TU), an inactive metabolite. The 6-MP that escapes this pathway crosses cell membranes, and the remainder of its metabolism then takes place intracellularly.
    Once intracellular, there are two competing routes of metabolism that reveal the reasons for therapeutic successes as well as failures.
    One route of metabolism is via HPRT (hypoxanthine phosphoribosyl transferase), considered an anabolic enzyme. This metabolic route eventually produces 6-thioguanine nucleotides (6-TG). These 6-TG nucleotides are incorporated into the DNA of cells and interfere with cell replication and production of messenger RNA and DNA. This results in interference with cell proliferation and the ability of the cells to have normal metabolic function, including cytokine production.
    The competing route is via TPMT (thiopurine methytransferase) enzyme (shown on bottom). This enzyme produces 6-methylmercaptopurine ribonucleotides (6-MMP). This is a catabolic pathway that results in an end product that has much less impact on the response to therapeutic use of AZA or 6-MP. However, 6-MMP can interfere with purine synthesis.
  • Methotrexate has a number of disadvantages in the treatment of CD. Of particular concern are the risks of hepatic and pulmonary toxicity, myelosuppression, and birth defects in offspring.66 Common AEs associated with methotrexate therapy are seen frequently during induction therapy. The significance of sustained elevated aminotransferases and their contribution to liver disease is not known. Myelosuppression should be monitored with periodic blood counts.
  • Treatment of ibd

    1. 1. IBD Therapy August 24,2012
    2. 2. What is CD AND UC?????   CD is a condition of chronic inflammation potentially involving any location of the GIT from mouth to anus. UC is an inflammatory disorder that affects the rectum and extends proximally to affect variable extent of the colon.
    3. 3. Common pyramid of treatment
    4. 4. Crohn’s Disease Therapy Tysabri Severity Surgery Corticosteroids, Immunomodulators 5-ASAs, Budesonide, Antibiotics Mild Infliximab, Adalimumab, Certilizumab
    5. 5. Ulcerative Colitis Treatment Pyramid Severe Infliximab Mild
    6. 6. Therapy Goals of therapy – Induce and maintain remission. – Ameliorate symptoms – Improve patient’s quality of life – Adequate nutrition – Prevent complication of both the disease and medication PRACTICAL CHALLENGES IN DRUG TREATMENT •How sick is the patient? •What is the disease distribution? •Are there complications  abscess, fistula, obstuction •Has the patient had prior surgery for Crohn’s disease?
    7. 7. 5-Aminosalicylates What are the drugs? • Sulfasalazine Tab 0.5-4g • Mesalamine – Pentasa 2 -4g QID (mesalamine DR tab) – Asacol 1.6-2.4g tid (mesalamine DR tab) – Rowasa – 4 g enema qd (mesalmine rectal enema) – Canasa – 1 gram supp QD (mesalamine rectal supp) – Lialda – 1.2 gram tablet QD (Mesalamine DR tab) • Balsalazide 6.75g Caps • Osalazine 1g Caps What are the issues? • Differ in release characteristics • Evidence based medicine greater role in UC than CD • Sulfasalazine have efficacy in colonic CD • Use in mild disease • Adverse events: worsening of disease activity, increased serum creatinine, pancreatitis, allergic reaction (rash).
    8. 8. Mechanism Of Action Arachidonic Acid 5-Lipoxygenase X Cyclo-oxygenase X SULFASALAZI NE MESALAMINE Leukotrienes Prostaglandins Inflammation
    9. 9. 5-amino salicylic acid(5-ASA)   The mainstay treatment of mild to moderately active UC and CD (induction). 5-ASA may act by blocking the production of prostaglandins and leukotrienes,  inhibiting bacterial peptide–induced neutrophil chemotaxis and adenosine-induced secretion,  scavenging reactive oxygen metabolites 
    10. 10. 5-amino salicylic acid   For patients with distal colonic disease, a suppository or enema form will be most appropriate. Maintenance treatment with a 5aminosalicylic acid can be effective for sustaining remission in ulcerative colitis but is of questionable value in Crohn's disease.
    11. 11. Location of Oral Mesalamine Release Stomach Jejunum Ileum Colon Sulfasalazine Colazal ® (balsalazide) Dipentum® (olsalazine) Asacol® (mesalamine) delayed-release tablets Lialda® (mesalamine) Mesalamine delayed release tab Pentasa® (mesalamine) controlled-release capsules
    12. 12. 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
    13. 13. Adverse effects - sulfapyridine • • • • • • • Heinz body anaemia; Megaloblastic anaemia Hypersensitivity reactions Orbital oedema Renal reactions Neurological reactions Oligoospermia Orange coloured urine & tears
    14. 14. Blood disorders • Agranulocytosis; aplastic anaemia; leucopenia; neutropenia; thrombocytopenia; methaemoglobinemia • Patients should advised to report any unexplained bleeding; bruising; purpura; sore throat; fever or malaise
    15. 15. Contraindications /cautions • 5-ASA - Salicylate hypersensitivity • Sulfapyridine + 5-ASA = Sulfasalazine(cleaved in colon by colonic bacteria) - G6PD deficiency (haemolysis) - Slow acetylator status (↑ risk of hepatic and blood disorders)
    16. 16. Steroids The National Cooperative Crohn’s Disease Study and The European Co-operative Crohn’s Disease Study demonstrated that steroids are efficacious-inducing remission ineffective- maintaining remission DRUGS:  Prednisolone oral/ enema  Hydrocortisone iv  Budesonide (poorly absorbed – used for iliocaecal CD/ UC) 
    17. 17. Budesonide in Crohn’s Disease Budesonide vs. Mesalamine Patients in remission Budesonide - Entocort • 3 mg capsules P/O BD • 9mg capsules P/O qd • Ileal release based on pH dependent mechanism • Steroid with rapid 1st pass metabolism  less systemic effects Thomsen et al 339 (6): 370
    18. 18. • Indicated in mild to moderate ileal Crohn’s disease • Prescribing information  for 9 week course of therapy – 3 weeks at each dose 9 mg, 6 mg, 3 mg • Can be used as a long term drug therapy in some patients • bone density- needs a check!!
    19. 19. Steroids and IBD • • • • • Role important role in the management of acute disease No maintenance role in either UC or CD Oral prednisone or prednisolone is used for moderately severe UC or CD, in doses ranging up to 60 mg per day. For acute disease 40 mg/day x 3 weeks then start taper at 5 mg q 1-2 weeks IV steroids for hospitalized, severely ill patient. Side effects • Osteoporosis • Cataracts • Poor tissue healing • Increased complications • Infections
    20. 20. IMMUNOSUPPRESSIVES • These agents are generally appropriate for patients in whom the dose of corticosteroids cannot be tapered or discontinued. • Azathioprine & 6-MP – The most extensively used immunosuppressive agents. – The mechanisms of action unknown but may include • suppressing the generation of a specific subgroup of T cells. – The onset of benefit takes several weeks up to six months. – Dose-related BM suppression is uniformly observed
    21. 21. CONTD.. • Methotrexate – Effective in steroid-dependent active CD and in maintaining remission. • Cyclosporine – Severe UC not responding to IV steroid &need urgent proctocolectomy. – 50% of the responders will need surgery within a year.
    22. 22. Azathioprine/6MP in IBD Efficacy/Issues • Effective in 50 – 70% of patients with IBD • 30% failure due to intolerance (15%) or no response (15%) • Metabolism issues TPMT • Uses – Steroid sparing – Post operative prophylaxis Intolerance/Risks • Bone marrow suppression • Pancreatitis • Hepatotoxicity • Nausea • Myalgias – flu like symptoms • Other Risks – Lymphoma – 4 fold – Infection
    23. 23. AZA/6MP Metabolism 6-TG 6-TU XO AZA 6-MP TPMT 6-MMP Circulation nucleotides HPRT DNA RNA 6-TImP TPMT 6-MMP ribonucleotides Intracellular Purine synthesis
    24. 24. 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 reg: sore throat/fever
    25. 25. Ciclosporin • Indicated in Severe UC • No value in CD • MOA:inhibitor of calcineurin preventing clonal expansion of T cells • S/E dose dependent nephrotoxicityhepatotoxicity;hypertension; hypertrichosis; gingival hypertrophy etc. • Need to monitor BP; FBC/ RF and levels
    26. 26. Methotrexate • Inducing remission/preventing relapse in CD (Unlicensed indication) • Refractory to or intolerant of Azathioprine • MOA: inhibitor of dihyrofolate reductase; antiinflammatory • S/E: myelosupression*;mucositis;GI; hepatotoxicity; pneumonitis • Co-administration of folinic acid reduces myelosupression;mucositis
    27. 27. Methotrexate • Immunomodulatory vs. Immunosuppressant • Active both in induction and maintenance of remission • 25 mg sc/week x 16 weeks then dosage reduce to 15 mg sc/week • Refractory to or intolerant of Azathioprine • MOA: inhibitor of dihyrofolate reductase; antiinflammatory • S/E: myelosupression*;mucositis;hepatotoxicity; pneumonitis • Co-administration of folinic acid reduces myelosupression;mucositis • Monitor LFTs, CBC
    28. 28. Metronidazole -Spectrum of activity E. histolytica Trichomonas vaginalis Giardia lambia Anaerobes : Gm+ve & Gm-ve Bacteroides fragilis, other species Clostridium Fusobacterium Peptococcus Peptostreptococcus Eubacterium Helicobacter 
    29. 29. Metronidazole - Mechanism of action   I t is a prodrug activated by the susceptible microorganisms to a highly reactive nitro radical anion that target the DNA and other molecules. Development of resistance limited.
    30. 30. Adverse effects of Methotrexate Serious Adverse Events • Hepatotoxicity • Hypersensitivity pneumonitis • Myelosuppression • Birth defects in offspring Common Adverse Events • Nausea and vomiting (42%) • Diarrhea(7%) • Headache (17%) • Abdominal pain (18%) • Joint pain (16%) • Elevated AST, ALT • Stomatitis
    31. 31. Anti-TNF Antibodies Chimeric monoclonal antibody Humanized Fab’ fragment Human recombinant antibody VL No Fc Mouse VH CH1 PEG Human IgG1 IgG1 PEG Infliximab PEG = Polyethylene glycol Adalimumab Certolizumab pegol
    32. 32. IMMUNEMODULATORS OTHERS INCLUDE….. •INFLIXIMAB •ADALIZUMAB •GOLIMUMAB •VISILIZUMAB •NATALIZUMAB •FONTOLIZUMAB Anti TNF antibody Anti TNF antibody Anti CD3 Anti alpha-4 antigen Anti –INF gamma
    33. 33. How do they differ? • Route of administration – Infliximab IV – Certilizumab and Adalimumab: SC – Natalizumab iv infusions • Amount of Mouse protein
    34. 34. INFLIXIMAB • Potent anti-inflammatory • Indicated active and fistulating CD - in severe CD refractory or intolerant of steroids & immunosupressants - for whom surgery is inappropriate • MOA: anti-TNF monoclonal antibody • S/E: infusion reactions/anaphylaxis- COMMON • infection (TB reactivation; overwhelming sepsis) ???? malignancy
    35. 35. Anti-TNF therapy • Infliximab (infusion) ▫ Induction ▫ Maintenance 5mg/kg IV at weeks 0, 2 and 6 5mg/k IV at 8 weeks • Cetolizumab pegol ( SC , nurse administered) ▫ Loading dose ▫ Maintenance 400 mg sc at weeks 0, 2 and 4 400 mg sc at 4 weeks • Adalimumab ( SC, prefilled syringe) ▫ Loading dose ▫ Maintenance 160 mg at week 0, 80 mg at week 2 40 mg sc EOW or weekly
    36. 36. According to AAFP Guidelines: • patients with Crohn's disease need vitamin and mineral supplementation. • vitamin B12, folic acid, fat soluable vitamins, and calcium should be considered, and periodic checks may be necessary. • Osteopenia and osteoporosis are potential complications of Crohn's disease, often aggravated by chronic steroid use. • Despite expanding evidence of the carcinogenic potential of longstanding Crohn's disease. Colonoscopic monitoring 10 years after the onset of disease is recommended, the frequency of which depends on the extent of colonic disease. • Research suggests that supplemental folate may have a protective effect against colon cancer.
    37. 37. GUIDELINES FOR MANAGEMENT OF IBD IN UNITED KINGDOM
    38. 38. http://www.aafp.org/afp/2003/0815/p707.html
    39. 39. Ulcerative Colitis Contiguous disease Mucosal involvement Crypt abscesses/chronicity Cultures negative
    40. 40. Treatment of UC CHALLENGES!! •Induction vs. Maintenance •Left-sided vs. pan-colonic •Fulminate disease •Steroid dependent disease •Chemoprevention of colon cancer
    41. 41. What do we know? • • • • • • • 5-Aminosalicylates Steroids Immunomodulators Anti-TNF Antibiotics Probiotics Nicotine
    42. 42. Surgical Therapy There are four surgical options in patients with UC: 1)Total proctocolectomy and ileostomy 2) total procto-colectomy with continent ileostomy (Koch pouch) 3) total procto-colectomy with ileal pouch-anal anastomosis (IPAA) 4) colectomy with ileorectal anastomosis THE SOCIETY FOR SURGERY OF ALIMENTARYT TRACT
    43. 43. REFERENCES • • • • • • • • • • • http://www.gastro.theclinics.com/article/S0889-8553(12)00005-2/pdf Management of Crohn’s disease-A practical Approach; American Family Physician; volume 68; Number 4; August 15,2003 Ulcerative Colitis- Diagnosis and Treatment; AAFP 2007 Annual Clinical Focus On Management Of Chronic illness; pg 1331 British Society Of Paediatric and Gastroenterology and Hepatology And Nutrition GUT, 2002 october, 51(4):616 Journal Of Clinical Gastroenterology ,August 22,2012 En.wikipedia/wiki/crohns disease.html En.wikipedia/wiki/ulcerative colitis.html Gastroenterology clinics, elsevier Disease Of Colon And Rectum; Wolter & Kluwers CMDT; 2010

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