1

What's Up with My Gut? What's Up with My Gut? Comparing Comparing Crohn's Crohn's Disease Disease

and Irritable Bowel and Irritable Bowel SyndromeSyndrome

Fl id Ph i A i iFl id Ph i A i iFlorida Pharmacist AssociationFlorida Pharmacist Association

St. Augustine, 2015St. Augustine, 2015

Jose Barboza, Jose Barboza, Pharm.DPharm.D., C.D.E.., C.D.E.Pharmacotherapeutics & Clinical ResearchPharmacotherapeutics & Clinical Research

University of South FloridaUniversity of South Florida College of PharmacyCollege of Pharmacy

ObjectivesObjectives

Compare and contrast functional disorders and inflammatory diseases

Recognize the differences in symptoms between Crohn’s Disease and Irritable Bowel Syndrome (IBS)y ( )

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 BowelDisease (IBD)

Inflammatory BowelDisease (IBD)

Ch i i fl i

Irritable BowelSyndrome (IBS)Irritable BowelSyndrome (IBS)

Pain/ DiscomfortChronic inflammation

of the intestine

Crohn disease (CD)

Ulcerative colitis (UC)

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: DefinitionIrritable Bowel Syndrome: Definition Gastrointestinal (GI) syndrome characterized by Gastrointestinal (GI) syndrome characterized by

abdominal pain or discomfort abdominal pain or discomfort associated with associated with altered altered bowel habits bowel habits in the in the absence of organic causeabsence of organic cause

Presents with chronically recurring symptomsPresents with chronically recurring symptomsL bd i l i Lower abdominal pain

Altered bowel function

Diarrhea predominant (IBS-D)

Constipation predominant (IBS-C)

Constipation and diarrhea (IBS-M)

Incomplete evacuation

Urgency

Bloating

Irritable Bowel Syndrome: DiagnosisIrritable 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

2 Onset associated with change in frequency of stool

3 Onset associated with a change in form of stool

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

Irritable Bowel Syndrome: Irritable Bowel Syndrome: EpidemiologyEpidemiology

Prevalence in US is 10Prevalence in US is 10--15%15% More common More common

FFemales (~2:1)emales (~2:1)

Young adulthoodYoung adulthood

15% of those affected seek medical attention15% of those affected seek medical attention

Most commonly diagnosed GI conditionMost commonly diagnosed GI condition 2525--50% of gastroenterologist referrals 50% of gastroenterologist referrals

Clin Epidemiol. 2014; 6: 71–80.

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Inflammatory Bowel DiseaseInflammatory Bowel Disease

https://gi.jhsps.org/GDL_Disease

Ulcerative ColitisUlcerative Colitis Inflammatory process in the Inflammatory process in the

colon and rectumcolon and rectum Affects the mucosa & Affects the mucosa & submucosasubmucosa

Continuous lesionsContinuous lesions

Inflammatory Bowel Disease: DefinitionInflammatory Bowel Disease: Definition

Crohn’s DiseaseCrohn’s Disease Inflammatory process in Inflammatory process in

any part any part of the GI tract of the GI tract BowelBowel--wall injury, wall injury,

narrowing of the intestinal narrowing of the intestinal Continuous lesionsContinuous lesionslumenlumen

Terminal ileum is the most Terminal ileum is the most common sitecommon site

Affects the entire wall of Affects the entire wall of the bowelthe bowel Discontinuous lesions Discontinuous lesions

https://gi.jhsps.org/GDL_Disease

Inflammatory Bowel Disease: Inflammatory Bowel Disease: EpidemiologyEpidemiology

Crohn’s DiseaseCrohn’s Disease 10.7 cases per 10.7 cases per 100,000 100,000 in in

USAUSA

33 00033 000

Ulcerative Colitis Ulcerative Colitis 12.2 cases 7 per 100,000 12.2 cases 7 per 100,000

in USAin USA

38 00038 000 33,000 new cases per year33,000 new cases per year

Equal prevalenceEqual prevalence

Typically diagnosed in Typically diagnosed in ages 15ages 15--35 (median age 35 (median age 29.5)29.5)

38,000 new cases per year38,000 new cases per year

Higher in malesHigher in males

Typically diagnosed at Typically diagnosed at ages 15ages 15--35 (median 34.935 (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 Clinical Presentation -- IBDIBD Crohn’s Disease:Crohn’s Disease:

Signs and symptoms:Signs and symptoms: Malaise and feverMalaise and fever Abdominal painAbdominal pain Frequent bowel Frequent bowel

movementsmovements HematocheziaHematochezia

Ulcerative ColitisUlcerative Colitis Signs and symptomsSigns and symptoms

Abdominal crampAbdominal cramp

Frequent bowel movementsFrequent bowel movements

HematocheziaHematochezia

Weight lossWeight lossHematocheziaHematochezia FistulaFistula Weight loss/malnutritionWeight loss/malnutrition ArthritisArthritis

Physical findings:Physical findings: Abdominal mass and Abdominal mass and

tendernesstenderness Perianal fissure or fistulaPerianal fissure or fistula

Laboratory testsLaboratory tests WBC, ESR, CRPWBC, ESR, CRP

Weight lossWeight loss

Blurred vision, photophobiaBlurred vision, photophobia

ArthritisArthritis

Physical findingsPhysical findings Hemorrhoids, anal fissures, or Hemorrhoids, anal fissures, or

perianal abscess perianal abscess

LabsLabs HctHct/Hg, ESR and CRP/Hg, ESR and CRP

Leukocytes and Leukocytes and hypoalbuminemiahypoalbuminemia

Differences: Intestinal SymptomsDifferences: Intestinal SymptomsIntestinal Symptoms IBS Crohn’s

DiseaseUlcerative Colitis

Alternatingdiarrhea/constipation

Yes

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 SymptomsDifferences: Intestinal SymptomsIntestinal Symptoms IBS Crohn’s

DiseaseUlcerative Colitis

Alternatingdiarrhea/constipation

Yes

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: Differences: Related ConditionsRelated Conditions

Intestinal Symptoms IBS Crohn’s Disease Ulcerative Colitis

Anxiety Yes Yes 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

IBSIBSPathophysiologyPathophysiology

Disturbed Disturbed GI GI motilitymotility

VVisceral hypersensitivityisceral hypersensitivity

Psychological stressPsychological stress

Altered levels of 5HTAltered levels of 5HT 5HT3 and 5HT4 are extensively found in the gut, 5HT3 and 5HT4 are extensively found in the gut,

responsible for secretion, sensitization, and motilityresponsible for secretion, sensitization, and motility

IIntestinal ntestinal microfloramicroflora and inflammationand inflammation

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

Physiological distribution of 5Physiological distribution of 5--HTHT

CNS CNS –– 5%5%

•• AlosetronAlosetron

•• PrucalopridePrucalopride•• 5HT5HT44 agonist agonist •• IBSIBS--CC

•• AlosetronAlosetron•• 5HT5HT33 antagonist antagonist •• IBSIBS--DD

GI tract GI tract –– 95%95%

Gershon, Aliment Pharmacol Ther.,1999

•• Causes altered GI Causes altered GI Pathophysiology:Pathophysiology:

•• MotilityMotility•• SensitivitySensitivity•• SecretionsSecretions

IBS IBS ––Positive Diagnosis and OutcomePositive Diagnosis and Outcome

Identify concernsIdentify concerns

Explain basis for patient’s symptomsExplain basis for patient’s symptoms

ReasssureReasssure

Cost effective evaluationCost effective evaluation Cost effective evaluationCost effective evaluation

Involve patient in decision makingInvolve patient in decision making

Provide continuityProvide continuity

Set realistic limitsSet realistic limits

No association between negative colonoscopy and No association between negative colonoscopy and reassurance or improved health related quality of life in reassurance or improved health related quality of life in IBSIBS

Gastrointest Endosc 2005; 62:892-9.

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IBS: Dietary ModificationsIBS: Dietary Modifications

Avoid caffeine, alcohol, and artificial sweetenersAvoid caffeine, alcohol, and artificial sweeteners They can irritate the gut and produce a laxative They can irritate the gut and produce a laxative

effecteffect

Evaluate for lactose intoleranceEvaluate for lactose intolerance Evaluate for lactose intoleranceEvaluate for lactose intolerance

Rule out Celiac Rule out Celiac spruesprue: Gluten avoidance: Gluten avoidance

Low FODMAP dietLow FODMAP diet FermentableFermentable OligosaccharidesOligosaccharides, , DisaccharidesDisaccharides, ,

MonosaccharidesMonosaccharides and and PolyolsPolyols

PPoorly absorbed by some > worsen symptoms oorly absorbed by some > worsen symptoms

IBS: IBS: NonNon--Pharmacologic Pharmacologic TherapyTherapy

Secondary constipation: Correct Secondary constipation: Correct the causethe cause

Dietary modification: Basis of therapyDietary modification: Basis of therapy Gradually increase fiber intake to 20Gradually increase fiber intake to 20--25 grams/day25 grams/day

Other lifestyleOther lifestyleOther lifestyleOther lifestyle Exercise (e.g., brisk walking after dinner)Exercise (e.g., brisk walking after dinner)

Adjust bowel habits (e.g., regular and adequate time)Adjust bowel habits (e.g., regular and adequate time)

Increase fluid intake Increase fluid intake

IBS: FiberIBS: FiberMOA/ Role in TherapyMOA/ Role in Therapy

MOA: Contain hydrophilic polysaccharide derivativesMOA: Contain hydrophilic polysaccharide derivatives Absorb water to: Increase bulk, soften the stool, and Absorb water to: Increase bulk, soften the stool, and

facilitate peristalsis and eliminationfacilitate peristalsis and elimination

Effects seen in 2Effects seen in 2--3 days3 days

Role in therapy: Role in therapy: Safest Safest

Acceptable in pregnancyAcceptable in pregnancy

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IBS: FiberIBS: FiberAgents and Availability Agents and Availability

AgentsAgents Methylcellulose (Citrucel)Methylcellulose (Citrucel)

Calcium Calcium PolycarbophilPolycarbophil ((FiberConFiberCon))

PsylliumPsyllium (Metamucil)(Metamucil)

Barley malt extract (Barley malt extract (MaltsupexMaltsupex))

Available as powders, flakes, granules, tablets, and liquidsAvailable as powders, flakes, granules, tablets, and liquids

Caution in diabetes due to glucose contentCaution in diabetes due to glucose content

Doses vary, typically administered in divided doses Doses vary, typically administered in divided doses

IBS: FiberIBS: FiberAdverse Effects/Drug InteractionsAdverse Effects/Drug Interactions Adverse effectsAdverse effects

Abdominal distention, cramping, and flatulenceAbdominal distention, cramping, and flatulence Minimized by gradual increase, resolved with continued useMinimized by gradual increase, resolved with continued use

Drug InteractionsDrug Interactions Possible binding to Possible binding to digoxindigoxin and warfarinand warfarin

Calcium Calcium polycarbophilpolycarbophil may bind with may bind with tetracyclinestetracyclines

Separate bulkSeparate bulk--forming agents by 1forming agents by 1--2 hours of other medications2 hours of other medications

CautionCaution Inappropriate for patients who must severely restrict fluid intakeInappropriate for patients who must severely restrict fluid intake

May cause May cause hypersentitivityhypersentitivity

Danger of fecal impaction or intestinal obstructionDanger of fecal impaction or intestinal obstruction Avoid in patients with intestinal ulcerations, Avoid in patients with intestinal ulcerations, stenosisstenosis, or disabling adhesions, or disabling adhesions

IBS: FiberIBS: FiberEvidenceEvidence

PsylliumPsyllium//ispaghulaispaghula husk showed improvement over husk showed improvement over placeboplacebo NNT=6 (IBS type not differentiated)NNT=6 (IBS type not differentiated)

Other agents are similar to placeboOther agents are similar to placebog pg p PsylliumPsyllium/ispaghula husk (20/ispaghula husk (20--30 g/day) improves 30 g/day) improves

constipationconstipation

Recommend BulkRecommend Bulk--forming agents for IBSforming agents for IBS--CC

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

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IBS: IBS: AntispasmodicsAntispasmodics//AnticholinergicsAnticholinergics MOA: Relax smooth muscles in the colon and MOA: Relax smooth muscles in the colon and

small bowel small bowel

Symptomatic relief Symptomatic relief –– PainPain

A P i ilA P i il h ih i i ii i Agents: Peppermint oil, Agents: Peppermint oil, hyoscinehyoscine, , cimetropiumcimetropium, , pinaveriumpinaverium, , mebeverinemebeverine, and , and otiloniumotilonium

Side Side effectseffects: Anticholinergic, generally safe: Anticholinergic, generally safe

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

IBS: AntidepressantsIBS: Antidepressants

MOA: Improve MOA: Improve dysregulationdysregulation of of neuroentericneuroenteric pathway pathway

Symptomatic Symptomatic treatment: Abdominal treatment: Abdominal painpain

Reserved Reserved for patients with severe for patients with severe or or refractory refractory painpain

Visceral analgesia, changes in motility, smooth muscle relaxationVisceral analgesia, changes in motility, smooth muscle relaxationg , g y,g , g y,

Agents: Paroxetine, fluoxetine, citalopram, Agents: Paroxetine, fluoxetine, citalopram, amitryptilineamitryptiline, and , and imipramineimipramine

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

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

IBS: ProbioticsIBS: Probiotics

MOA: restore normal floraMOA: restore normal flora Alterations may causeAlterations may cause

Increased fermentation of food Increased fermentation of food

Changes in intestinal motor and sensory function,Changes in intestinal motor and sensory function,Changes in intestinal motor and sensory function, Changes in intestinal motor and sensory function,

MMucosal immune activationucosal immune activation

Malabsorption Malabsorption

Multiple agents studiedMultiple agents studied Lactobacillus, Lactobacillus, bifidobacteriumbifidobacterium, streptococcus, streptococcus

Limitations in clinical trialsLimitations in clinical trials

Generally safeGenerally safe

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IBSIBS--D: D: LoperamideLoperamide

EEvaluated in randomized controlled trialsvaluated in randomized controlled trials

Effective for treatment of diarrheaEffective for treatment of diarrhea

No impact on abdominal bloating or global IBS No impact on abdominal bloating or global IBS symptomssymptoms

ACG Task Force on IBS. Am J Gastro. 2009

IBSIBS--D: AlosetronD: AlosetronMOA/AgentMOA/Agent

MOA: Potent and selective MOA: Potent and selective 55--HTHT33 antagonist antagonist Results in modulation of the enteric nervous Results in modulation of the enteric nervous systmsystm

Alosetron (Alosetron (LotronexLotronex))A d i h iA d i h i IBSIBS DD f i hf i h Approved in chronicApproved in chronic, severe IBS, severe IBS--D D for patients who for patients who failed to responded failed to responded to conventional to conventional treatmentstreatments

Starting dose: 0.5mg BIDStarting dose: 0.5mg BID

Reassess at 4 weeksReassess at 4 weeks No adequate control of symptoms: Increase to 1mg BIDNo adequate control of symptoms: Increase to 1mg BID

ReRe--assess at 4 weeksassess at 4 weeks No adequate control of symptoms: Discontinue medicationNo adequate control of symptoms: Discontinue medication

IBSIBS--D: D: AlosetronAlosetronRestricted Use/PrecautionsRestricted Use/Precautions

Adverse effects (dose related)Adverse effects (dose related) Constipation Constipation

GI discomfort/painGI discomfort/pain

Restricted useRestricted use Restricted useRestricted use

FFemales onlyemales only

Enroll in Prometheus prescribing programEnroll in Prometheus prescribing program

IIschemic colitis (FDA warning)schemic colitis (FDA warning)

1.1 cases/1,000 patient1.1 cases/1,000 patient--yearsyears

Precautions: Constipation, ischemic colitisPrecautions: Constipation, ischemic colitis

Chang L et al. Am J Gastro 2010

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IBSIBS--D: D: AlosetronAlosetronContraindicationsContraindications

CConstipationonstipation

intestinal intestinal obstruction, stricture, toxic obstruction, stricture, toxic megacolonmegacolon, , gastrointestinal perforation, and/or adhesionsgastrointestinal perforation, and/or adhesions

Ischemic Ischemic colitis, impaired intestinal circulation, colitis, impaired intestinal circulation, thrombophlebitis, or thrombophlebitis, or hypercoagulablehypercoagulable statestate

Crohn's disease or ulcerative colitisCrohn's disease or ulcerative colitis

DiverticulitisDiverticulitis

Severe Severe hepatic impairmenthepatic impairment

Concomitant fluvoxamine useConcomitant fluvoxamine use

IBSIBS--D: RifaximinD: Rifaximin

Broad spectrum antibiotic with low bioavailabilityBroad spectrum antibiotic with low bioavailability <0.4% absorbed<0.4% absorbed

Not FDA approvedNot FDA approved

Dose: 550mg BIDDose: 550mg BID TID for 2 weeksTID for 2 weeks Dose: 550mg BIDDose: 550mg BID--TID for 2 weeks TID for 2 weeks Improvement shown in up to 10 weeksImprovement shown in up to 10 weeks

Showed to improve global IBS symptomsShowed to improve global IBS symptoms TARGET 1 and 2 trialsTARGET 1 and 2 trials

Adverse effects: Flatulence, abdominal pain, Adverse effects: Flatulence, abdominal pain, tenesmustenesmus, fecal incontinence, nausea, and headaches, fecal incontinence, nausea, and headaches

IBSIBS--C: Osmotic LaxativesC: Osmotic LaxativesMOA/ Role in TherapyMOA/ Role in Therapy

MOA: Osmotic agent, causes water retention in the MOA: Osmotic agent, causes water retention in the stool and increases stool frequencystool and increases stool frequency Not absorbed systemicallyNot absorbed systemically

Onset 1Onset 1--4 days4 days

Role in therapyRole in therapy Low doses for constipationLow doses for constipation

Bowel cleansing before diagnostic or colorectal proceduresBowel cleansing before diagnostic or colorectal procedures

Safe use chronically, studied in up to 6 monthsSafe use chronically, studied in up to 6 months

Other names: PEGOther names: PEG

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IBSIBS--C: Osmotic LaxativesC: Osmotic LaxativesAgentsAgents

AgentsAgents Polyethylene Glycol 3350 (Polyethylene Glycol 3350 (MiralaxMiralax))

Prescription onlyPrescription only

Available with and without electrolytesAvailable with and without electrolytes Available with and without electrolytesAvailable with and without electrolytes

Constipation Constipation 1010––30 g or 1730 g or 17––34 g per 12034 g per 120––240 240 mLmL QD or BID QD or BID

Also used for Also used for bbowel prepsowel preps

IBSIBS--C: Osmotic Laxatives:C: Osmotic Laxatives:Side Effects/ PrecautionsSide Effects/ Precautions

Side effectsSide effects Bloating, abdominal discomfort, cramping, flatulenceBloating, abdominal discomfort, cramping, flatulence

PrecautionsPrecautions LavageLavage is NOT recommended for routine treatment of is NOT recommended for routine treatment of

constipationconstipation

ContraindicationContraindication GI obstructionGI obstruction

IBSIBS--C: Chloride Channel ActivatorC: Chloride Channel ActivatorLubiprostoneLubiprostone-- MOA/ AgentMOA/ Agent

MOA: Chloride channel activatorMOA: Chloride channel activator Open chloride channels locally on the GI luminal epitheliumOpen chloride channels locally on the GI luminal epithelium

Stimulates chlorideStimulates chloride--rich fluid secretion into the lumenrich fluid secretion into the lumen

Results in softening of the stool and increased motility Results in softening of the stool and increased motility

Onset: 24Onset: 24--48 hours48 hours

Agent: Agent: LubiprostoneLubiprostone ((AmitizaAmitiza) ) Rx onlyRx only

Approved to treat chronic constipation in adultsApproved to treat chronic constipation in adults

Constipation: 24mcg BID with foodConstipation: 24mcg BID with food

Approved for IBSApproved for IBS--C: C: 8 mcg BID with food8 mcg BID with food

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IBSIBS--C: Chloride Channel ActivatorC: Chloride Channel ActivatorLubiprostoneLubiprostone-- Role in Therapy/ Adverse EffectsRole in Therapy/ Adverse Effects

Role in therapyRole in therapy Chronic constipation in those who fail firstChronic constipation in those who fail first--line agentsline agents

Adverse effects Adverse effects Nausea (dose dependent), diarrhea, abdominal pain, Nausea (dose dependent), diarrhea, abdominal pain,

flatulence, headaches, dyspneaflatulence, headaches, dyspnea

Pregnancy (category C)Pregnancy (category C)

ContraindicationContraindication GI obstructionGI obstruction

IBSIBS--C: Guanylate CyclaseC: Guanylate Cyclase--C C agonisagonisttLinaclotideLinaclotide-- MOA/ AgentsMOA/ Agents

MOA: MOA: GuanylateGuanylate cyclasecyclase--C agonistC agonist Act on the luminal surface of the intestinal epitheliumAct on the luminal surface of the intestinal epithelium

Stimulates the secretion of chloride and bicarbonate into the Stimulates the secretion of chloride and bicarbonate into the intestinal lumenintestinal lumen

Results in increased intestinal fluid and accelerated GI transitResults in increased intestinal fluid and accelerated GI transit

Decreased visceral pain Decreased visceral pain

Agent: Agent: LinaclotideLinaclotide ((LinzessLinzess))-- Approved in August 2012Approved in August 2012

Chronic Constipation: 145 mcg PO QD on an empty stomach Chronic Constipation: 145 mcg PO QD on an empty stomach at least 30 minutes prior to the first meal of the dayat least 30 minutes prior to the first meal of the day

Approved for IBSApproved for IBS--C: 290mcg PO C: 290mcg PO QD on an empty stomach QD on an empty stomach at least 30 minutes prior to the first meal of the dayat least 30 minutes prior to the first meal of the day

IBSIBS--C: Guanylate CyclaseC: Guanylate Cyclase--C C agonisagonisttSide Effects/ ContraindicationsSide Effects/ Contraindications

Side effects:Side effects: Diarrhea, abdominal pain, flatulenceDiarrhea, abdominal pain, flatulence

P t CP t C Pregnancy category CPregnancy category C

ContraindicatedContraindicated GI obstructionGI obstruction

Children <6 years oldChildren <6 years old

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IBSIBS--C: Serotonin AgonistsC: Serotonin AgonistsPrucalopridePrucalopride

MOAMOA Selective Selective high affinity 5high affinity 5--HTHT44

receptor agonistreceptor agonist

Promotes enteric neurons toPromotes enteric neurons to

SafetySafety TegaserodTegaserod-- withdrawn from the withdrawn from the

market due to CV adverse market due to CV adverse events likely due to its actions events likely due to its actions

Promotes enteric neurons to Promotes enteric neurons to stimulate the peristaltic reflex, stimulate the peristaltic reflex, intestinal secretions, and GI intestinal secretions, and GI motility motility

AgentsAgents PrucalopridePrucalopride-- Not available in Not available in

USA, available in EuropeUSA, available in Europe

yyon on hERGhERG channel channel

Prucalopride: no actions on Prucalopride: no actions on hERGhERG channel and higher channel and higher affinity to affinity to --5HT5HT44

PrucalopridePrucalopride has been safely has been safely tolerated in clinical trialstolerated in clinical trials No adverse CV effects compared No adverse CV effects compared

to placeboto placebo

Treatment AlgorithmTreatment Algorithm

Symptomatic treatment

Stress management and patient educations

Symptomatic treatment

Stress management and patient educations

Constipation PredominantConstipation Predominant Diarrhea PredominantDiarrhea Predominant

Di t L t f nd ff in fr di tDi t L t f nd ff in fr di tIncrease: Fiber and Liquid intakeIncrease: Fiber and Liquid intake

Add bulk-forming laxatives, consider antispasmodic agentsAdd bulk-forming laxatives,

consider antispasmodic agents

Add 5HT-4 agonists (prucalopride) or

guanylate cyclase-c agonist (linaclotide)

Add 5HT-4 agonists (prucalopride) or

guanylate cyclase-c agonist (linaclotide)

Diet: Lactose-fee and caffeine-free diet, avoid other diarrhea causing agents

Diet: Lactose-fee and caffeine-free diet, avoid other diarrhea causing agents

Add loperamide or antispasmodic agentsAdd loperamide or antispasmodic agents

Add 5HT-3 antagonists (alosetron)

Add 5HT-3 antagonists (alosetron)

Add psychotherapeutic behavior modifications, consider antidepressants

Add psychotherapeutic behavior modifications, consider antidepressants

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

Altered Bowel Motility

Pain:Antispasmodics

Altered Bowel Motility: IBS-DRifaximin, loperamide, 5HT3 receptor antagonistsEmerging Therapies:•Bile acid sequestrants•Crofelemer•ASA derivatives

Altered Bowel Motility: IBS-CPsyllium, osmotic laxatives (PEG), sorbitol/lactulose, lubiprostone, linaclotide, 5HT4 receptor agonists, STW5Emerging Therapies•IBAT

BloatingPain

Antispasmodics, antidepressants, probiotics, STW5, melatoninEmerging Therapies•Mixed visceral Mu-opioid •Receptor agonists/antagonists, •Pregabalin•Selective visceral K opioid receptor agonist•H1 receptor antagonists•NK receptor antagonists

Bloating:Antispasmodics, antiflatulents, probiotics, linaclotide, rifaximin, antidepressants: citalopram, fluxoetineDrugs. 2014 Oct;74(16):1849-70.

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IBD: Pharmacologic TreatmentsIBD: Pharmacologic Treatments

AminosalicylatesAminosalicylates

CorticosteroidsCorticosteroids

ImmunosuppressantsImmunosuppressants

AntimicrobialsAntimicrobials

BiologicsBiologics TNFTNFαα inhibitorsinhibitors

Inhibitors of leukocyte adhesion/migrationInhibitors of leukocyte adhesion/migration

Ulcerative Colitis: ClassificationUlcerative Colitis: Classification

Mild: <4 stools/day, no systemic disturbance, Mild: <4 stools/day, no systemic disturbance, normal ESRnormal ESR

Moderate: >4 stools/day, minimal systemic Moderate: >4 stools/day, minimal systemic dist rbancedist rbancedisturbancedisturbance

Severe: >6 stools/day with blood, evidence of Severe: >6 stools/day with blood, evidence of systemic disturbance (fever, tachycardia, anemiasystemic disturbance (fever, tachycardia, anemia, , or or ESR of greater than 30 mm/h (8.3 ESR of greater than 30 mm/h (8.3 μmμm/s/s))

Fulminant: >10 stools/day, bleeding, toxicity, Fulminant: >10 stools/day, bleeding, toxicity, abdominal tendernessabdominal tenderness, requirement for , requirement for transfusion, and colonic dilationtransfusion, and colonic dilation

Crohn’s Disease: ClassificationCrohn’s Disease: Classification

Mild/moderate: Ambulatory, no evidence of Mild/moderate: Ambulatory, no evidence of dehydration, toxicity, loss of weight, or abdominal dehydration, toxicity, loss of weight, or abdominal tenderness, mass, or obstructiontenderness, mass, or obstruction

Moderate/ severe: Fail to respond to treatment for Moderate/ severe: Fail to respond to treatment for mild/ moderate OR fever weight loss abdominalmild/ moderate OR fever weight loss abdominalmild/ moderate OR fever, weight loss, abdominal mild/ moderate OR fever, weight loss, abdominal pain, vomiting, intestinal obstruction, or significant pain, vomiting, intestinal obstruction, or significant anemiaanemia

Severe/fulminant: Persistent symptoms OR Severe/fulminant: Persistent symptoms OR systemic toxicity despite corticosteroid or biologic systemic toxicity despite corticosteroid or biologic therapy, or presence of cachexia, rebound therapy, or presence of cachexia, rebound tenderness, obstruction, or abscesstenderness, obstruction, or abscess

Disease activity is correlated with CRPDisease activity is correlated with CRP

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IBD: IBD: AminosalicylatesAminosalicylatesMOA and AgentsMOA and Agents

MOA: Specific mechanism is unknownMOA: Specific mechanism is unknown Thought to modulate chemical mediators of Thought to modulate chemical mediators of

inflammation or act as a inflammation or act as a ffree radical scavenger or ree radical scavenger or inhibitor of tumor necrosis factorinhibitor of tumor necrosis factor

A tA t AgentsAgents MesalamineMesalamine ((AsacolAsacol, , DDelzicolelzicol, , LialdaLialda, , PentasaPentasa), ),

sulfasalazine, sulfasalazine, balsalazidebalsalazide, , olsalazineolsalazine MesalamineMesalamine doses >3g/day in UCdoses >3g/day in UC

Place in therapy: Mild/moderate IBDPlace in therapy: Mild/moderate IBD OffOff--label for Crohn’s Diseaselabel for Crohn’s Disease

IBD: IBD: AminosalicylatesAminosalicylatesAdverse effectsAdverse effects and Precautionsand Precautions

Adverse effects:Adverse effects: Nausea, dyspepsia, skin rash, headache, abdominal Nausea, dyspepsia, skin rash, headache, abdominal

painpain

Occur in 45% of patients with sulfasalazine and 15%Occur in 45% of patients with sulfasalazine and 15% Occur in 45% of patients with sulfasalazine and 15% Occur in 45% of patients with sulfasalazine and 15% of patients with of patients with mesalaminemesalamine

ContraindicationsContraindications (sulfasalazine): sulfa allergy, (sulfasalazine): sulfa allergy, intestinal or urinary obstruction, porphyriaintestinal or urinary obstruction, porphyria

Warnings: Hepatic or renal impairmentWarnings: Hepatic or renal impairment

IBD: CorticosteroidsIBD: CorticosteroidsMOA and AgentsMOA and Agents

MOA: Suppress cytokine migration modulating MOA: Suppress cytokine migration modulating the immune system and decreasing inflammationthe immune system and decreasing inflammation

Agents: budesonide prednisone, prednisoloneAgents: budesonide prednisone, prednisoloneB d id P l b b d li i d i iB d id P l b b d li i d i i Budesonide: Poorly absorbed, limited toxicityBudesonide: Poorly absorbed, limited toxicity

Regimens varyRegimens vary Many wean therapy by decreasing 5mg/day at Many wean therapy by decreasing 5mg/day at

weekly intervalsweekly intervals

Place in therapy: Induce remission in IBDPlace in therapy: Induce remission in IBD

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IBD: CorticosteroidsIBD: CorticosteroidsAdverse Effects and PrecautionsAdverse Effects and Precautions Adverse effects: Adverse effects: many, edema, CV affects, many many, edema, CV affects, many

endocrine and metabolic effects i.e. adrenal endocrine and metabolic effects i.e. adrenal suppression and hyperglycemiasuppression and hyperglycemia

Preca tions: Heart fail re hypertension MIPreca tions: Heart fail re hypertension MI Precautions: Heart failure, hypertension, MI, Precautions: Heart failure, hypertension, MI, hepatic impairment, osteoporosis, thyroid hepatic impairment, osteoporosis, thyroid disease, and advanced agedisease, and advanced age

Drug interactions: care when combining more Drug interactions: care when combining more than one immunosuppressant drug than one immunosuppressant drug ––contraindicated with Natalizumab, may increase contraindicated with Natalizumab, may increase toxic effects of NSAIDStoxic effects of NSAIDS

IBD: IBD: ThiopurinesThiopurinesMOA and AgentsMOA and Agents

MOA: Induce TMOA: Induce T--cell apoptosis by modulating cell apoptosis by modulating cell signalingcell signaling

Agents: Agents: A hi iA hi i (AZA) 1 5(AZA) 1 5 2 5 /k /d2 5 /k /d llll Azathioprine Azathioprine (AZA) 1.5(AZA) 1.5--2.5mg/kg/day 2.5mg/kg/day orallyorally

MercaptopurineMercaptopurine (MP) (MP) 1.51.5--2.5mg/kg/day orally2.5mg/kg/day orally

Place in therapy: Adjunctive in IBDPlace in therapy: Adjunctive in IBD OffOff--labellabel

Test for Test for thiopurinethiopurine methyl methyl transferasetransferasepolymorphism polymorphism

IBD: IBD: ThiopurinesThiopurinesAdverse Effects and PrecautionsAdverse Effects and Precautions Adverse effects (20% of patients): Fever, arthralgia, rashAdverse effects (20% of patients): Fever, arthralgia, rash

Typically occur in 2Typically occur in 2--3 weeks, cease when medication is 3 weeks, cease when medication is withdrawnwithdrawn

LongLong--term benefit can be expected if tolerated for 3 weeksterm benefit can be expected if tolerated for 3 weeks

Precaution: Precaution: GI toxicity, hepatotoxicity, infections, hematologic toxicityGI toxicity, hepatotoxicity, infections, hematologic toxicity

Malignancy:Malignancy:

Risk of nonRisk of non--melanoma skin cancer, melanoma skin cancer, lymphoproliferativelymphoproliferativedisorders (1% risk with 10 years)disorders (1% risk with 10 years)

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

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IBD: MethotrexateIBD: MethotrexateMOA and AgentMOA and Agent

MOA: Inhibits MOA: Inhibits dihydrofolatedihydrofolate reductasereductase, cytokine, , cytokine, and eicosanoid synthesisand eicosanoid synthesis

Methotrexate (MTX)15Methotrexate (MTX)15--25mg 25mg weekly weekly IM/IV/orallyIM/IV/orally

Place in therapy: SecondPlace in therapy: Second--line in patients resistant line in patients resistant or tolerant to AZA or MP (offor tolerant to AZA or MP (off--label)label)

IBD: MethotrexateIBD: MethotrexateAdverse Effects and PrecautionsAdverse Effects and Precautions

Adverse Effects (27Adverse Effects (27--49%) d/c in 1049%) d/c in 10--25%25% Early: Nausea (co administer with folate to limit), Early: Nausea (co administer with folate to limit),

vomiting, diarrhea, and stomatitisvomiting, diarrhea, and stomatitis

Long term: Hepatotoxicity, pneumonitis, and infectionsLong term: Hepatotoxicity, pneumonitis, and infections

PrecautionsPrecautions Acute renal failure, bone marrow suppression, CNS, Acute renal failure, bone marrow suppression, CNS,

dermatologic, fertility, GI, hepatotoxicity, infections, dermatologic, fertility, GI, hepatotoxicity, infections, pneumonitis, secondary malignancy, and tumor pneumonitis, secondary malignancy, and tumor lysislysissyndromesyndrome

Contraindication: Pregnancy Contraindication: Pregnancy

IBD: CyclosporineIBD: Cyclosporine MOA: Inhibits MOA: Inhibits calcineurincalcineurin preventing the clonal preventing the clonal

expansion of T cell subsetsexpansion of T cell subsets

Cyclosporine 4mg/kg/day IVCyclosporine 4mg/kg/day IV

Place in therapy: Refractory in ulcerative colitis (offPlace in therapy: Refractory in ulcerative colitis (off--label)label)

No place in Crohn’s diseaseNo place in Crohn’s disease

Adverse effects (31Adverse effects (31--51%): tremor, malaise, paresthesia, 51%): tremor, malaise, paresthesia, headache, liver function abnormality, gingival headache, liver function abnormality, gingival hyperplasia, hyperplasia, hirsutismhirsutism

Precautions: Hypertension, malignancy and skin Precautions: Hypertension, malignancy and skin cancer, nephrotoxicity, infections, neurotoxicitycancer, nephrotoxicity, infections, neurotoxicity Not recommended in lactationNot recommended in lactation

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IBD: AntiIBD: Anti--TNFTNFMOA and AgentMOA and Agent

MOA: Inhibits MOA: Inhibits dihydrofolatedihydrofolate reductasereductase, cytokine, , cytokine, and eicosanoid synthesisand eicosanoid synthesis

IBDIBD Infliximab (Infliximab (RemicadeRemicade) 5mg/kg at 0, 2, and 6 weeks ) 5mg/kg at 0, 2, and 6 weeks

followed by 5mg/kg every 8 weeks thereafterfollowed by 5mg/kg every 8 weeks thereafter

AdalimumabAdalimumab ((HumiraHumira) 40mg ) 40mg subQsubQ every other weekevery other week

Crohn’s DiseaseCrohn’s Disease CertolizumabCertolizumab ((CimziaCimzia): 400mg at 0, 2, and 4 followed by ): 400mg at 0, 2, and 4 followed by

400mg every 4 weeks 400mg every 4 weeks

NatalizumabNatalizumab ((TsyabriTsyabri)300mg IV every 4 weeks)300mg IV every 4 weeks

Place in therapy: Moderate/severe IBDPlace in therapy: Moderate/severe IBD

AntiAnti--TNFTNFAdverse Effects and PrecautionsAdverse Effects and Precautions

Baseline screening for TB requiredBaseline screening for TB required

Adverse Effects: Infections, infusion site reactions, Adverse Effects: Infections, infusion site reactions, autoimmunityautoimmunity

Precautions: Antibody formation, malignancy, Precautions: Antibody formation, malignancy, y , g y,y , g y,demyelination, congestive heart failuredemyelination, congestive heart failure NatalizumabNatalizumab should not be used with should not be used with immunosuppressantsimmunosuppressants or TNF or TNF

inhibitors and can cause inhibitors and can cause leukoencephalopathyleukoencephalopathy

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

Contraindication (infliximab): heart failure (high doses)Contraindication (infliximab): heart failure (high doses)

IBD Complications: AntibioticsIBD Complications: Antibiotics

Treat secondary complications in IBDTreat secondary complications in IBD

Abscess and bacterial overgrowthAbscess and bacterial overgrowth MetronidazoleMetronidazole

Ci fl iCi fl i Ciprofloxacin Ciprofloxacin

RifaximinRifaximin

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Crohn’s Disease: Treatment Algorithm Crohn’s Disease: Treatment Algorithm

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

Therapy in Moderately Severe Therapy in Moderately Severe Crohn’s DiseaseCrohn’s Disease

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

Remission in Moderately Severe Remission in Moderately Severe Crohn’s DiseaseCrohn’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 assessmentIBD Severity assessment Patient wellPatient well--beingbeing

Patient assessmentPatient assessment Stool frequencyStool frequency

Presence of bloodPresence of blood

FeverFever

PulsePulse

Abdominal tendernessAbdominal tenderness

Radiologic endoscopic findingsRadiologic endoscopic findings

Laboratory testsLaboratory tests EElectrolyteslectrolytes, CBC, renal and hepatic function, ESR and CRP, CBC, renal and hepatic function, ESR and CRP

IBD Special ConsiderationsIBD Special Considerations Systemic complicationsSystemic complications

Treating IBD can helpTreating IBD can help

AnemiaAnemia

Treat with iron, Treat with iron, transfusionstransfusions

Osteoporosis: Osteoporosis:

Supplement calcium Supplement calcium and vitamin Dand vitamin D

Consider Consider bisphosphonatebisphosphonate

Monitor for B12 or Monitor for B12 or folate folate malabsorptionmalabsorption

Toxic Toxic megacolonmegacolon: :

Can be life threateningCan be life threatening

Requires aggressive Requires aggressive treatment, possibly surgerytreatment, possibly surgery

NSAIDSNSAIDS

My exacerbate IBDMy exacerbate IBD

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SummarySummary IBS and IBD result in similar symptoms and can IBS and IBD result in similar symptoms and can

be difficult to managebe difficult to manage Diagnosis can be difficult Diagnosis can be difficult

IBS: Increased morbidityIBS: Increased morbidity

IBD: Increased morbidity and mortalityIBD: Increased morbidity and mortality

Cost of therapy can be highCost of therapy can be high

Monitor for medication adverse effects, Monitor for medication adverse effects, precautions, and contraindicationsprecautions, and contraindications

Questions?Questions?

Jbarboza@health.usf.eduJbarboza@health.usf.edu