APPROACH TO THE PATIENT WITH CONSTIPATION

APPROACH TO THE PATIENT WITH CONSTIPATION

HERNOMO KUSUMOBROTO

Gastro-Hepatology CenterAirlangga University School of Medicine

Soetomo Hospital Surabaya

DEFINITIONDEFINITION

• Constipation is passage of small amounts of hard,dry bowel movements, usually fewer than three timesa week.

• People who are constipated may find it difficult andpainful to have a bowel movement.

• Other symptoms of constipation include feelingbloated, uncomfortable, and sluggish.

DEFINITIONDEFINITION

Constipation is a symptom rather than a disease and is the mostcommon digestive complaint in the United States.

A standard set of criteria has been suggested that includes at least 2of the following symptoms present for at least 3 months:

1. Hard stools2. Straining at defecation3. Sensation of incomplete evacuation at least 25% of the time4. Two or fewer bowel movements per week

EPIDEMIOLOGYEPIDEMIOLOGY

• In the US :- > 4 million people have frequent constipation,- a prevalence of about 2%.- estimated 2.5 million physician visits per year.

• Most patients with constipation can be treatedmedically, resulting in complete success orimprovement.

• However, a small percentage of patients are quitedebilitated as a result of constipation.

• Some patients with functional constipation (ie. colonicinertia) require total abdominal colectomy withileorectal anastomosis.

EPIDEMIOLOGYEPIDEMIOLOGY

Constipation• Affects people of color : whites = 1.3 : 1.• Male : female, approximately 1 : 3.• Can occur in all ages, from newborns to elderly

persons.• An age-related increase in the incidence of

constipation exists, with 30-40% of adults older than65 years citing constipation as a problem.

Age-specific increase in the prevalence of constipation in the US, by age and sex

Age-specific increase in the prevalence of constipation in the US, by age and sex

Men

Women

Men

Women

12 -

10 -

8 -

6 -

4 -

2 -

0 -0-44 45-64 65-74 75+

Age-

spec

ific

Prev

alen

ce (P

erce

nt)

4500 -

4000 -

3500 -

3000 -

2500 -

1500 -

1000 -

500 -

0- I I I I I I0-9 10-19 20-39 40-59 60-64 65+Ph

ysici

an vi

sits p

er 10

0,000

pop

ulat

ion60 -

50 -

40 -

30 -

20 -

10 -

0

AGE GROUP0-4 5-14 15-24 25-44 45-64 65-74 75+

U S AU S AENGLAND AND WALESENGLAND AND WALES

Phys

ician

Visi

ts P

er 10

0,000

Pat

ients

MALES FEMALES

Constipation Increases With Age And Is More Common In Women

Constipation Increases With Age And Is More Common In Women

PATHOPHYSIOLOGYPATHOPHYSIOLOGY

• The hard and dry stools of constipation occur when the colon absorbs too much water.

• This happens because the colon's muscle contractions are slow or sluggish, causing the stool to move through the colon too slowly

SEROTONIN (5-hydroxytryptamine = 5-HT)

5-HT is found in the enteric nervous system where it has been implicated in controlling gastrointestinal motor function.

A number of receptor or recognition sites has been identified in the gut, i.e. :

5-HT1, 5-HT2, 5-HT3 and 5-HT4

But recently most attention has focused on the 5-HT3 and 5-HT4.

SEROTONIN (5-hydroxytryptamine = 5-HT)

5-HT is found in the enteric nervous system where it has been implicated in controlling gastrointestinal motor function.

A number of receptor or recognition sites has been identified in the gut, i.e. :

5-HT1, 5-HT2, 5-HT3 and 5-HT4

But recently most attention has focused on the 5-HT3 and 5-HT4.

The functional role of the 5-HT3 receptor remains incompletely understood, but it is probably involved in the modulation of colonic motility and visceral pain in the gut.

A number of selective 5-HT3 antagonists have been developed including : ondansetron, granisetron, tropisetron, renzapride and zacopride.

While the substituted benzamide prokinetics (for example, metoclopramide and cisapride) also block 5-HT3 receptors in high concentration, their prokinetic action is believed to be on the basis of their agonist effects on the putative 5-HT4 receptors.

(Talley, 1992)(Talley, 1992)

5-HT3 and 5-HT45-HT3 and 5-HT4

• 5-HT3 modulation of colonic motilityand visceral pain in the gut.

• 5-HT4 stimulates motility throughout theGI tract, and has a key role in themodulation of visceral sensitivity.

95% of the Body’s 5-HT is Found in the GI Tract

CNS – 5%

– enterochromaffin cellsenterochromaffin cells– neuronalneuronal

GI tract – 95%

Gershon. Aliment Pharmacol Ther 1999;13(suppl 2):15–30

Present on enteric nerves and non-neuronal tissue (entero-chromaffin cells, enterocytes and smooth muscle cells)

– Stimulation (initiation)of the peristaltic reflex– Modulation of smooth muscle tone– Stimulation of intestinal CI-/H2O secretion– Modulation of visceral sensitivity/pain via direct

inhibition of spinal afferents.

Present on enteric nerves and non-neuronal tissue (entero-chromaffin cells, enterocytes and smooth muscle cells)

– Stimulation (initiation)of the peristaltic reflex– Modulation of smooth muscle tone– Stimulation of intestinal CI-/H2O secretion– Modulation of visceral sensitivity/pain via direct

inhibition of spinal afferents.

Distribution and Function of 5-HT4Receptors in the GI Tract

Distribution and Function of 5-HT4Receptors in the GI Tract

The enteric nervous system (ENS) and its connections with the CNSThe enteric nervous system (ENS) and its connections with the CNS

Spinal afferent fibre

Sympathetic preganglionic fibres

Sympathetic postganglionic fibres

Longitudinal muscle

Myenteric plexus

Circular muscle

Submucosa with submucosal plexus

Muscularis mucosae

Mucosa

Spinal cord Brain stemSpinal cord Brain stem

Afferent and efferent fibres of the vagus nerve

Afferent and efferent fibres of the vagus nerve

ENSENS

Interstitial cell of CajalInterstitial cell of Cajal

= 5-HT receptors

Extrinsic afferents (5HT3)

Motor response

ENS

Ach/VIP

Na+

Na+

K+ Cl-Cl-

Secretion

3

3

3 33

EC cells

Immune cells

3

Mucosal afferent Muscle mechanoreceptor

Intrinsic afferent (5HT4)

55--HTHT receptorreceptor--mediated effectsmediated effects

Grider JR et al. Gastroenterology 1998;115:370–380

5-HT

Excitatorymotor neuron(contraction)

5-HTreceptors

Inhibitorymotor neuron (relaxation)

Enterochromaffin cells

Interneurons

Sensoryneuron

Role of 5-HT in Motor Activity

Tegaserod Stimulates the Peristaltic Reflex Through Activation of Intrinsic Sensory Pathways

CGRP5-HT4receptor

Enterochromaffin cells5-HTTegaserod

Grider JR et al. Gastroenterology 1998;115:370–80

ACh/SPMotorneurons

VIP/PACAP/NOSMotor neurons

Tegaserod triggers the peristaltic reflex in human, rat and guinea pig intestine (MEC » 5nM)

Release ofCGRP, VIP, SP (MEC 10nM)

ETIOLOGYETIOLOGY

• A. Secondary constipation• (dietary, structural, endocrinopathy/• metabolic, neurologic, drugs, • collagen, psychologic)

• B. Functional constipation• (simple, IBS, idiopathic, weak pelvic• floor, chr. obstr., etc)

Secondary Causes of Functional Constipation1Secondary Causes of Functional Constipation1

Metabolic and Endocrine DisordersDiabetes mellitusHypothyroidismHypercalcemia, hypokalemiaPregnancyPorphyriaPanhypopituitarismPheochromocytomaGlucagonoma

Neurogenic DisordersPeripheralHirschsprung’s diseaseChagas’ diseaseNeurofibromatosisAutonomic neuropathyHypoganglionosisIntestinal pseudoobstruction (myopathy, neuropathy)

Secondary Causes of Functional Constipation2Secondary Causes of Functional Constipation2

CentralMultiple sclerosisSpinal cord lesionsParkinson’s diseaseShy-Drager syndromeTrauma to nervl erigentesCerebrovascular accidents

CollagenSystemic sclerosisAmyloidosisDermatomytositisMyotonic dystrophy

Drugs Associated With ConstipationDrugs Associated With ConstipationAnalgesicsAnticholinergics

AntispasmodicsAntidepressantsAntipsychoticsAntiparkinsonian drugs

Cation-Containing AgentsIron supplementsAluminum (antacids, sucralfate)Calcium (antacids, supplements)Barium sulfateMetallic intoxication (arsenic, lead, mercury)

Neutrally Active AgentsOplatesAntihypertensiveGanglionic blockersVinca alkaloidsAnticonvulsantsCalcium channel blockers

DIAGNOSISDIAGNOSIS

1. History2. Physical examination (RT)3. Lab studies4. Radiology (plain photo, Ba enema)5. Endoscopy (proctoscopy,

sigmoidoscopy, colonoscopy)

DefecationInfrequent stools (may relate to concept of “normal”)No urgeStools difficult to pass (small, or large, hard; much effort

needed)Ineffective strainingNeed to digitateSense of incomplete evacuationAnal or perineal painProlapse “comes down “ at the anusSoiling of clothes

Symptoms Associated With The Term Constipation

Symptoms Associated With The Term Constipation

AbdomenBloating (distention)Discomfort or pain, related or unrelated to defecation

GeneralBad taste in the mouthHeadacheNauseaMalaise

Symptoms Associated With The Term Constipation

Symptoms Associated With The Term Constipation

DIAGNOSISDIAGNOSIS

Other studies :1. Colonic transit study,2. Defecography,3. Manometry,4. Electromyography.

Algorithm for evaluating a patient a patient with severe constipation who has not responded to simple dietary measures

Algorithm for evaluating a patient a patient with severe constipation who has not responded to simple dietary measures

DEFINE COMPLAINT

INFREQUENT DEFECATION DEFECATORY STRAINING

Colonic Transit Time

ColonicInertia

OutletObstructionNormal

Normal Anorectal Manometry

PsychologicalProfile

Esophageal, gastric,and email intestinalstudies to evaluatefor gastrointestinalpseudoobstruction

DefecographyAnorectal Manometry

NormalAbnormalExpulsionPattern

AnatomicalAbnormalities

Hirschsprung’sDisease

TREATMENT TREATMENT

1. Lifestyle changes

2. Pharmacological treatment

3. Other treatment

LIFESTYLE CHANGESLIFESTYLE CHANGES

1. Dietary modification

2. Enough liquid

3. Exercise

Dietary ModificationDietary Modification

• The most common cause of constipation is a diet lowin fiber found in vegetables, fruits, and whole grainsand high in fats found in cheese, eggs, and meats.

• People who eat plenty of high-fiber foods are lesslikely to become constipated.

• A low-fiber diet also plays a key role in constipationamong older adults. They often lack interest in eatingand may choose fast foods low in fiber. In addition,loss of teeth may force older people to eat soft foodsthat are processed and low in fiber.

Dietary ModificationDietary Modification

• Fiber--soluble and insoluble--is the part of fruits,vegetables, and grains that the body cannot digest.

• Soluble fiber dissolves easily in water and takes on asoft, gel-like texture in the intestines.

• Insoluble fiber passes almost unchanged through theintestines. The bulk and soft texture of fiber helpprevent hard, dry stools that are difficult to pass.

Merchanisms By Which Dietary Unasorbed Carpohydrate May Increase Stool Bulk. Emg, Electromyograph.

(From Cumming, J. H 1999)

Merchanisms By Which Dietary Unasorbed Carpohydrate May Increase Stool Bulk. Emg, Electromyograph.

(From Cumming, J. H 1999)

Unabsorbed Carbohydrate

Large Bowel Microflora

Increase Bulk in Colon

Faster Transit

Increased stool bulk

Well Fermenied

Microbial Growth

Gas production

Poorly fermented

Physical properties maintained

Mechanical effectWater holding

Less water absorption Improved efficiency of bacterical growth

Nonstrach polysaccharides Ressistance starchFructo-olisaccheridesPolydextrose, lactuloseMucus

Food Sources of Dietary Fiber1Food Sources of Dietary Fiber1

Amount of Amount / 100 gServing (g) of Food

Breakfast CerealsAII-Bran 9.9 26.70Comflakes 2.8 11.00Rice Krisples 1.4 4.51Shredded Wheat 3.0 12.31Special K 1.7 5.41

BreadsWhile bread 0.8 2.71Whole wheat 2.4 8.51

FruitsApple 3.2 1.41Banana 5.9 1.71Peach 2.1 2.38Pear 3.1 2.41Strawberry 3.3 2.12

Food Sources of Dietary Fiber2Food Sources of Dietary Fiber2

Amount of Amount / 100 gServing (g) of Food

NutsBrazil 5.4 7.71Peanut 5.7 9.31Peanut butter 2.1 7.51

VegetalesBroccoli 5.6 4.11Cabbage 1.9 2.81Sauliflower 2.5 1.81Lettuce 0.8 1.51Carrot 3.7 3.20Baked beans 18.6 7.31Peas 11.3 6.31Tomato 3.0 1.41

Enough LiquidEnough Liquid

• Liquids like water and juice add fluid to the colon and bulkto stools, making bowel movements softer and easier topass.

• People who have problems with constipation should drinkenough of these liquids every day, about eight 8-ounceglasses.

• Other liquids, like coffee and soft drinks, that containcaffeine seem to have a dehydrating effect.

ExerciseExercise

• Lack of exercise can lead to constipation,although doctors do not know preciselywhy.

• For example, constipation often occurs afteran accident or during an illness when onemust stay in bed and cannot exercise.

PHARMACOLOGICALPHARMACOLOGICAL

• The mainstay of treatment is a high-fiber diet.• Bulking agents usually are the next line of treatment.• Enemas can be used to assist in complete stool

evacuation.• Avoid irritant or peristaltic stimulants (eg, senna).

Chronic use has been reported to induce damage tothe myenteric plexus, which may eventually impairbowel motility.

PHARMACOLOGICAL TREATMENT

PHARMACOLOGICAL TREATMENT

LaxativesBulk forming agents Emollients or softeners Emollient stool softeners in combination with stimulants Osmotic laxatives

Prokinetics Metoclopramide, Domperidone, cisapride, clebopridePrucaloprideTegaserod

Laxatives1Laxatives1

Type Of Laxative Usual Adult Onset Of Side EffectsDose Action

Bulk-Forming LaxativesNatural (psyllium) 7 g PO 12-72 h Impaction above stricturesSynthetic (methylcellulose) 4-6 g PO 12-72 h Fluid overload

Emollient LaxativesDucosate salts 50-500 mg PO 24-72 h Skin rashesMineral oil 15-45 mL PO 6-8 h Decreased absorption

of vitaminsLipid pneumoniaDecreased absorption

of Coumadin, oralcontraceptives

Hyperosmolar LaxativesPolyethylene glycol 3-22 L PO 1 h Abdominal bloatingLactulose 15-60 mL PO 24-48 h Abdominal bloatingSorbitol 120 mL of 25% solution PO 24-48 h Abdominal bloatingGlycerine 3 g suppository 15-60 min Rectal iritation

5-15 mL enema 15-30 min Rectal iritation

Laxatives2Laxatives2

Type Of Laxative Usual Adult Onset Of Side EffectsDose Action

Saline LaxativesMagnesium sulfate 15 g PO 0.5-3 h Magnesium toxicity

(with renal insufficiency)Magnesium phosphate 10 gm PO 0.5-3 hMagnesium citrate 200 mL PO 0.5-3 h

Stimulant LaxativesCastor oil 15-60 mL PO 2-6 h Nutrient malabsorptionDiphenylmethanes

Phenolphthalein 60-100 mg PO 6-8 h Skin rashesBisacodyl 30 mg PO 6-10 h Gastric iritation

10 mg PR 0.25-1 h Rectal stimulationAnthraquinones

Cascara sagrada 1 mL PO 6-12 h Melanosis coliSenna 2 mL PO 6-12 h Degeneration ofAloe (casanthrol) 250 mg PO 6-12 h Meissner’s and Auerbach’s plexusesDanthron 75-150 mg PO 6-12 h Hepatotoxicity (with docusate)

Sekas G. The use and abuse of laxatives. Pract Gastroenterol 1987;11:33.

PROKINETICSPROKINETICS

Prokinetics (Metoclopramide, Dompeidone, Cisapride):- 5-HT3 antagonist and 5-HT4 agonist- improvement in patients with chronic constipation

Tegaserod :- partial 5-HT4 agonist- accelerates oro-caecal transit - without effect on gastric emptying

Prucalopride :- full 5-HT4 agonist - accelerates gastric, small bowel, and colonic transit

Cisapride Metoclopramide Erythromycin BethanecholCisapride Metoclopramide Erythromycin BethanecholHyman, 1996Hyman, 1996

ACTIVITY OF PROKINETIC DRUGS IN THE BRAIN AND THE GI TRACT

Tegaserod:

Cisapride:5-HT4 receptor binding (KB 59nM, human)

5-HT4 agonist (FS-GPI: EC50 79nM)

5-HT3 receptor antagonist (KB 135nM)

D2 antagonist (KB 300nM)

QT prolongation (EC50 @ 10nM)

5-HT4 receptor binding (KB 18nM)

5-HT4 agonist (FS-GPI: EC50 12nM)(partial agonism)(peristalsis: EC50 3–8nM)

5-HT3 receptor binding (KB 7,200nM)

No QT prolongation (Cmax 10,000nM)

Pharmacological Profile

F

O

O

N

N

NH2H

OO

CI

NH

N NH

ONH

NH

Tegaserod Stimulates Postprandial GI Motility

Stimulation of motor activity throughout the GI tractThe upper GI tract is more susceptible to tegaserod30

25

20

15

10

5

0

Mot

ility

inde

x (g

.min

/hou

r)

Antrum Duodenum Jejunum Colon

Control0.03mg/kg i.v.0.1mg/kg i.v.0.3mg/kg i.v.

Fioramonti J et al. Gastroenterology 1998;114(4):A752:G3103

Res

pons

e (%

)Tegaserod Improves Abdominal Pain and

Discomfort

DSGA of Abdominal Pain/Discomfort*p<0.05; +p=0.06 (12mg/day vs placebo)

*40

30

20

10

0Month 1 Month 2 Month 3

*

Month 1 Month 2 Month 3

*

40

30

20

10

0R

espo

nse

(%)

B301 B351

Tegaserod 12mg/day Placebo

+

Schmitt C et al. Gut 1999;45(Suppl. V):A258:P0960Müller-Lissner S et al. Gastroenterology 2000;118(4):A175:1000

Change in abdominal pain scores

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0.0

1 2 3 4 5 6 7 8 9 10 11 12

WD

1

WD

2

WD

3

WD

4

Week

Mea

n ch

ange

from

bas

elin

e

12 mg/d

†

†

†

†

† † ††

† ††

†P < .05 versus placebo

† † † †

ZAP (ZAP (ZZelmac in elmac in AAsia sia PPacific)acific)

Placebo

Change in abdominal pain scores

Change in number of bowel movements

0.0

0.5

1.0

1.5

2.0

2.5

3.0

1 2 3 4 5 6 7 8 9 10 11 12

WD

1

WD

2

WD

3

WD

4

Week

Mea

n ch

ange

from

bas

elin

e

†P < .05 versus placebo

†

†

† †

†

ZAP (ZAP (ZZelmac in elmac in AAsia sia PPacific)acific)

Placebo 12 mg/d

Adverse Events: Tegaserod Similar to Placebo

0

10

20

30 Tegaserod 12mg/day (n=560)Placebo (n=837)

Patie

nts

repo

rtin

g A

E (%

)

Headache Abdominal Diarrhea Nausea Flatulence Back painpain

Whorwell P et al. Gut 1999;45(Suppl. V):A260:P0966

OTHER TREATMENTOTHER TREATMENT

In chronic constipation caused by anorectal dysfunction can usebiofeedback to retrain the muscles that control release of bowelmovements. Biofeedback involves using a sensor to monitormuscle activity that at the same time can be displayed on acomputer screen allowing for an accurate assessment of bodyfunctions. A health care professional uses this information tohelp the patient learn how to use these muscles.

Surgical removal of the colon may be an option for people withsevere symptoms caused by colonic inertia. However, thebenefits of this surgery must be weighed against possiblecomplications, which include abdominal pain and diarrhea.

ComplicationsComplications

• Anal fissures• Fecal impaction• Bowel obstruction• Fecal incontinence• Stercoral ulceration• Megacolon• Volvulus• Rectal prolapse• Urinary retention• Syncope

PROGNOSISPROGNOSIS

Most active patients do well with medicalmanagement.

Constipation is an ongoing problem forpatients who are bedridden or otherwisedebilitated.

Colectomy usually is reserved for patientswith slow transit constipation who fail torespond to 6 months of medical managementwith good patient compliance.

Patient EducationPatient Education

Listening to patients' concepts of normal bowelactivity is important.

Instituting a behavior modification program allowspatients to become more aware of and responsive tonormal urges to defecate.

Emphasize the importance of a high-fiber diet.Emphasize adequate fluid intake.Emphasize regular exercise.

Surabaya, 8 February 2003