What's Up with My Gut? Comparing Crohn's Disease and Irritable Bowel Syndrome Fl id Ph i A i i Florida Pharmacist Association St. Augustine, 2015 Jose Barboza, Pharm.D., Pharm.D., C.D.E. Pharmacotherapeutics & Clinical Research University of South Florida College of Pharmacy

Objectives 

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Compare and contrast functional disorders and inflammatory diseases Recognize the differences in symptoms between y (IBS) ( ) Crohn’s Disease and Irritable Bowel Syndrome Review the medications used to treat Crohn’s disease and IBS Identify the mechanism of action, contraindications and major adverse effects of the medications used to treat Crohn’s disease and IBS

Compare and Contrast: Definition Inflammatory Bowel Disease (IBD) Chronic Ch i iinflammation fl i of the intestine

Crohn disease (CD) Ulcerative colitis (UC)

Irritable Bowel Syndrome (IBS) Pain/ Discomfort Change in Bowel habits Absence of organic cause

Diarrhea (IBS-D) Constipation (IBS-C) Alternating/Mixed (IBS-M)

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Irritable Bowel Syndrome: Definition Gastrointestinal (GI) syndrome characterized by abdominal pain or discomfort associated with altered bowel habits in the absence of organic cause Presents with chronically recurring symptoms

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L Lower abdominal bd i l pain i Altered bowel function  Diarrhea predominant (IBS-D)  Constipation predominant (IBS-C)  Constipation and diarrhea (IBS-M) Incomplete evacuation Urgency Bloating

Irritable Bowel Syndrome: Diagnosis Rome III Criteria for Irritable Bowel Syndrome Recurrent abdominal pain or discomfort occurring for three episodes per month in the last 3 months associated with two or more of: 1

Improvement with defecation

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Onset associated with change in frequency of stool

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Onset associated with a change in form of stool

Am J Gastroenterol, 2009. 104 Suppl 1: p. S1-35.

Irritable Bowel Syndrome: Epidemiology 

Prevalence in US is 1010-15% 

More common  

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Females (~2:1) Young adulthood

15% of those affected seek medical attention

Most commonly diagnosed GI condition 

25--50% of gastroenterologist referrals 25

Clin Epidemiol. 2014; 6: 71–80.

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Inflammatory Bowel Disease

https://gi.jhsps.org/GDL_Disease

Inflammatory Bowel Disease: Definition 

Crohn’s Disease 

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Ulcerative Colitis

Inflammatory process in any part of the GI tract Bowel--wall injury, Bowel narrowing of the intestinal lumen  Terminal ileum is the most common site

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Inflammatory process in the colon and rectum

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Affects the mucosa & submucosa 

Continuous lesions

Affects the entire wall of the bowel 

Discontinuous lesions

https://gi.jhsps.org/GDL_Disease

Inflammatory Bowel Disease: Epidemiology 

Crohn’s Disease

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10.7 cases per 100,000 in USA  33,000 33 000 new cases per year  Equal prevalence  Typically diagnosed in ages 15 15--35 (median age 29.5) 

Ulcerative Colitis 12.2 cases 7 per 100,000 in USA  38,000 38 000 new cases per year  Higher in males  Typically diagnosed at ages 15 15--35 (median 34.9 

http://www.ccfa.org/assets/pdfs/updatedibdfactbook.pdf

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Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014.

Clinical Presentation - IBD 

Crohn’s Disease: 

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Signs and symptoms      

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Abdominal mass and tenderness Perianal fissure or fistula

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Hemorrhoids, anal fissures, or perianal abscess

Labs 

WBC, ESR, CRP

Abdominal cramp Frequent bowel movements Hematochezia Weight loss Blurred vision, photophobia Arthritis

Physical findings 

Laboratory tests 

Ulcerative Colitis 

Malaise and fever Abdominal pain Frequent bowel movements Hematochezia Fistula Weight loss/malnutrition Arthritis

Physical findings: 

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Signs and symptoms:

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Hct/Hg, ESR and CRP Hct/Hg, Leukocytes and hypoalbuminemia

Differences: Intestinal Symptoms Intestinal Symptoms

IBS

Alternating diarrhea/constipation

Yes

Crohn’s Disease

Ulcerative Colitis

Abdominal pain

Yes

Yes

Yes

Bloating/Distention

Yes

Yes

Yes

Mucus

Yes

Yes

Yes

Persistent Diarrhea

Yes

Yes

Yes

Loss of Appetite

Yes

Yes

Rectal bleeding

Yes

Yes

Fistulas

Yes

Strictures

Yes

Non-intestinal symptoms with IBD: Anemia, delayed growth, eye conditions, fever, skin irritation, and weight loss

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Differences: Intestinal Symptoms Intestinal Symptoms

IBS

Alternating diarrhea/constipation

Yes

Crohn’s Disease

Ulcerative Colitis

Abdominal pain

Yes

Yes

Yes

Bloating/Distention

Yes

Yes

Yes

Mucus

Yes

Yes

Yes

Persistent Diarrhea

Yes

Yes

Yes

Loss of Appetite

Yes

Yes

Rectal bleeding

Yes

Yes

Fistulas

Yes

Strictures

Yes

Non-intestinal symptoms with IBD: Anemia, delayed growth, eye conditions, fever, skin irritation, and weight loss

Differences: Related Conditions Intestinal Symptoms

IBS

Crohn’s Disease

Anxiety

Yes

Yes

Ulcerative Colitis Yes

Depression

Yes

Yes

Yes

Fibromyalgia

Yes

Yes

Yes

Urinary

Yes

Yes

Yes

Arthritis

Yes

Yes

Colon Cancer

Yes

Yes

Hepatic

Yes

Yes

Osteoporosis

Yes

Yes

IBS Pathophysiology    

Disturbed GI motility Visceral hypersensitivity Psychological stress Altered levels of 5HT 

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5HT3 and 5HT4 are extensively found in the gut, responsible for secretion, sensitization, and motility

Intestinal microflora and inflammation

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Drugs. 2014 Oct;74(16):1849-70.

Physiological distribution of 55--HT CNS – 5%

• Prucalopride • 5HT4 agonist • IBS IBS--C

• Alosetron • 5HT3 antagonist • IBS IBS--D

GI tract – 95% • Causes altered GI Pathophysiology: • Motility • Sensitivity • Secretions

Gershon, Aliment Pharmacol Ther.,1999

IBS –Positive Diagnosis and Outcome        

Identify concerns Explain basis for patient’s symptoms Reasssure Cost effective evaluation Involve patient in decision making Provide continuity Set realistic limits No association between negative colonoscopy and reassurance or improved health related quality of life in IBS Gastrointest Endosc 2005; 62:892-9.

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IBS: Dietary Modifications 

Avoid caffeine, alcohol, and artificial sweeteners 

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They can irritate the gut and produce a laxative effect

Evaluate for lactose intolerance Rule out Celiac sprue sprue:: Gluten avoidance Low FODMAP diet Fermentable Oligosaccharides, Oligosaccharides, Disaccharides Disaccharides,, Monosaccharides and Polyols  Poorly absorbed by some > worsen symptoms 

IBS: NonNon-Pharmacologic Therapy 

Secondary constipation: Correct the cause Dietary modification: Basis of therapy

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Other lifestyle

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Gradually increase fiber intake to 2020-25 grams/day Exercise (e.g., brisk walking after dinner) Adjust bowel habits (e.g., regular and adequate time) Increase fluid intake

IBS: Fiber MOA/ Role in Therapy 

MOA: Contain hydrophilic polysaccharide derivatives Absorb water to: Increase bulk, soften the stool, and facilitate peristalsis and elimination  Effects seen in 2 2--3 days 

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Role in therapy:  

Safest Acceptable in pregnancy

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IBS: Fiber Agents and Availability 

Agents    

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Methylcellulose (Citrucel) Calcium Polycarbophil (FiberCon FiberCon)) Psyllium (Metamucil) Barley malt extract ((Maltsupex Maltsupex))

Available as powders, flakes, granules, tablets, and liquids Caution in diabetes due to glucose content Doses vary, typically administered in divided doses

IBS: Fiber Adverse Effects/Drug Interactions 

Adverse effects 

Abdominal distention, cramping, and flatulence 

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Minimized by gradual increase, resolved with continued use

Drug Interactions Possible binding to digoxin and warfarin Calcium polycarbophil may bind with tetracyclines Separate bulk bulk--forming agents by 11--2 hours of other medications

Caution   

Inappropriate for patients who must severely restrict fluid intake May cause hypersentitivity Danger of fecal impaction or intestinal obstruction 

Avoid in patients with intestinal ulcerations, stenosis, stenosis, or disabling adhesions

IBS: Fiber Evidence 

Psyllium/ispaghula husk showed improvement over Psyllium/ placebo

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Other agents g are similar to placebo p

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Psyllium/ispaghula husk (20Psyllium/ispaghula (20-30 g/day) improves constipation Recommend Bulk Bulk--forming agents for IBS IBS--C

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NNT=6 (IBS type not differentiated)

Drugs. 2014 Oct;74(16):1849-70.

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IBS: Antispasmodics/ Antispasmodics /Anticholinergics 

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MOA: Relax smooth muscles in the colon and small bowel Symptomatic relief – Pain A Agents: P Peppermint i oil, il hyoscine h hyoscine, i , cimetropium, cimetropium i i , pinaverium,, mebeverine pinaverium mebeverine,, and otilonium Side effects effects:: Anticholinergic, generally safe

Drugs. 2014 Oct;74(16):1849-70.

IBS: Antidepressants 

MOA: Improve dysregulation of neuroenteric pathway

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Symptomatic treatment: Abdominal pain

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Visceral analgesia, g , changes g in motility, y, smooth muscle relaxation

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Agents: Paroxetine, fluoxetine, citalopram, amitryptiline, amitryptiline, and imipramine

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Adverse effects (antibiotic dependent): insomnia, restlessness, sexual dysfunction, nausea, constipation, diarrhea

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Reserved for patients with severe or refractory pain

Drugs. 2014 Oct;74(16):1849-70.

IBS: Probiotics 

MOA: restore normal flora 

Alterations may cause Increased fermentation of food Changes in intestinal motor and sensory function,  Mucosal immune activation  Malabsorption  

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Multiple agents studied  

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Lactobacillus, bifidobacterium bifidobacterium,, streptococcus Limitations in clinical trials

Generally safe

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IBS--D: Loperamide IBS   

Evaluated in randomized controlled trials Effective for treatment of diarrhea No impact on abdominal bloating or global IBS symptoms

ACG Task Force on IBS. Am J Gastro. 2009

IBS-D: Alosetron IBSMOA/Agent 

MOA: Potent and selective 5-HT3 antagonist 

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Results in modulation of the enteric nervous systm

Alosetron (Lotronex (Lotronex)) A Approved d iin chronic, chronic h i , severe IBSIBS-D for f patients i who h failed to responded to conventional treatments  Starting dose: 0.5mg BID  Reassess at 4 weeks 

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No adequate control of symptoms: Increase to 1mg BID

Re--assess at 4 weeks Re 

No adequate control of symptoms: Discontinue medication

IBS-D: Alosetron IBSRestricted Use/Precautions 

Adverse effects (dose related)  

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Constipation GI discomfort/pain

Restricted use  Females only  Enroll in Prometheus prescribing program Ischemic colitis (FDA warning)  1.1 cases/1,000 patientpatient-years Precautions: Constipation, ischemic colitis Chang L et al. Am J Gastro 2010

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IBS-D: Alosetron IBSContraindications Constipation intestinal obstruction, stricture, toxic megacolon megacolon,, gastrointestinal perforation, and/or adhesions Ischemic colitis, impaired intestinal circulation, thrombophlebitis, or hypercoagulable state Crohn's disease or ulcerative colitis Diverticulitis Severe hepatic impairment Concomitant fluvoxamine use

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IBS--D: Rifaximin IBS 

Broad spectrum antibiotic with low bioavailability 

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Not FDA approved Dose: 550mg BIDBID-TID for 2 weeks 

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Improvement shown in up to 10 weeks

Showed to improve global IBS symptoms 

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10 stools/day, bleeding, toxicity, abdominal tenderness, tenderness, requirement for transfusion, and colonic dilation

Crohn’s Disease: Classification 

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Mild/moderate: Ambulatory, no evidence of dehydration, toxicity, loss of weight, or abdominal tenderness, mass, or obstruction Moderate/ severe: Fail to respond to treatment for mild/ moderate OR fever, fever weight loss, loss abdominal pain, vomiting, intestinal obstruction, or significant anemia Severe/fulminant: Persistent symptoms OR systemic toxicity despite corticosteroid or biologic therapy, or presence of cachexia, rebound tenderness, obstruction, or abscess Disease activity is correlated with CRP

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IBD: Aminosalicylates MOA and Agents 

MOA: Specific mechanism is unknown 

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A t Agents  

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Thought to modulate chemical mediators of inflammation or act as a free radical scavenger or inhibitor of tumor necrosis factor Mesalamine (Asacol, Asacol, Delzicol, elzicol, Lialda, Lialda, Pentasa), Pentasa), sulfasalazine, balsalazide balsalazide,, olsalazine Mesalamine doses >3g/day in UC

Place in therapy: Mild/moderate IBD 

Off--label for Crohn’s Disease Off

IBD: Aminosalicylates Adverse effects and Precautions 

Adverse effects: Nausea, dyspepsia, skin rash, headache, abdominal pain  Occur in 45% of patients with sulfasalazine and 15% of patients with mesalamine 

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Contraindications (sulfasalazine): sulfa allergy, intestinal or urinary obstruction, porphyria Warnings: Hepatic or renal impairment

IBD: Corticosteroids MOA and Agents 

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MOA: Suppress cytokine migration modulating the immune system and decreasing inflammation Agents: budesonide prednisone, prednisolone 

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Regimens vary 

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B d Budesonide: id Poorly P l absorbed, b b d limited li i d toxicity i i Many wean therapy by decreasing 5mg/day at weekly intervals

Place in therapy: Induce remission in IBD

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IBD: Corticosteroids Adverse Effects and Precautions 

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Adverse effects: many, edema, CV affects, many endocrine and metabolic effects i.e. adrenal suppression and hyperglycemia Preca tions: Heart failure, Precautions: fail re hypertension, hypertension MI, MI hepatic impairment, osteoporosis, thyroid disease, and advanced age Drug interactions: care when combining more than one immunosuppressant drug – contraindicated with Natalizumab, may increase toxic effects of NSAIDS

IBD: Thiopurines MOA and Agents 

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MOA: Induce T T--cell apoptosis by modulating cell signaling Agents:  

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Place in therapy: Adjunctive in IBD 

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A hi i (AZA) 1.5Azathioprine 1.5 1 5-2.5mg/kg/day 2 5 /k /d orally ll Mercaptopurine (MP) 1.51.5-2.5mg/kg/day orally Off--label Off

Test for thiopurine methyl transferase polymorphism

IBD: Thiopurines Adverse Effects and Precautions 

Adverse effects (20% of patients): Fever, arthralgia, rash 

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Precaution:  

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Typically occur in 22--3 weeks, cease when medication is withdrawn Long--term benefit can be expected if tolerated for 3 weeks Long GI toxicity, hepatotoxicity, infections, hematologic toxicity Malignancy:  Risk of nonnon-melanoma skin cancer, lymphoproliferative disorders (1% risk with 10 years)

Contraindication (AZA): Pregnancy (RA), RA and treatment with alkylating agents

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IBD: Methotrexate MOA and Agent 

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MOA: Inhibits dihydrofolate reductase reductase,, cytokine, and eicosanoid synthesis Methotrexate (MTX)15(MTX)15-25mg weekly IM/IV/orally Place in therapy: SecondSecond-line in patients resistant or tolerant to AZA or MP (off (off--label)

IBD: Methotrexate Adverse Effects and Precautions 

Adverse Effects (27(27-49%) d/c in 1010-25% Early: Nausea (co administer with folate to limit), vomiting, diarrhea, and stomatitis  Long term: Hepatotoxicity, pneumonitis, and infections 

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Precautions 

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Acute renal failure, bone marrow suppression, CNS, dermatologic, fertility, GI, hepatotoxicity, infections, pneumonitis, secondary malignancy, and tumor lysis syndrome

Contraindication: Pregnancy

IBD: Cyclosporine 

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MOA: Inhibits calcineurin preventing the clonal expansion of T cell subsets Cyclosporine 4mg/kg/day IV Place in therapy: Refractory in ulcerative colitis (off (off-label)  No place in Crohn’s disease Adverse effects (31 (31--51%): tremor, malaise, paresthesia, headache, liver function abnormality, gingival hyperplasia, hirsutism Precautions: Hypertension, malignancy and skin cancer, nephrotoxicity, infections, neurotoxicity 

Not recommended in lactation

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IBD: AntiAnti-TNF MOA and Agent 

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MOA: Inhibits dihydrofolate reductase reductase,, cytokine, and eicosanoid synthesis IBD 

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Infliximab (Remicade (Remicade)) 5mg/kg at 0, 2, and 6 weeks followed by 5mg/kg every 8 weeks thereafter Adalimumab (Humira) Humira) 40mg subQ every other week

Crohn’s Disease

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Certolizumab (Cimzia Cimzia): ): 400mg at 0, 2, and 4 followed by 400mg every 4 weeks Natalizumab (Tsyabri Tsyabri)300mg )300mg IV every 4 weeks

Place in therapy: Moderate/severe IBD

Anti-TNF AntiAdverse Effects and Precautions  

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Baseline screening for TB required Adverse Effects: Infections, infusion site reactions, autoimmunity Precautions: Antibodyy formation,, malignancy, g y, demyelination, congestive heart failure 

Natalizumab should not be used with immunosuppressants or TNF inhibitors and can cause leukoencephalopathy

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Drug interactions: other biologics and immunosuppressants, immunosuppressants, may decrease effects of vaccinations

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Contraindication (infliximab): heart failure (high doses)

IBD Complications: Antibiotics  

Treat secondary complications in IBD Abscess and bacterial overgrowth Metronidazole Ci fl Ciprofloxacin i  Rifaximin  

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Crohn’s Disease: Treatment Algorithm

Intest Res. 2012 Feb;10(1):26-66.

Therapy in Moderately Severe Crohn’s Disease

Gastroenterology. 2013 Dec;145(6):1459-63.

Remission in Moderately Severe Crohn’s Disease

Gastroenterology. 2013 Dec;145(6):1459-63.

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Beaulieu and Schwartz. Ulcerative Colitis: The Current Approach to Diagnosis and Care. CME Medscape multispecialty. July 2012.

IBD Severity assessment  

Patient well well--being Patient assessment Stool frequency Presence of blood  Fever  Pulse  Abdominal tenderness  Radiologic endoscopic findings  

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Laboratory tests 

Electrolytes, lectrolytes, CBC, renal and hepatic function, ESR and CRP

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Systemic complications  Treating IBD can help  Anemia  Treat with iron, transfusions  Monitor for B12 or folate malabsorption Toxic megacolon megacolon::  Can be life threatening  Requires aggressive treatment, possibly surgery

IBD Special Considerations

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Osteoporosis:  Supplement calcium and vitamin D  Consider bisphosphonate NSAIDS  My exacerbate IBD

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Summary 

IBS and IBD result in similar symptoms and can be difficult to manage Diagnosis can be difficult IBS: Increased morbidity  IBD: Increased morbidity and mortality  

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Cost of therapy can be high Monitor for medication adverse effects, precautions, and contraindications

Questions?

[email protected]

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