Inflammatory bowel disease.2014


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Inflammatory bowel disease.2014

  1. 1. Clinical Case  C.M., a 25-year-old female college student, has had episodic, watery diarrhea and colicky abdominal pain relieved by defecation for the past 9 months.  Eight weeks before, the diarrhea increased to 3 to 5 semi-formed stools daily. The frequency of the stools gradually increased to 5 to 10 times a day 1 week ago.  At that time, C.M. noted bright red blood in the stools.  She feels a great urgency to defecate, even though the volume is small.  No H/O recent infection or travel to endemic area.  C.M. complains of anorexia and a 10-lb weight loss over the past 2 months.  For the past 4 months, she has had intermittent swelling, warmth, and tenderness of the left knee, which is unassociated with trauma.  C.M. appears to be a slightly anxious and tired young woman of normal body habitus.  Her temperature is 100°F; her pulse rate is 100 beats/minute and regular  Physical examination is normal, except for evidence of acute arthritis of the left knee and tenderness of the left lower abdomen to palpation.  Stool examination shows a watery effluent that contains numerous red and white cells with no trophozoites. Stool cultures and an amebiasis indirect hemagglutination test are negative. 03/05/14 Dr Afzal Haq Asif 1
  2. 2. Clinical Case  Laboratory Data include hematocrit (HCT), 32% , hemoglobin (Hgb), 8.5 g/dL ; white blood cell (WBC) count, 15,000/mm 3 with 82% PMNs ; ESR, 70 mm/hour ; serum albumin, 2.4 g/dL and alanine aminotransferase (ALT), 55 U/mL  Sigmoidoscopy showed evidence of granular, edematous, and friable mucosa with continuous ulcerations extending from the anus throughout the colon.  What is the most likely cause of C.M.'s diarrheal illness, and what is the evidence for this?   How should the signs and symptoms be managed and monitored? 03/05/14 Dr Afzal Haq Asif 2
  3. 3. Reference: Pharmacotherapy: Pathophysiologic approach Applied Therapeutics Ann Gastroenterol 2011; 24 (3): 164 -172
  4. 4. ILO’s  Define IBD and its types Differentiate between UC and CD Discuss the proposed etiologies of inflammatory bowel disease (IBD). Identify the common extra-intestinal manifestations associated with IBD. Describe the typical clinical presentation of UC and CD, Describe the major complications of IBD and their management. Formulate treatment goals for management of patients with active IBD. Discuss the role of nutritional and surgical interventions in the management of patients with IBD. 03/05/14 Dr Afzal Haq Asif 4
  5. 5. ILO’s Explain the pharmacologic options for remission for patients with active UC or CD. List the main adverse effects of drugs used Construct monitoring plan for evaluating the efficacy and toxicity of Drugs used 03/05/14 Dr Afzal Haq Asif 5
  6. 6. 03/05/14 Dr Afzal Haq Asif 6
  7. 7. Forms of IBD “The two clinically distinguished forms of inflammatory bowel diseases (IBD), which are chronic remittent or progressive inflammatory diseases Crohns disease (CD)  affect the gastrointestinal tract Ulcerative colitis (UC)  only the colonic mucosa. Both genetic and environmental factors contribute to the pathophysiology of IBD” 03/05/14 Dr Afzal Haq Asif 7
  8. 8. Two Forms of IBD Ulcerative Colitis, a mucosal inflammatory condition confined to the rectum and colon Crohn's disease, a transmural inflammation of gastrointestinal (GI) mucosa that may occur in any part of the GI tract The etiologies of both conditions are unknown, but may have a common pathogenetic mechanism. 03/05/14 Dr Afzal Haq Asif 8
  9. 9. 03/05/14 Dr Afzal Haq Asif 9
  10. 10. Ulcerative colitis is categorized according to location: Proctitis involves only the rectum Proctosigmoiditis affects the rectum and sigmoid colon Left-sided colitis encompasses the entire left side of the large intestine Pancolitis inflames the entire colon 03/05/14 Dr Afzal Haq Asif 10
  11. 11. Crohn’s Disease C r o h n 03/05/14 Dr Afzal Haq Asif 11
  12. 12. Epidemiology  Most common in Westernized countries such as the United States.  UC affects up to 500,000 people and CD affects up to 480,000 people in US  The age of initial presentation of IBD is bimodal,  between the age ranges of 20 to 40 years or  60 to 80 years.5  The peak incidence of CD occurs in the second and third decades of life, with a smaller peak in the fifth decade.2,5 Peak incidence of UC occurs between the ages of 15 and 25 years.6  Men and women are approximately equally affected  Whites are affected more often than blacks,  Jewish have higher incidences of IBD.  Greatest risk factors is a positive family history of the disease.  The incidence of IBD is 10 to 40 times greater in patients with a first- degree relative who has IBD compared to the general population 03/05/14 Dr Afzal Haq Asif 12
  13. 13. 03/05/14 Dr Afzal Haq Asif 13
  14. 14. 03/05/14 Dr Afzal Haq Asif 14
  15. 15. Etiological Factors for IBD  Infectious agents Viruses (e.g., measles) L-Forms of bacteria L form of bcteria Mycobacteria Chlamydia Genetics Metabolic defects(Crohn’s disease in Galactosemia, glycogen storage disease) Connective tissue disorders Environmental Factors Diet Smoking (Crohn's disease) Immune defects Altered host susceptibility Immune-mediated mucosal damage Psychologic factors Stress Emotional or physical trauma Occupation 03/05/14 Dr Afzal Haq Asif 15
  16. 16. 03/05/14 Dr Afzal Haq Asif 16
  17. 17. Initiating Perpetuatin Immunoregulator Tissue Clinical events g events → y abnormalities → damage → symptom → s Infection Luminal s bacteria Genetic susceptibility PMN Diarrhea Macrophage Toxins T lymphocytes ↑IL-1/IL-1ra TH1 vs. TH2 Tx, LT, PAF Bleeding O2, NO NSAIDs Bacterial products Dietary antigens HLA-DR? Anitgen presentation Proteases Pain Complemen t ↓Weight IFN-γ TNF-α Pathophysiology of IBD 03/05/14 Dr Afzal Haq Asif 17
  18. 18. Clinical Presentation: IBD: General  Signs and symptoms  Abdominal cramping  Frequent bowel movements, often with blood in the stool  Weight loss  Fever and tachycardia in severe disease  Blurred vision, eye pain, and photophobia with ocular involvement  Arthritis  Raised, red, tender nodules that vary in size from 1 cm to several centimeters  Physical examination  Hemorrhoids, and fissures, or perirectal abscesses may be present  Iritis, uveitis, episcleritis, and conjunctivitis with ocular involvement  Dermatologic findings with erythema nodosum, pyoderma gangrenosum, or aphthous ulceration  Laboratory tests  Decreased hematocrit/hemoglobin  Increased erythrocyte sedimentation rate  Leukocytosis and Dr Afzal Haq Asif hypoalbuminemia with severe disease 03/05/14 18
  19. 19. Extra-Intestinal Menifestation Erythema Nodosum Pyoderma Gangrenosum Aphthous ulceration  03/05/14 Dr Afzal Haq Asif 19
  20. 20. 03/05/14 Dr Afzal Haq Asif 20
  21. 21. Comparison of the Clinical and Pathologic Features of Crohn and colitis
  22. 22. 1.ULCERATIVE COLITIS Patholophysiology:      03/05/14 confined to the colon and rectum affects primarily the mucosa and the submucosa The primary lesion occurs in the crypts of the mucosa (crypts of Lieberkuhn) in the form of a crypt abscess minor complications include hemorrhoids, anal fissures, or perirectal abscesses. Dr Afzal Haq Asif 22
  23. 23. Complications of UC  Toxic Megacolon: a severe condition that occurs in up to 7.9% of ulcerative colitis patients admitted to hospitals.  High fever, tachycardia, distended abdomen, elevated white blood cell count, and a dilated colon  Colonic Carcinoma:  Risk is much greater in patients with ulcerative colitis as compared with the general population  Hepato-biliary Complications:  Approximately 11% of patients have fatty liver, pericholangitis, chronic active hepatitis, cirrhosis, sclerosing cholangitis, cholangiocarcinoma, and gallstones 03/05/14 Dr Afzal Haq Asif 23
  24. 24. Complications of UC Arthritis: Common, asymptomatic and migratory. involves one or a few large joints such as the knees, hips, ankles, wrists, and elbows. Ocular Complications: iritis, epi-scleritis, and conjunctivitis) occur in up to 10% of patients. Dermatologic or Mucosal complications: 5 to 10% of patients experience (erythema nodosum, pyoderma ganrenosum, aphthous stomatitis 03/05/14 Dr Afzal Haq Asif 24
  25. 25. Grading of UC (Montreal classification S0 Clinical remission Asymptomatic S1 Mild UC Passage of four or fewer stools/day (with or without blood), absence of any systemic illness, and normal inflammatory markers (ESR) S2 Moderate UC S3 Severe UC 03/05/14 Passage of more than four stools per day but with minimal signs of systemic toxicity Passage of at least six bloody stools daily, pulse rate of at least 90 beats per minute, temperature of at least 37.5°C, haemoglobin of less than 10.5 g/100 ml, Dr Afzaland ESR of at least 30 mm/h Haq Asif 25
  26. 26. Fulminant UC Severe diarrhea with abdominal pain, bleeding, fever, sepsis, electrolyte disturbances, and dehydration. 03/05/14 Dr Afzal Haq Asif 26
  27. 27. 03/05/14 Dr Afzal Haq Asif 27
  28. 28. 2. CROHN'S DISEASE: Pathophysiology Trans-mural inflammatory process. Terminal ileum is the most common site but may occur in any part of the GI tract. Two thirds of patients have some colonic involvement, 15% to 25% of patients have only colonic disease. Complications : May involve the intestinal tract or organs unrelated to it. Small-bowel stricture and subsequent obstruction: may require surgery.  03/05/14 Fistula formation is common and occurs much 28 Dr Afzal Haq Asif
  29. 29. 03/05/14 Dr Afzal Haq Asif 29
  30. 30. Crohn’s disease:Clinical presentation Highly variable A single episode or continuous,disease. A patient may present with diarrhea and abdominal pain or a perirectal or perianal lesion Periods of remission and exacerbation. Some patients may be free of symptoms for years, while others experience chronic problems in spite of medical therapy 03/05/14 Dr Afzal Haq Asif 30
  31. 31. Crohn’s Disease: Clinical presentation Signs and symptoms  Malaise and fever  Abdominal pain  Frequent bowel movements  Hemotachezia (bright red blood per rectum: BRBPR)  Fistula (an abnormal connection or passageway between two epithelium- lined organs or vessels that normally do not connect)  Weight loss  Arthritis Physical examination  Abdominal mass and tenderness  Perianal fissure or fistula Laboratory tests  Increased white blood cell count and erythrocyte sedimentation rate 03/05/14 Dr Afzal Haq Asif 31
  32. 32. 03/05/14 Dr Afzal Haq Asif 32
  33. 33. Grading of Crohn's disease  Asymptomatic remission : CDAI <150  Asymptomatic either spontaneously or after medical or surgical intervention. (but not on steroids) Mild to moderate: Crohn disease CDAI 150-220 –  Ambulatory patients able to tolerate an oral diet  Have no dehydration, toxicity, abdominal tenderness, mass, obstruction, or >10 percent weight loss.  Moderate to severe Crohn disease : CDAI 220-45  Failed treatment for mild to moderate disease or  Have prominent symptoms such as fever, weight loss, abdominal pain and tenderness, intermittent nausea or vomiting, or anemia.  Severe-fulminant disease : CDAI >450  Persisting symptoms despite conventional glucocorticoids or biologic agents as outpatients, or individuals presenting with high fevers, persistent vomiting, intestinal obstruction, significant peritoneal signs, cachexia, or evidence of an abscess 03/05/14 Dr Afzal Haq Asif 33
  34. 34. CDAI calculator Patient reported stool pattern Average number of liquid or soft stools per day over seven days (14 points per stool) Using diphenoxylate or loperimide for diarrhea (30 points) Average abdominal pain rating over seven days None (0 points) Mild pain (35 points) Moderate pain (70 points) Severe pain (105 points) General well being each day over seven days Well (0 points) Slightly below average (49 points) Poor (98 points) Very poor (147 points) Terrible (196 points) 03/05/14 Dr Afzal Haq Asif 34
  35. 35. CDAI calculator Complications Arthritis or arthralgia (20 points) Iritis or uveitis (20 points) Erythema nodosum, pyoderma gangrenosum or aphthous stomatitis (20 points) Anal fissure, fistula or abcess (20 points) Other fistula (20 points) Temperature over 100 °F (37.8 °C) in the last week (20 points) Finding of an abdominal mass No mass (0 points) Possible mass (20 points) Definite mass (50 points) Anemia and weight change Absolute deviation of hematocrit from 47% in males or 42% in females (6 points per percent deviation) Percentage deviation from standard weight (1 point for each percent deviation) 03/05/14 Dr Afzal Haq Asif 35
  36. 36. 03/05/14 Dr Afzal Haq Asif 36
  37. 37. Summary of differences in CD &UC Clinical Feature Crohn's Disease Ulcerative Colitis Malaise, fever Common Uncommon Rectal bleeding Common Common Abdominal tenderness Common May be present Abdominal mass Common Absent Abdominal pain Common Unusual Abdominal wall and internal fistulas Common Absent Distribution Discontinuous Mouth to anus Continuous (L.I and Rectum) Aphthous or linear ulcers Common Rare 03/05/14 Dr Afzal Haq Asif 37
  38. 38. Summary of differences in CD &UC Pathologic Feature Crohn's Disease Ulcerative Colitis Rectal involvement Rare Common Ileal involvement Very common Rare Strictures Common Rare Fistulas Common Rare Transmural involvement Common Rare Crypt abscesses Rare Very common Granulomas Common Rare Linear clefts Common Rare Cobblestone appearance Common Absent 03/05/14 Dr Afzal Haq Asif 38
  39. 39. 03/05/14 Dr Afzal Haq Asif 39
  40. 40. Goals ofof acute inflammatory processes, Therapy 1. Resolution 2. Resolution of complications if present(e.g., fistulas, abscesses), 3. Relief in systemic manifestations (e.g., arthritis), 4. Maintenance of remission from acute inflammation, 5. Surgical palliation or cure. 03/05/14 Dr Afzal Haq Asif 41
  41. 41. General Measures Alterations to diet Some of the dietary changes that may be appropriate for a person with IBD include:  Low fibre diet –  to ease diarrhoea and reduce abdominal cramping. Particularly when a narrowed small intestine  Low fat diet  Low lactose diet - the milk sugar lactose is broken down by the enzyme lactase, commonly found in the lining of the small intestine. Patient of Crohn's disease may lack this enzyme,  Liquid diet - a person with severe Crohn's disease may need a nutritionally balanced liquid diet.  Plenty of water - people with IBD need to drink plenty of fluids to prevent dehydration. 03/05/14 Dr Afzal Haq Asif 42
  42. 42. Vitamins and Mineral Supplement A patient on a low fibre diet may need vitamin C and folic acid supplementation because they don't consume enough fruit and vegetables. A patient with Crohn's disease who experiences steatorrhoea may need calcium and magnesium supplements.  Almost all children with IBD to take supplements to lower risk of impaired growth and development. 03/05/14 Dr Afzal Haq Asif 43
  43. 43. Drug T/M of U.C: To induce remission  Mild to Moderate Disease  The first line of drug any one of the following Oral sulfasalazine or an oral mesalamine or, or topical mesalamine or steroids for distal disease  Dose 4 g/day, up to 8 g/day of sulfasalazine to control active disease ( start with 500 mg/day and increase gradually  Oral mesalamine alternative but not more effective than Sulfazalazine  If not responsive: STEROIDS:  Are equally effective as sulfasalazine, but effect appear sooner.  Prednisone up to 1 mg/kg/day or 40 to 60 mg daily  Rectally administered steroids or mesalamine can be used as initial therapy for patients with ulcerative proctitis or distal colitis.  Nicotine Transdermal improves symptoms of patients with mild to moderate active ulcerative colitis in daily doses of 15 to 25 mg.  03/05/14 Dr Afzal Haq Asif 44
  44. 44. T/M: Severe U.C.: Induce remission Hospitalization Steroids: help to avoid colectomy in severe UC Hydrocortisone 100 mg iv 6-8 hourly till remission Shift to oral prednisolone ( 1mg/kg/day)after remission (prednisolone) All patients before surgery should be given trial of Steroids If refractory to steroids, continuous IV infusion of cyclosporine (4 mg/kg/day) If no response :Surgical procedures may be required. 03/05/14 Dr Afzal Haq Asif 45
  45. 45. Maintenance of Remission Sulfasalazine : 2 g/day orally Mesalamine derivatives, can be used, but not as effective as sulfasalazine. No role of steroids: withdraw gradually after remission is induced (over 3 to 4 weeks) Azathioprine: effective in preventing relapse of ulcerative colitis for periods exceeding 4 years. However, 3 to 6 months may be required for beneficial effect Infliximab: continue if patient initially responded to it : 5 mg/kg every 8 weeks as maintenance therapy is an alternative for steroid dependent patients 03/05/14 Dr Afzal Haq Asif 46
  46. 46. Treatment Plan for Ulcerative Colitis 03/05/14 Dr Afzal Haq Asif 47
  47. 47. 03/05/14 Dr Afzal Haq Asif 48
  48. 48. Treatment of Crohn’s Disease 03/05/14 Dr Afzal Haq Asif 49
  49. 49. Crohn’s Disease: Induce Remission Main Drugs: Sulfasalazine, mesalamine derivatives, or steroids, Other choices, according to situation Azathioprine, mercaptopurine, methotrexate, infliximab, Metronidazole, Ciprofloxacin?? 03/05/14 Dr Afzal Haq Asif 50
  50. 50. Crohn’s Disease: Induce Remission If Colon is Involved:  Sulfasalazine is more effective Why?? If Ileal disease:  Mesalamine derivatives (Pentasa or Asacol) more effective. why?? Steroids  When active and severe disease Unresponsive to amino-salicylates. Budesonide first-line option for patients with mild to moderate ileal or right-sided disease. Systemic steroids induce remission in up to 70% of patients and should be reserved for patients with moderate to severe disease who have failed aminosalicylates or budesonide. 03/05/14 Dr Afzal Haq Asif 51
  51. 51. Crohn’s Disease: Induce remission  Metronidazole orally up to 20 mg/kg/day  In patients with colonic or ileocolonic involvement  The combination with ciprofloxacin is efficacious in some patients.  Immunosuppressive agents: azathioprine and mercaptopurine  For those not achieving adequate response to standard therapy,  To reduce steroid doses when toxic doses are required.  Dose: azathioprine is 2 to 3 mg/kg/day and mercaptopurin: 1 to 1.5 mg/kg/day for  Duration: Up to 3 to 4 months may be required to observe a response.  Starting doses are typically 50 mg/day and increased at 2-week intervals while  Monitoring:  Complete blood count  Determine TPMT or TPMT before start of therapy Patients deficient in thiopurine S-methyltransferase (TPMT) are at greater risk of bone 03/05/14 marrow suppression Asif Dr Afzal Haq 52
  52. 52. Crohn’s Disease: Induce remission Cyclosporine  Symptomatic and severe perianal or cutaneous fistulas.  An oral dose of 7.9 mg/kg/day. However, toxic  Monitor dose by whole-blood concentrations. Methotrexate,  5 to 25 mg iv/week, for induction of remission and maintenance therapy.  The risks bone marrow suppression, hepatotoxicity, and pulmonary toxicity Infliximab moderate to severe active disease  failing immunosuppressive therapy,  Corticosteroid dependent,  Treatment of fistulizing disease.  Dose: 5 mg/kg infusion every day for 8 weeks.  Additional doses at2 and 6 weeks following the initial dose results 03/05/14 Dr Afzal Haq Asif 53
  53. 53. Crohn’s Disease: Induce remission Adalimumab effective in 54% of patients with moderate to severe disease who have lost response to infliximab. Dosage is 160 mg subcutaneously initially, followed by 80 mg subcutaneously at week 2, with subsequent doses of 40 mg subcutaneously every other week 03/05/14 Dr Afzal Haq Asif 54
  54. 54. Maintain Remission Difficult than that in U.C. Sulfasalazine and oral mesalamine derivatives are effective Steroids have no place Azathioprine, mercaptopurine, methotrexate, infliximab, and adalimumab are effective in maintaining remission in selected patients Crohn’s disease. 03/05/14 Dr Afzal Haq Asif 55
  55. 55. Treatment Plan for Crohn’s Disease 03/05/14 Dr Afzal Haq Asif 56
  56. 56. Rationale of Antibacterials Based upon a large body of evidence demonstrating that luminal bacteria have an important role in the pathogenesis of IBD Decreasing the concentrations of bacteria and fungi in the gut lumen Altering the composition of the intestinal microbiota to favor beneficial bacteria Decreasing bacterial tissue invasion and treating microabscesses Decreasing bacterial translocation and systemic dissemination 03/05/14 Dr Afzal Haq Asif 57
  57. 57. Fulminant Colitis and Toxic Megacolon Acute fulminant colitis : severe diarrhea with abdominal pain, bleeding, fever, sepsis, electrolyte disturbances, and dehydration. Toxic mega colon: in 1%-2% of patients with UC; the colon becomes atonic and modestly dilates, systemic toxicity is the dominant feature. Treatment  Keep NPO, with NG suction if there is evidence of small-bowel ileus.  Treat dehydration and electrolyte disturbances  Anticholinergic and opioid medication should be discontinued.  Intensive therapy with IV corticosteroids (hydrocortisone, 100 mg IV q6h or equivalent)  Broad-spectrum antimicrobials: Metro+Ciprofloxacin  Surgery: Urgent total colectomy   03/05/14 Clinical deterioration/lack of improvement despite 7-10 days of management, Evidence of bowel perforation, or peritoneal signs Dr Afzal Haq Asif 58
  58. 58. Pregnancy & IBD Pregnancies are well managed in patients with these diseases. Same indications for medical and surgical treatment First attack: standard treatment with sulfasalazine or steroids Folic acid supplementation, 1 mg twice daily,  Metronidazole or methotrexate should not be used during pregnancy. Azathioprine and mercaptopurine may be associated with fetal deformities. 03/05/14 Dr Afzal Haq Asif 59
  59. 59. Evaluation of Therapeutic Outcomes:C.D Crohn Disease Activity Index EIGHT parameters:The Crohn’s Disease Activity Index is used for evaluation of patients during clinical trials.  1) number of stools in the past 7 days  2) sum of abdominal pain ratings from the past 7 days 3) rating of general well-being in the past 7 days  4) use of antidiarrheals  5) body weight  6) hematocrit  7) finding of abdominal mass  8) a sum of symptoms present in the past week.  Elements of this index provide a guide to assess the effectiveness of treatment regimens. 03/05/14 Dr Afzal Haq Asif 60
  60. 60. Evaluation of Therapeutic Outcomes: U.C Look for: Stool frequency Presence of blood in the stool Mucosal appearance (from endoscopy) Physician’s global assessment based on physical examination, endoscopy, and laboratory data. 03/05/14 Dr Afzal Haq Asif 61
  61. 61. Surgery in IBD 03/05/14 Dr Afzal Haq Asif 62
  62. 62. Surgery in IBD For ulcerative colitis, colectomy may be performed: If disease uncontrolled by maximum medical therapy Complications of the disease such as colonic perforation, toxic dilatation (megacolon), uncontrolled colonic hemorrhage, or colonic strictures. In Crohn’s disease surgery is reserved for The complicated disease. But there is a high recurrence rate of Crohn’s disease after surgery. 03/05/14 Dr Afzal Haq Asif 63
  63. 63. • Objectives for this section: • After completion of this section, the student will be able to • • 03/05/14 Select rationalizd therapy Know the adverse effect for follow up evaluation Dr Afzal Haq Asif 64
  64. 64. Drug used in Treatment of IBD 5-Aminosalicylic acid (ASA) compounds  Sulfasalazine  Newer 5-ASA preparations lack the sulfa moiety   Mesalamine (5-ASA) Olsalazine  Glucocorticoids  Prednisone  Budesonide  Hydrocortisone  Antibiotics  Metronidazole.  Ciprofloxacin  Sulfamethoxazole-trimethoprim Immunomodulating agents  6-Mercaptopurine  Azathioprine  Methotrexate  cyclosporine Infliximab Sargramostim  recombinant granulocyte-macrophage colony-stimulating factor 03/05/14 Dr Afzal Haq Asif 65
  65. 65. Sulfasalazine  Reaches the colon intact, where it is metabolized into 5-ASA and a sulfa-pyridine. Used for colonic disease (UC and Crohn's disease limited to the colon), either as initial therapy (0.5 g PO bid, increased as tolerated to 0.5--1.5 g PO qid) or to maintain remission (1 g PO bid to qid).  Adverse effects: Mainly caused by the sulfa pyridine moiety  Headache, nausea, vomiting, and abdominal pain; a reduction in dose may be beneficial.  Can cause drug induced pancreatitis  Hypersensitivity reactions are less common and include skin rash, fever, agranulocytosis, hepatotoxicity, and aplastic anemia.  Reversible reduction in sperm counts can be seen in males.  Paradoxic exacerbation of colitis is a rare adverse effect.  Folic acid supplementation is recommended, as sulfasalazine impairs folate absorption.  STUDY ASSIGNEMENT: Mechanism of action of ASA’s (Ref:Katzung Pharmacology, 03/05/14 Dr Afzal Haq Asif 66
  66. 66. Newer 5-ASA preparations  Mesalamine (5-ASA) is available in several formulations. An oral preparation released at pH >7 (Asacol, 800 to 1,600 mg PO tid) is useful in UC as well as ileocecal/colonic Crohn's disease.  Balsalazide (2.25 g PO tid for active disease, 1.5 g PO bid for maintenance), is cleaved by colonic bacteria to mesalamine and an inert carrier molecule and is useful for colonic inflammation  Olsalazine is a 5-ASA dimer that is cleaved by bacteria in the colon and can be used in UC and Crohn's colitis. Diarrhea is a major side effect and can limit its use Adverse effectsRare hypersensitivity reactions occur and include pneumonitis, pancreatitis, hepatitis, and nephritis. . 03/05/14 Dr Afzal Haq Asif 67
  67. 67. Glucocorticoids-1 Beneficial in inducing remission of active UC and Crohn's disease.  Can be used concurrently with other anti-inflammatory agents in  moderate to severe disease,  In exacerbations of the disease  Extra colonic manifestations of inflammatory bowel disease ocular lesions,  skin disease,  peripheral arthritis  Not recommended for mild disease  Not recommended for maintenance therapy Dose:  Prednisone is 40-60 mg orally, once a day in the morning. can be reduced by 10 mg every 5-10 days and tapered off in 3-6 weeks  Methylprednisolone, 20-40 mg INTRAVENOUS daily to bid, up to 1 mg/kg/d) In    severe disease in Patients who cannot tolerate oral medication brief periods;  higher doses are used in refractory disease  Budesonide (9 mg/d) may have less systemic side effects compared to glucocorticoids when used for mild to moderate ileocolonic Crohn's disease 03/05/14 Dr Afzal Haq Asif 68
  68. 68. Immunosuppressive agents  6-Mercaptopurine, and Azathioprine,  Cause preferential suppression of T-cell activation and antigen recognition.  Are used orally in doses of 1-1.5 mg/kg body weight daily  More favorable side effect profiles than do glucocorticoids  Are used as steroid-sparing agents in severe or refractory inflammatory bowel disease (IBD).  Response after up to 1-2 months.  Adverse effects    Reversible bone marrow suppression, Pancreatitis, Allergic reactions Methotrexate (15-25 mg IM or PO weekly)  used as a steroid-sparing agent in Crohn's disease.  Adverse effects   03/05/14 hepatic fibrosis, bone marrow suppression, alopecia, pneumonitis, allergic reactions, and teratogenicity Dr Afzal Haq Asif 70
  69. 69. Immunosuppressive agents Cyclosporine has been used INTRAVENOUSLY in refractory cases of UC. The benefit is temporary. Adverse effects  nephrotoxicity,  hepatotoxicity,  hypertrichosis,  seizures,  lymphoproliferative disorders 03/05/14 Dr Afzal Haq Asif 71
  70. 70. Infliximab  Monoclonal antibody against tumor necrosis factor-Î  induces inflammatory cell lysis by binding to tumor necrosis factor receptors on the cell surface.  Infliximab is used for  fistulous Crohn's disease,  refractory inflammatory-type Crohn's disease unresponsive to conventional therapy,  severe ulcerative colitis.  Dose: IV infusions of 5 mg/kg)  Induction regimens typically consist of doses at 0, 2, and 6 weeks, with maintenance doses every 8 weeks.  Adverse Effects:  Congestive heart failure may worsen after therapy.  Sepsis and reactivation of latent tuberculosis or histoplasmosis may occur; a tuberculin test may be indicated to evaluate for latent tuberculosis.  Serious infusion reactions may occur, and constant monitoring is essential during infusion. 03/05/14 Dr Afzal Haq Asif 72
  71. 71. Antibacterial Agents Metronidazole (250-500 mg PO tid)  first-line agent or adjunctive therapy in mild to moderate Crohn's disease.  Peripheral neuropathy is a concern with long-term use. Ciprofloxacin (500 mg PO bid) has also been used in Crohn's disease. The two agents can be used concurrently in perianal Crohn's disease for prolonged periods with good results.  An alternative agent is Co-trimoxazole 03/05/14 Dr Afzal Haq Asif 73
  72. 72. Thank you very much 03/05/14 Dr Afzal Haq Asif 74