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- 1. CHRONIC CONDITIONS OF THE BOWEL L I B B Y D A U G H E R T Y P H A R M . D . C A N D I D A T E , C L A S S O F 2 0 1 7 A P P E 3 – A M B U L A T O R Y C A R E – E N C O M P A S S R X A U G U S T 1 0 , 2 0 1 6
- 2. OVERVIEW • Irritable Bowel Syndrome – IBS with Diarrhea (IBS-D) – IBS with Constipation (IBS-C) – Mixed IBS (IBS-M) • Inflammatory Bowel Disease – Ulcerative Colitis (UC) – Crohn’s Disease (CD) • Most prevalent in developed countries, especially in the northern hemisphere. – North America – Northern Europe – Great Britain • Incidence is increasing worldwide • Women prone to IBS and CD • Men prone to UC • Older age at onset of symptoms is associated with better outcomes
- 3. IRRITABLE BOWEL SYNDROMEW I T H D I A R R H E A ( K 5 8 . 0 )
- 4. CLINICAL PRESENTATION • Gastrointestinal syndrome characterized by: – Chronic abdominal pain • Not nocturnal • Not progressive – Altered bowel habits • Diarrhea • Constipation – In the absence of any organic cause • Infection • Celiac disease • Colorectal cancer • Inflammatory disease • Caused by: – Infectious gastroenteritis • The only proven cause of IBS • Food poisoning leads to chronic IBS in 10% of patients • Other Possible Causes: – Bacterial overgrowth • 60% of IBS-D patients have excessive enterobacteracea in their small intestines – Food sensitivity – Genetics
- 5. DIAGNOSIS • The Manning Criteria – Chronic or recurrent abdominal pain for at least 6 months – Two or more of the following: • Abdominal pain relieved with defecation • Abdominal pain associated with more frequent stools • Abdominal pain associated with looser stools • Abdominal distension • Feeling of incomplete evacuation after defecation • Mucus in stools • Rome IV Diagnostic Criteria – Recurrent abdominal pain for at least 1 day per week in the last 3 months – Two or more of the following: • Related to defecation • Associated with a change in frequency of stool • Associated with a change in form/appearance of stool – For at least 6 months
- 6. TREATMENT Diet • Patient-specific • Lactose • Gluten • Gas-producing foods • FODMAP Laxatives (IBS-C) • Osmotic laxatives • Chloride channel activators • Amitiza (Lubiprostone) • Guanylate cyclase agonists • Linzess (Linaclotide) • 5-HT4 Agonists • Zelnorm (Tegaserod) Antidiarrheals (IBS-D) • Immodium (Loperamide) • Viberzi (Eluxadoline) • Bile acid sequestrants • 5-HT3 Antagonists • Lotronex (Alosetron) Antispasmodics • Bentyl (Dicyclomine) • Donnatal (Hyoscyamine, Atropine, Scopolomine, Phenobarbital) Antidepressants • Elavil (Amitryptyline) • Pamelor (Nortriptyline) • Tofranil (Imipramine) • Norpramin (Desipramine) Antibiotics • Xifaxan (Rifaximin)
- 7. XIFAXAN (RIFAXIMIN) FOR IBS-D • Bacteriostatic antibiotic: Inhibits bacterial RNA synthesis by binding to bacterial RNA polymerase • Absorption based on hepatic function – Healthy liver = low systemic absorption • 550mg TID x 14 Days – Provides 6 to 24 weeks of symptomatic relief • 50% abdominal pain • 70% diarrhea – Average relief = 10 weeks – May repeat two times if symptoms recur • Common side effects – Headache – Dizziness – Fatigue • Serious side effects: – Hypersensitivity reaction
- 8. INFLAMMATORY BOWEL DISEASEU L C E R A T I V E C O L I T I S ( K 5 1 ) C R O H N ’ S D I S E A S E ( K 5 0 )
- 9. ULCERATIVE COLITIS CLINICAL PRESENTATION • Diarrhea that lasts for weeks to months (often bloody) • Colicky abdominal pain • Urgency • Tenesmus • Incontinence • Systemic symptoms – Fatigue – Weight loss • Progressive/gradual onset • Intermittent exacerbations (“flare-ups”) alternating with periods of symptomatic remission • 67% of patients have at least one relapse 10 years after initial diagnosis • Complications include severe bleeding, toxic megacolon, perforation, strictures, dysplasia, and colorectal cancer • 20-30% of patients will eventually require a colectomy for complications or intractable disease
- 10. U L C E R A T I V E C O L I T I S D I A G N O S I S Endoscopy Loss of vascular markings (haustra) Pseudopolyps Ulceration, often with gross bleeding Inflammation limited to rectum and colon Biopsy Crypt abscesses/distortion Imaging Barium enema MRI CT
- 11. CROHN’S DISEASE CLINICAL PRESENTATION • More variable than UC • Prolonged diarrhea • With or without bleeding • Abdominal pain • Systemic symptoms – Fatigue – Weight loss • Secondary symptoms – Fistulas – Abscesses – Perianal disease – Malabsorption • Progressive/gradual onset • Intermittent exacerbations (“flare-ups”) alternating with periods of symptomatic remission • 10-20% of patients experience prolonged remission after initial presentation • 13% have a relapse-free course • 20% have annual relapses • 67% have a combination of years in relapse and years in remission • <5% have continuous active disease • Many patients ultimately require surgical intervention
- 12. C R O H N ’ S D I S E A S E D I A G N O S I S Endoscopy Polypoid mucosal changes that give a “cobblestone” appearance Skip areas Fissures Can involve the entire GI tract and usually involves multiple sites Biopsy Focal ulcerations Acute and chronic inflammation Imaging Most useful for upper GI Serologic markers
- 13. TREATMENT Nutritional Support Elimination of food that exacerbates symptoms Enteral supplementation Probiotics Aminosalicylates Sulfasalazine Mesalamine Corticosteroids Prednisone Prednisolone Budesonide Hydrocortisone Methylprednisolone Immunomodulators 6-mercaptopurine (6-MP) Azathioprine Methotrexate Cyclosporine Biologics Tumor Necrosis Factor (TNF- α) Inhibitors Selective Adhesion- Molecule Inhibitors Surgery Fistula repair Resection Total Colectomy
- 14. U L C E R A T I V E C O L I T I S Possible to achieve remission in mild/moderate disease with just aminosalicylates and/or steroids. Topical aminosalicylates are more effective than oral ones. Steroids are particularly effective at relieving tenesmus, but less effective than ASAs for other. Systemic steroids are used regardless of disease location. Biologics are only used after all other therapies have failed.
- 15. C R O H N ’ S D I S E A S E Aminosalisylates have not been shown to be efficacious in CD but are still often used as first-line therapy. Steroids are chosen according to location of disease. Immunomodulators cannot induce remission, but they can maintain steroid-induced remission. Combination therapy of biologics and immunomodulators has been shown to be more efficacious than either agent alone, but this regimen may increase the chance of serious side effects like lymphomas.
- 16. BIOLOGICS Drug Class Route UC CD Remicade (Infliximab) TNF-α Inhibitors IV Infusion X X Humira (Adalimumab) SQ Injection X X Cimzia (Certolizumab pegol) SQ Injection X Simponi (Golimumab) SQ Injection X Entyvio (Vedolizumab) Selective Adhesion- Molecule Inhibitors IV Infusion X X Tysabri (Natalizumab) IV Infusion X
- 17. • 5mg/kg at 0, 2, and 6 weeks • 5mg/kg every 8 weeks • 160mg on Day 1 • 80mg every 2 weeks • 400mg at 0, 2, and 4 weeks • 400mg every 4 weeks • CD only • 200mg on Day 1 • 100mg on Day 15 • 100mg every 4 weeks • UC only TNF-α INHIBITORS • Reduce activity of TNF-α to decrease inflammation • Common Side Effects – Infusion/Injection site reactions – Predisposition to infections • Serious Side Effects – Lymphoma (Black Box Warning) – Bone marrow suppression – Heart failure exacerbation – Reactivation of infections • Avoid in patients with active or recurrent infections • Contraindicated in patients with NYHA class III/IV Heart Failure
- 18. SELECTIVE ADHESION-MOLECULE INHIBITORS • Anti alpha-4 integrin antibodies • Inhibit leukocyte adhesion to reduce inflammation • Indicated for patients unresponsive to conventional treatment and TNF-α inhibitors • Common Side Effects – Infusion reactions – Headache – Arthralgia • Serious Side Effects – Progressive multifocal leukoencephalopathy (Black Box Warning) – Hepatotoxicity – Depression • 300mg over 30 minutes at 0, 2, 6 weeks • 300mg every 8 weeks • Discontinue after 14 weeks if no evidence of therapeutic benefit • 300mg over 1 hour every 4 weeks • Discontinue after 12 weeks if no evidence of therapeutic benefit • CD only
- 19. REFERENCES • A. W. (2016, June 16). Clinical manifestations and diagnosis of irritable bowel syndrome in adults (N. J. Talley, Ed.). Retrieved August 09, 2016, from UpToDate. • About Xifaxan. (n.d.). Retrieved August 09, 2016, from https://www.xifaxan.com/About-Xifaxan • Fabel, P. H., & Shealy, K. M. (2014). Diarrhea, Constipation, and Irritable Bowel Syndrome. In J. T. DiPiro (Author), Pharmacotherapy: A pathophysiologic approach. New York; Madrid: McGraw-Hill Education. • Hemstreet, B. A. (2014). Inflammatory Bowel Disease. In J. T. DiPiro (Author), Pharmacotherapy: A pathophysiologic approach. New York; Madrid: McGraw-Hill Education. • Peppercorn, M. A., & Kane, S. V. (2015, December 17). Clinical manifestations, diagnosis and prognosis of Crohn disease in adults (P. R., Ed.). Retrieved August 09, 2016, from UpToDate. • Peppercorn, M. A., & Kane, S. V. (2015, December 21). Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults (P. Rutgeerts, Ed.). Retrieved August 9, 2016, from UpToDate.
- 20. QUESTIONS?T H A N K Y O U F O R Y O U R A T T E N T I O N !
Hinweis der Redaktion
- IBS presents as either diarrhea- or constipation-predominant disease. Inflammatory Bowel Disease (IBD) is a group of chronic and inflammatory disorders that affect the intestines and the colon IBD encompasses both Crohn’s disease (CD) and ulcerative colitis (UC) Chronic, uncontrolled inflammation of the intestinal mucosa is the hallmark of IBD
- Manning = 1970’s, debatable predictive ability Rome Criteria updated from III to IV in May 2016 Abdominal “discomfort” removed, now only “pain” qualifies Threshold increased from 3 days/month to 1 day/week + Absence of alarm symptoms
- Gas-producing foods Beans, onions, celery, carrots, raisins, bananas, apricots, prunes, Brussel sprouts, wheat germ, pretzels, bagels, caffeine, alcohol Fermentable oligo-, di- and monosaccharide and polyols – FODMAPs Fructose, honey, apples, pears, mangoes, cherries, wheat (Zelnorm) Tegaserod – pulled from US market due to
- Weight loss d/t decreased appetite – pts feel better when they do not eat
- Nutritional support is tricky because these patients are usually malnourished due to malabsorption and reduced appetites. Supplemental enteral nutrition increases remission rates. Probiotics have not been shown to be efficacious but they also do no harm. Most patients with mild to moderate UC can be managed with oral/topical ASAs. Treatment of UC and CD has traditionally used a “step-up” approach. Those drugs are much cheaper but also are less efficacious and have arguably more severe side effects.
- “STEP-UP VERSUS TOP-DOWN THERAPY — There are two general approaches to the treatment of mild to moderate Crohn disease: step-up therapy and top-down therapy. Step-up therapy typically starts with medications that are less potent and (often) associated with fewer side effects. If those therapies are ineffective, more potent (and potentially more toxic) medications are used. Top-down therapy starts with more potent therapies, such as biologic therapy or immunomodulator therapy, relatively early in the course of the disease before patients become glucocorticoid dependent, and possibly even before they receive glucocorticoids. The relative merits of these strategies have not been extensively studied. One of the largest controlled trials included a total of 133 patients with newly diagnosed Crohn disease who were randomly assigned to combined immunosuppression (with infliximab andazathioprine) or conventional management with glucocorticoids followed by azathioprine and infliximab as needed [4]. Significantly more patients in the initial immunosuppression (top-down) group were in clinical remission at 26 weeks (60 versus 36 percent) and at 52 weeks (62 verus 42 percent). Serious adverse events were seen in a similar proportion of both groups (31 versus 25 percent). Similarly, in a study of 508 moderate and severely ill patients with Crohn disease who had not previously received immunosuppressive or biologic agents, the combination of infliximab and azathioprine was more effective than either infliximab or azathioprine alone at inducing a glucocorticoid-free remission.”
- TNF-α are contraindicated in NYHA class III/IV heart failure. Remicade is preferred by the guidelines Humira is indicated for patients who no longer respond to infliximab Cimzia has higher response rates in patients with CR P> 10mg/L
- Stelara currently indicated for Psoriatic arthritis and Plaque psoriasis. Phase II trials for UC and CD indications completed. Currently recruiting for Phase III trial for UC.