Brooks Cash MDBrooks Cash. MD

National Naval Medical CenterBethesda, MD

MulticomponenFunctional G

MulticomponenFunctional G

• Establish therapeutic relations• Establish therapeutic relations

• Assess patient’s medical h• Assess patient’s medical h

pp

• Assess quality of life an• Assess quality of life an

• Take psychosocial h• Take psychosocial hp yp y

• Order appropria• Order appropria

• Make a conf• Make a conf

• Explain• Explain

• In• In

nt Approach to GI Disordersnt Approach to GI Disorders

shipship

istory, personality, and familyistory, personality, and family

pp

nd level of daily functioningnd level of daily functioning

historyhistoryyy

ate diagnostic testingate diagnostic testing

fident diagnosisfident diagnosis

n and reassuren and reassure

stitute appropriate treatmentstitute appropriate treatment

Suggested Genfor Cons

Suggested Genfor Cons

• Discontinue constip

• Correct endocrine di

• Discontinue constip

• Correct endocrine diCorrect endocrine di

• Treat depression

Correct endocrine di

• Treat depression

• Reassure• Reassure

• Regular visits to the intake, and exercise

• Regular visits to the intake, and exercise

neral Measures stipationneral Measures stipation

ating medications

iseases

ating medications

iseasesiseasesiseases

toilet, increased fluid toilet, increased fluid

Institute AppropInstitute Approp

• Dietary advice• Dietary adviceDietary advice• Lifestyle advice

J di i d t t

Dietary advice• Lifestyle advice

J di i d t t• Judicious drug treatmen–Many in primary care d

Use when work or soci

• Judicious drug treatmen–Many in primary care d

Use when work or soci–Use when work or soci–Should be evidence-ba–Target troublesome sym

–Use when work or soci–Should be evidence-ba–Target troublesome symTarget troublesome sym–Prescribe short-term o

E f ll

Target troublesome sym–Prescribe short-term o

E f ll• Encourage follow-up• Encourage follow-up

priate Treatmentpriate Treatment

ttntdo not need drugsial function are impaired

ntdo not need drugsial function are impairedial function are impairedasedmptoms

ial function are impairedasedmptomsmptomsr as neededmptomsr as needed

Dietary Dietary

• No standard F• No standard F• Avoid excess

– Caffeine, cho• Avoid excess

– Caffeine, cho,– Antidiarrheal– Sorbitol

F tt j k

,– Antidiarrheal– Sorbitol

F tt j k– Fatty or junk

• Encourage Di t fib

– Fatty or junk

• Encourage Di t fib– Dietary fiber

– Antireflux me– Allow sufficie

– Dietary fiber – Antireflux me– Allow sufficieAllow sufficieAllow sufficie

AdviceAdvice

FGID diet!FGID diet!socolate, alcoholsocolate, alcohol,ls

f d

,ls

f dfood

f h d t l

food

f h d t lfor hard stoolseasures for heartburnent time and quiet for meals

for hard stoolseasures for heartburnent time and quiet for mealsent time and quiet for mealsent time and quiet for meals

General MeasuresGeneral Measures

ConstipConstipmedicmedic

ConstipConstipmedicmedic

Address other Address other causescauses

Address other Address other causescauses

DieDieDieDieDieDieDieDie

s for Constipations for Constipation

pating pating ationsationspating pating ationsations

etaryetaryetaryetary LifestyleLifestyleLifestyleLifestyleetaryetaryetaryetary yyimagesimages

yyimagesimages

Medications AssociatMedications AssociatNonprescription drugs

Antacids especially calcium-

Nonprescription drugs

Antacids especially calcium-Antacids, especially calciumcontaining

Calcium supplements

Antacids, especially calciumcontaining

Calcium supplements

Iron supplements

Antidiarrheal agents

Iron supplements

Antidiarrheal agents

Nonsteroidal antiinflammatoryagents Nonsteroidal antiinflammatoryagents

Locke GR III et al. Gastroenterology 2000; 119:1766

ted With Constipationted With ConstipationPrescription drugs

Opioids

Prescription drugs

OpioidsOpioids

Anticholinergic agents

Tricyclic antidepressants

Opioids

Anticholinergic agents

Tricyclic antidepressantsy p

Calcium channel blockers

Statin agents

y p

Calcium channel blockers

Statin agents

Anti-Parkinsonian drugs

Sympathomimetics

Anti-Parkinsonian drugs

Sympathomimetics

Antipsychotics

Diuretics

Antipsychotics

Diuretics

Antihistamines Antihistamines

Fiber SupplemBulk LaxativesFiber Supplem

Bulk Laxatives

Wh t bWh t b• Wheat bran

Whole grain food produ

• Wheat bran

Whole grain food produ• Whole-grain food produ

• Soluble fiber bulk laxati

• Whole-grain food produ

• Soluble fiber bulk laxati• Soluble-fiber bulk laxati

• Insoluble-fiber bulk laxa

• Soluble-fiber bulk laxati

• Insoluble-fiber bulk laxaInsoluble fiber bulk laxaInsoluble fiber bulk laxa

mentation and s Classificationmentation and s Classification

uctsuctsucts

ives

ucts

ivesives

atives

ives

ativesativesatives

Wheat Bran andA Dose R

Wheat Bran andA Dose R

90

75

45

60Increase in Increase in

stool weight stool weight

15

30over baseline over baseline

(g)(g)

0

15

0 5 100 5 10

WWStephen AM et al. Br J Nutrition 1986; 56:349

d Stool Weight:Responsed Stool Weight:

Response

P<0.01n-6P<0.01n-6

15 20 25 3015 20 25 30

Wheat fiber (g)Wheat fiber (g)

Efficacy of FEfficacy of F

• 13 randomized clinical trialWheat bran corn fiber cal

• 13 randomized clinical trialWheat bran corn fiber cal– Wheat bran, corn fiber, caland psyllium

– Low-intermediate quality s

– Wheat bran, corn fiber, caland psyllium

– Low-intermediate quality s– Ispaghula (4/5 studies) imp

and ease of stool passage– Ispaghula (4/5 studies) imp

and ease of stool passage

• Side effects: may increase abdominal discomfortAppropriate for constipatio

• Side effects: may increase abdominal discomfortAppropriate for constipatio• Appropriate for constipatio• Appropriate for constipatio

Brandt LJ et al. Am J Gastroenterol 2002;97 suppl:S7-26Lesbros-Pantoflickova D et al. Aliment Pharmacol Ther 2004;20:1253

iber in IBS-Ciber in IBS-C

slcium polycarbophil ispaghulaslcium polycarbophil ispaghulalcium polycarbophil, ispaghula,

studies with small sample sizes

lcium polycarbophil, ispaghula,

studies with small sample sizesproved global IBS symptoms but not pain.proved global IBS symptoms but not pain.

intestinal gas, bloating and

on predominant symptoms

intestinal gas, bloating and

on predominant symptomson-predominant symptomson-predominant symptoms

Fiber/Bulking AEffect on Glob

Fiber/Bulking AEffect on GlobQuality

Study score (n/N) (n/N)Arthurs 3 29/40 24/38Cook 4 3/14 4/14

QualityStudy score (n/N) (n/N)Arthurs 3 29/40 24/38Cook 4 3/14 4/14Cook 4 3/14 4/14Fowlie 3 15.25 17/24Jalihal 2 7/20 2/20Longstreth 4 20/26 24.34

Cook 4 3/14 4/14Fowlie 3 15.25 17/24Jalihal 2 7/20 2/20Longstreth 4 20/26 24.34Lucey 2 22/28 20/28Nigam 2 41/84 22/84Pnor 4 66/80 42/80Ritchie 1979 2 33/48 23/48

Lucey 2 22/28 20/28Nigam 2 41/84 22/84Pnor 4 66/80 42/80Ritchie 1979 2 33/48 23/48Ritchie, 1979 2 33/48 23/48Ritchie, 1980 2 20/28 8/28Snook 4 37/71 38/71Soltoft 3 15.29 15/23

Ritchie, 1979 2 33/48 23/48Ritchie, 1980 2 20/28 8/28Snook 4 37/71 38/71Soltoft 3 15.29 15/23Toskes 2 23/48 13/48Total (05% CI) 344/557 263/556Total high-quality 344/285 164/284studies (95% CI)

Toskes 2 23/48 13/48Total (05% CI) 344/557 263/556Total high-quality 344/285 164/284studies (95% CI)studies (95% CI)studies (95% CI)

Lesbros-Pantoflickova D et al. APT 2004; 20:1253

Agents for IBS: bal SymptomsAgents for IBS: bal Symptoms

95 % CI random95 % CI random

0. 010. 01Favors placebo Favors fiberFavors placebo Favors fiber

100100110. 10. 1 1010

Stimulant LaxativesMechanism

Stimulant LaxativesMechanism

• Anthraquinones(sennosides)

• Anthraquinones(sennosides)

Stimulanlaxative

Stimulanlaxative

( )

• Bisacodyl

( )

• Bisacodyl

• Castor oil

• Diphenylmethane

• Castor oil

• DiphenylmethaneDiphenylmethanederivativesDiphenylmethanederivatives

Locke GR III et al. Gastroenterology 2000; 119:1766

s: Classification and m of Actions: Classification and m of Action

• Absorption• Absorption

• Motility

• Prostaglandins

• Motility

• Prostaglandinsnt ent e ProstaglandinsProstaglandins

Stimulant LaxativesMechanism

Stimulant LaxativesMechanism

• Anthraquinones(sennosides)

• Anthraquinones(sennosides)

EE

• Bisacodyl• Bisacodyl

EE

Locke GR II et al. Gastroenterology 2000; 119:1766

s: Classification and m of Actions: Classification and m of Action

• Laxative is cleaved by

• Laxative is cleaved bycleaved by bacteriacleaved by bacteria

• Enteric nerves are stimulated

• Enteric nerves are stimulatedEnteric nervesEnteric nerves are stimulatedare stimulatedEnteric nervesEnteric nerves

Efficacy of StimEfficacy of Stim

• 4 randomized comparative tri• 4 randomized comparative trip–None placebo-controlled–Low-quality study design–No difference between stim

p–None placebo-controlled–Low-quality study design–No difference between stimNo difference between stimlaxative in stool frequency

• In 1 study

No difference between stimlaxative in stool frequency

• In 1 studyIn 1 study–Lactulose was superior to vs 42% were passing a no

In 1 study–Lactulose was superior to vs 42% were passing a no

• Insufficient evidence to makeregarding efficacy

• Insufficient evidence to makeregarding efficacy

Brandt LJ et al. Am J Gastroenterol 2005; 100:S5Brandt LJ et al. Am J Gastroenterol 2005; 100:S5

mulant Laxativesmulant Laxatives

ialsials

mulant laxative and controlmulant laxative and controlmulant laxative and control y or consistencymulant laxative and control y or consistency

the “irritant laxative:” 58% ormal stool by day 7

the “irritant laxative:” 58% ormal stool by day 7

e a recommendation e a recommendation

Osmotic LaxativeOsmotic Laxative

• Poorly absorbed mon• Poorly absorbed mon–Lactulose–Mannitol

S bit l

–Lactulose–Mannitol

S bit l–Sorbitol–Glycerin supposito–Sorbitol–Glycerin supposito

• Saline laxatives–Magnesium: citrate

Sodium and disodi

• Saline laxatives–Magnesium: citrate

Sodium and disodi–Sodium and disodi

• OtherP l h l l

–Sodium and disodi

• OtherP l h l l–Polyethylene glyco–Polyethylene glyco

es: Classificationes: Classification

o- and disaccharideso- and disaccharides

oriesories

e, sulphate, hydroxideum phosphate

e, sulphate, hydroxideum phosphateum phosphate

l (PEG)

um phosphate

l (PEG)ol (PEG)ol (PEG)

Osmotic Laxatives: MoOsmotic Laxatives: Mo

LaxativeLaxative

Bass P, Dennis S. J Clin Gastroenterol. 1981; 3 (Suppl 1):23Ramkumar D, Rao SS. Am J Gastroenterol. 2005; 100:936Bass P, Dennis S. J Clin Gastroenterol. 1981; 3 (Suppl 1):23Ramkumar D, Rao SS. Am J Gastroenterol. 2005; 100:936

ono- and Disaccharidesono- and Disaccharides

• Laxatives metabolized by bacteria . . .

• Laxatives metabolized by bacteria . . . yy

Osmotic Laxatives: MoOsmotic Laxatives: Mo

LaxativeLaxative

Bass P, Dennis S. J Clin Gastroenterol. 1981; 3 (Suppl 1):23Ramkumar D, Rao SS. Am J Gastroenterol. 2005; 100:936Bass P, Dennis S. J Clin Gastroenterol. 1981; 3 (Suppl 1):23Ramkumar D, Rao SS. Am J Gastroenterol. 2005; 100:936

ono- and Disaccharidesono- and Disaccharides

• Laxatives metabolized by bacteria . . .

• Laxatives metabolized by bacteria . . . yy

• . . . to short-chain fatty acids

• . . . to short-chain fatty acidsacids,acids,

• increasing the osmotic • increasing the osmotic load and changing the pHload and changing the pH

Effectiveness and SafeEffectiveness and Safe

Summary andSummary andSummary andStudies Recommendations

Summary andStudies Recommendations

3 RPCTs Improves stool frequency and

3 RPCTs Improves stool frequency andconsistencyconsistency

Brandt LJ et al. Am J Gastroenterol. 2005; 100(suppl 1):S5. Physicians’ Desk Reference 2005. Montvale, NJ. Thomson PDR; 2005Brandt LJ et al. Am J Gastroenterol. 2005; 100(suppl 1):S5. Physicians’ Desk Reference 2005. Montvale, NJ. Thomson PDR; 2005

RPCT = randomized placebo-controlled trialRPCT = randomized placebo-controlled trial

ety Profile of Lactuloseety Profile of Lactulose

Adverse PregnancyAdverse PregnancyAdverse Pregnancys Events Category

Adverse Pregnancys Events Category

Nausea BVomitingNausea BVomitingBloatingFlatulenceIntestinal cramps

BloatingFlatulenceIntestinal crampsIntestinal crampsIntestinal cramps

Osmotic LaxativesOsmotic Laxatives

CalciumCalcium PP

Water is incompletelyWater is incompletelyincompletelyabsorbedincompletelyabsorbed

s: Saline Laxativess: Saline Laxatives

PotassiumPotassium

Electrolyte loss

Electrolyte loss

CalciumCalciumPotassiumPotassium

lossloss

Net fluxNet fluxNet flux of water, which remains in

Net flux of water, which remains inremains in lumenremains in lumen

Effectiveness and SafeEffectiveness and Safe

Summary andSummary andSummary andStudies Recommendations

Summary andStudies Recommendations

5 RCTs Effective atimproving stool

5 RCTs Effective atimproving stoolfrequency andconsistencyfrequency andconsistency

RCTs = randomized controlled trialsRCTs = randomized controlled trials

Brandt LJ et al. Am J Gastroenterol. 2005; 100(suppl 1):S5.Tran LC et al. J Clin Gastroenterol. 2005; 39:600Physicians’ Desk Reference 2005. Montvale, NJ. Thomson PDR; 2005

Brandt LJ et al. Am J Gastroenterol. 2005; 100(suppl 1):S5.Tran LC et al. J Clin Gastroenterol. 2005; 39:600Physicians’ Desk Reference 2005. Montvale, NJ. Thomson PDR; 2005

ety Profile of PEG 3350ety Profile of PEG 3350

Adverse PregnancyAdverse PregnancyAdverse Pregnancys Events Category

Adverse Pregnancys Events Category

Nausea CBloatingNausea CBloatingCrampingCramping

Caution regarding Caution regarding g gelectrolyte

disturbances

g gelectrolyte

disturbances

Long-Term Effectivin Chronic C

Long-Term Effectivin Chronic C

Successful treatmSuccessful treatm

**6060

7070

**

4040

5050PEPEPlaPla

% ofpatients

% ofpatients *

2020

3030patientspatients *P<

00

1010

AllAll

Dipalma JA et al. Am J Gastroenterol. 2007; 102:1436Dipalma JA et al. Am J Gastroenterol. 2007; 102:1436

Alln=304

Alln=304

veness of PEG 3350 Constipationveness of PEG 3350 Constipation

ment after 6 monthsment after 6 months

**EGEGaceboacebo

<0.001

Eld lEld lElderlyn=75

Elderlyn=75

Chloride Channels inChloride Channels in

H OH O ClClH2OH2ONa+Na+

I TI T

CFTRchannelCFTR

channelEnterocytesEnterocytes

K+K+

Ion TIon T

N +N +KK

H2OH2O

Na+Na+

Na+Na+ 22Na+Na+

n Intestinal Transportn Intestinal Transport

Cl-Cl-l-l- ClCl

Tight junctionTight junction

T tT t

Cl C2channel

Cl C2channel

K+K+

TransportTransport

++ K+K+++

K+K+2Cl-2Cl-

Effects of LubiprosSpontaneous Bo

Effects of LubiprosSpontaneous Bo

77

55

66P = 0.0001P = 0.0001

24 µg l24 µg lMean SBMs

per week

Mean SBMs

per week 33

44

55

per weekper week

11

22

33

Intent-toIntent-to00

11

BaselineBaseline Week 1Week 1

SBM = spontaneous bowel movementsSBM = spontaneous bowel movementsJohanson JF et al. Am J Gastroenterol. 2008;103:170.Johanson JF et al. Am J Gastroenterol. 2008;103:170.

stone on Number of owel Movementsstone on Number of owel Movements

P = 0.0017P = 0.0017 P = 0.0002P = 0.0002 P = 0.0002P = 0.0002

lubiprostone bidlubiprostone bid

PlaceboPlacebo

n = 242n = 242

o-treat populationo-treat population

Week 2Week 2 Week 3Week 3 Week 4Week 4

LubiprostonData from 2 P

LubiprostonData from 2 P

50

%%Overall Overall

RespondersResponders

* P=0.001* P=0.001

17.917.925

RespondersResponders

Lubiprostone8 mcg bid

Lubiprostone8 mcg bid

0

Drossman DA et al. Gastroenterology 2007; 132:639f Drossman DA et al. Gastroenterology 2007; 132:639f

n=780n=780

ne for IBS-C:Phase III Trialsne for IBS-C:Phase III Trials

• 12- week treatment period• 12- week treatment period12 week treatment period• Overall responder=monthly responder

for at least 2 of 3 months• Monthly responder=at least moderate

12 week treatment period• Overall responder=monthly responder

for at least 2 of 3 months• Monthly responder=at least moderate

relief for 4/4 weeks or significant relief for 2/4 weeksrelief for 4/4 weeks or significant relief for 2/4 weeks

10.110.1

PlaceboPlacebo

n=387n=387

Effect of Linaclotide on Effect of Linaclotide on

4.54.5BaBaM + SEMM + SEM

3.53.5PoPo

Mean + SEMMean + SEM

1 51 5

2.52.5GC 48GC 48

0.50.5

1.51.5

00Placebo

n = 12Placebo

n = 12

*P=0.01 vs placeboGC 48 = geometric center at 48 hours*P=0.01 vs placeboGC 48 = geometric center at 48 hoursAndresen V et al. Gastroenterology 2007; 133:761Andresen V et al. Gastroenterology 2007; 133:761

Colonic Transit in IBS-CColonic Transit in IBS-C

**aselineaselineost treatmentost treatment

Linaclotide100 mgn = 12

Linaclotide100 mgn = 12

Linaclotide1000 mg

n = 12

Linaclotide1000 mg

n = 12

Graded TreatmGraded Treatm

• Multidisciplinary• Psychological tre• Multidisciplinary• Psychological trePsychological tre• Improve function

Psychological tre• Improve function

++• Manage stress• Pharmacotherapy• Manage stress• Pharmacotherapy

++• Diet, lifestyle advice• Positive diagnosis• Diet, lifestyle advice• Positive diagnosis

++Positive diagnosis

• Explain, reassurePositive diagnosis

• Explain, reassure

ment Responsement Response

y approacheatments

y approacheatmentseatmentsningeatmentsning

SSevere

M d tModerate

Mild