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
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