617
C HAP T E R
38
KEY CONCEPTS
 Diarrhea is caused by many viral and bacterial organisms. It is
most often a minor discomfort, not life-threatening, and it is
usually self-limited.
 The four pathophysiologic mechanisms of diarrhea have been
linked to the four broad diarrheal groups, which are secretory,
osmotic, exudative, and altered intestinal transit. The three
mechanisms by which absorption occurs from the intestines
are active transport, diffusion, and solvent drag.
 Management of diarrhea focuses on preventing excessive wa-
ter and electrolyte losses, dietary care, relieving symptoms,
treating curable causes, and treating secondary disorders.
 Bismuth subsalicylate is marketed for indigestion, relieving ab-
dominal cramps, and controlling diarrhea, including traveler’s
diarrhea, but may cause interactions with several components
if given excessively.
 Underlying causes of constipation should be identified when
possible and corrective measures taken (e.g., alteration of diet
or treatment of diseases such as hypothyroidism).
 The foundation of treatment of constipation is dietary fiber or
bulk-forming laxatives that provide 10 to 15 g/day of raw fiber.
 Irritable bowel syndrome (IBS) is one of the most common
gastrointestinal disorders. It is characterized by lower abdomi-
nal pain, disturbed defecation, and bloating. Many nongas-
trointestinal manifestations also exist with IBS. Recent studies
have found that visceral hypersensitivity is a major culprit in the
pathophysiology of the disease.
Diarrhea-predominant IBS should be managed by dietary mod-
ification and when diet changes alone are insufficient to pro-
mote control of symptoms, by drugs such as loperamide.
Several drug classes are involved in the treatment of the pain The epidemiology of diarrhea varies in developed versus developing
associated with IBS, including tricyclic compounds and the gut-
selective calcium channel blockers.
DIARRHEA
Diarrhea is a troublesome discomfort that affects most individuals
in the United States at some point in their lives and can be thought
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Diarrhea, Constipation, and
Irritable Bowel Syndrome
WILLIAM J. SPRUILL AND WILLIAM E. WADE
of as both a symptom and a sign. Usually diarrheal episodes begin
abruptly and subside within 1 or 2 days without treatment. This
chapter focuses primarily on noninfectious diarrhea, with only
minor reference to infectious diarrhea (see Chap. 117 for a discus-
sion of gastrointestinal infections). Diarrhea is often a symptom of
a systemic disease and not all possible causes of diarrhea are
discussed in this chapter. Acute diarrhea is commonly defined as
<14 days’ duration, persistent diarrhea as more than 14 days’
duration, and chronic diarrhea as more than 30 days’ duration.
To understand diarrhea, one must have a reasonable definition of
the condition; unfortunately, the literature is extremely variable on
this. Simply put, diarrhea is an increased frequency and decreased
consistency of fecal discharge as compared to an individual’s normal
bowel pattern. Frequency and consistency are variable within and
between individuals. For example, some individuals defecate as often
as three times per day, whereas others defecate only two or three times
per week. A Western diet usually produces a daily stool weighing
between 100 and 300 g, depending on the amount of nonabsorbable
materials (mainly carbohydrates) consumed. Patients with serious
diarrhea may have a daily stool weight in excess of 300 g; however, a
subset of patients experience frequent small, watery passages. Addi-
tionally, vegetable fiber-rich diets, such as those consumed in some
Eastern cultures, such as those in Africa, produce stools weighing
more than 300 g/day.
Diarrhea may be associated with a specific disease of the intestines
or secondary to a disease outside the intestines. For instance, bacillary
dysentery directly affects the gut, whereas diabetes mellitus causes
neuropathic diarrheal episodes. Furthermore, diarrhea can be consid-
ered as acute or chronic disease. Infectious diarrhea is often acute;
diabetic diarrhea is chronic. Congenital disorders in gastrointestinal
ion-transport mechanisms are another cause of chronic diarrhea.1
Whether acute or chronic, diarrhea has the same pathophysiologic
causes that help identification of specific treatments.
EPIDEMIOLOGY
countries.2,3 In the United States, diarrheal illnesses are usually not
reported to the Centers for Disease Control and Prevention (CDC)
unless associated with an outbreak or an unusual organism or
condition. For example, the acquired immune deficiency syndrome
(AIDS) has been identified with protracted diarrheal illness. Diar-
rhea is a major problem in daycare centers and nursing homes,
probably because early childhood and senescence plus environ-
mental conditions are risk factors. Although an exact epidemio-
logic profile in the United States is not available through the CDC
or published literature, chronic diarrhea affects approximately 5%
of the adult population and ranges from 3% to 20% in children
worldwide.4 In developing countries, diarrhea is a leading cause of
illness and death in children, creating a tremendous economic strain
on healthcare costs.
 618
 Most cases of acute diarrhea are caused by infections with
viruses, bacteria, or protozoa and are generally self-limited.5 Although
SECTION 4
viruses are more commonly associated with acute gastroenteritis,
bacteria are responsible for more cases of acute diarrhea.6
Evaluation of a noninfectious cause is considered if diarrhea
persists and no infectious organism can be identified, or if the patient
falls into a high-risk category for metabolic complications with
persistent diarrhea. Common causative bacterial organisms include
Shigella, Salmonella, Campylobacter, Staphylococcus, and Escherichia
coli. Food-borne bacterial infection is a major concern, as several
Gastrointestinal Disorders
major food poisoning episodes have occurred that were traced to
poor sanitary conditions in meat-processing plants. Acute viral infec-
tions are attributed mostly to the Norwalk and rotavirus groups.
PHYSIOLOGY
In the fasting state, 9 L of fluid enters the proximal small intestine each
day. Of this fluid, 2 L are ingested through diet, while the remainder
consists of internal secretions. Because of meal content, duodenal
chyme is usually hypertonic. When chyme reaches the ileum, the
osmolality adjusts to that of plasma, with most dietary fat, carbohy-
drate, and protein being absorbed. The volume of ileal chyme decreases
to about 1 L/day upon entering the colon, which is further reduced by
colonic absorption to 100 mL daily. If the small intestine water
absorption capacity is exceeded, chyme overloads the colon, resulting
in diarrhea. In humans, the colon absorptive capacity is about 5 L daily.
Colonic fluid transport is critical to water and electrolyte balance.
Absorption from the intestines back into the blood occurs by three
mechanisms: active transport, diffusion, and solvent drag. Active
transport and diffusion are the mechanisms of sodium transport.
Because of the high luminal sodium concentration (142 mEq/L),
sodium diffuses from the sodium-rich gut into epithelial cells, where
it is actively pumped into the blood and exchanged with chloride to
maintain an isoelectric condition across the epithelial membrane.
Hydrogen ions are transported by an indirect mechanism in the
upper small intestine. As sodium is absorbed, hydrogen ions are
secreted into the gut. Hydrogen ions then combine with bicarbonate
ions to form carbonic acid, which then dissociates into carbon
dioxide and water. Carbon dioxide readily diffuses into the blood for
expiration through the lung. The water remains in the chyme.
Paracellular pathways are major routes of ion movement. As ions,
monosaccharides, and amino acids are actively transported, an
osmotic pressure is created, drawing water and electrolytes across the
intestinal wall. This pathway accounts for significant amounts of ion
transport, especially sodium. Sodium plays an important role in
stimulating glucose absorption. Glucose and amino acids are actively
transported into the blood via a sodium dependent cotransport mech-
anism. Cotransport absorption mechanisms of glucose-sodium and
amino acid-sodium are extremely important for treating diarrhea.
Gut motility influences absorption and secretion. The amount of
time in which luminal content is in contact with the epithelium is
under neural and hormonal control. Neurohormonal substances,
such as angiotensin, vasopressin, glucocorticoid, aldosterone, and
neurotransmitters also regulate ion transport.
PATHOPHYSIOLOGY
 Four general pathophysiologic mechanisms disrupt water and
electrolyte balance, leading to diarrhea, and are the basis of diagno-
sis and therapy. These are (a) a change in active ion transport by
either decreased sodium absorption or increased chloride secretion;
(b) change in intestinal motility; (c) increase in luminal osmolarity;
and (d) increase in tissue hydrostatic pressure. These mechanisms
have been related to four broad clinical diarrheal groups: secretory,
osmotic, exudative, and altered intestinal transit.
Secretory diarrhea occurs when a stimulating substance either
increases secretion or decreases absorption of large amounts of water
and electrolytes. Substances that cause excess secretion include
vasoactive intestinal peptide (VIP) from a pancreatic tumor, unab-
sorbed dietary fat in steatorrhea, laxatives, hormones (such as secre-
tion), bacterial toxins, and excessive bile salts. Many of these agents
stimulate intracellular cyclic adenosine monophosphate and inhibit
Na+/K+-adenosine triphosphatase (ATPase), leading to increased
secretion. Also, many of these mediators inhibit ion absorption
simultaneously. Clinically, secretory diarrhea is recognized by large
stool volumes (>1 L/day) with normal ionic contents and osmolality
approximately equal to plasma. Fasting does not alter the stool
volume in these patients.
Poorly absorbed substances retain intestinal fluids, resulting in
osmotic diarrhea. This process occurs with malabsorption syn-
dromes, lactose intolerance, administration of divalent ions (e.g.,
magnesium-containing antacids), or consumption of poorly soluble
carbohydrate (e.g., lactulose). As a poorly soluble solute is trans-
ported, the gut adjusts the osmolality to that of plasma; in so doing,
water and electrolytes flux into the lumen. Clinically, osmotic diar-
rhea is distinguishable from other types, as it ceases if the patient
resorts to a fasting state.
Inflammatory diseases of the gastrointestinal tract discharge
mucus, serum proteins, and blood into the gut. Sometimes bowel
movements consist only of mucus, exudate, and blood. Exudative
diarrhea affects other absorptive, secretory, or motility functions to
account for the large stool volume associated with this disorder.
Altered intestinal motility produces diarrhea by three mecha-
nisms: reduction of contact time in the small intestine, premature
emptying of the colon, and bacterial overgrowth. Chyme must be
exposed to intestinal epithelium for a sufficient time period to enable
normal absorption and secretion processes to occur. If this contact
time decreases, diarrhea results. Intestinal resection or bypass sur-
gery and drugs (such as metoclopramide) cause this type of diarrhea.
On the other hand, an increased time of exposure allows fecal
bacteria overgrowth. A characteristic small intestine diarrheal pat-
tern is rapid, small, coupling bursts of waves. These waves are
inefficient, do not allow absorption, and rapidly dump chyme into
the colon. Once in the colon, chyme exceeds the colonic capability to
absorb water.
Etiologic Examination of the Stool
Stool characteristics are important in assessing the etiology of
diarrhea. A description of the frequency, volume, consistency, and
color provides diagnostic clues. For instance, diarrhea starting in the
small intestine produces a copious, watery or fatty (greasy), and
foul-smelling stool; contains undigested food particles; and is usu-
ally free from gross blood. Colonic diarrhea appears as small, pasty,
and sometimes bloody or mucoid movements. Rectal tenesmus
with flatus accompanies large intestinal diarrhea.
CLINICAL PRESENTATION
Table 38–1 outlines the clinical presentation of diarrhea and Table
38–2 shows common drug-induced causes of diarrhea. A medication
history is extremely important in identifying drug-induced diarrhea.
Many agents, including antibiotics and other drugs, cause diarrhea
or, less commonly, pseudomembranous colitis. Self-inflicted laxative
abuse for weight loss is popular.
Most acute diarrhea is self-limiting, subsiding within 72 hours.
However, infants, young children, the elderly, and debilitated
persons are at risk for morbid and mortal events in prolonged or
voluminous diarrhea. These groups are at risk for water, electro-
lyte, and acid–base disturbances, and potentially cardiovascular
collapse and death. The prognosis for chronic diarrhea depends on
 619

TABLE 38-1 Clinical Presentation of Diarrhea TABLE 38-2 Drugs Causing Diarrhea

CHAPTER 38
General Laxatives
• Usually, acute diarrheal episodes subside within 72 hours of onset, whereas Antacids containing magnesium
chronic diarrhea involves frequent attacks over extended time periods. Antineoplastics
Signs and symptoms Auranofin (gold salt)
• Abrupt onset of nausea, vomiting, abdominal pain, headache, fever, chills, and Antibiotics
malaise. Clindamycin
• Bowel movements are frequent and never bloody, and diarrhea lasts 12 to 60 Tetracyclines
hours. Sulfonamides
• Intermittent periumbilical or lower right quadrant pain with cramps and Any broad-spectrum antibiotic

Diarrhea, Constipation, and Irritable Bowel Syndrome

audible bowel sounds is characteristic of small intestinal disease.
• When pain is present in large intestinal diarrhea, it is a gripping, aching
sensation with tenesmus (straining, ineffective, and painful stooling). Pain
localizes to the hypogastric region, right or left lower quadrant, or sacral region.
• In chronic diarrhea, a history of previous bouts, weight loss, anorexia, and
chronic weakness are important findings.
Physical examination
• Typically demonstrates hyperperistalsis with borborygmi and generalized or
local tenderness.
Laboratory tests
• Stool analysis studies include examination for microorganisms, blood, mucus,
fat, osmolality, pH, electrolyte and mineral concentration, and cultures.
• Stool test kits are useful for detecting gastrointestinal viruses, particularly
rotavirus.
• Antibody serologic testing shows rising titers over a 3- to 6-day period, but this
test is not practical and is nonspecific.
• Occasionally, total daily stool volume is also determined.
• Direct endoscopic visualization and biopsy of the colon may be undertaken to
assess for the presence of conditions such as colitis or cancer.
• Radiographic studies are helpful in neoplastic and inflammatory conditions.
the cause; for example, diarrhea secondary to diabetes mellitus
waxes and wanes throughout life.
TREATMENT
Diarrhea
■ PREVENTION
Acute viral diarrheal illness often occurs in daycare centers and
nursing homes. As person-to-person contact is the mechanism by
which viral disease spreads, isolation techniques must be initiated,
For bacterial, parasite, and protozoal infections, strict food han-
dling, sanitation, water, and other environmental hygiene practices
can prevent transmission. If diarrhea is secondary to another illness,
controlling the primary condition is necessary. Antibiotics and
bismuth subsalicylate are advocated to prevent traveler’s diarrhea,
in conjunction with treatment of drinking water and caution with
consumption of fresh vegetables.
■ DESIRED OUTCOME
 If prevention is unsuccessful and diarrhea occurs, therapeutic
goals are to (a) manage the diet; (b) prevent excessive water,
electrolyte, and acid–base disturbances; (c) provide symptomatic
relief; (d) treat curable causes; and (e) manage secondary disorders
causing diarrhea (Figs. 38–1 and 38–2).
Clinicians must clearly understand that diarrhea, like a cough,
may be a body defense mechanism for ridding itself of harmful
substances or pathogens. The correct therapeutic response is not
necessarily to stop diarrhea at all costs.
■ NONPHARMACOLOGIC MANAGEMENT
Dietary management is a first priority in the treatment of diarrhea.
Most clinicians recommend discontinuing consumption of solid
Antihypertensives
Reserpine
Guanethidine
Methyldopa
Guanabenz
Guanadrel
Angiotensin-converting enzyme inhibitors
Cholinergics
Bethanechol
Neostigmine
Cardiac agents
Quinidine
Digitalis
Digoxin
Nonsteroidal antiinflammatory drugs
Misoprostol
Colchicine
Proton pump inhibitors
H2-receptor blockers
foods and dairy products for 24 hours. However, fasting is of ques-
tionable value, as this treatment modality has not been extensively
studied. In osmotic diarrhea, these maneuvers control the problem. If
the mechanism is secretory, diarrhea persists. For patients who are
experiencing nausea and/or vomiting, a mild, digestible, low-residue
diet should be administered for 24 hours. If vomiting is present and
uncontrollable with antiemetics (see Chap. 37), nothing is taken by
mouth. As bowel movements decrease, a bland diet is begun.
Feeding should continue in children with acute bacterial diar-
rhea. Fed children have less morbidity and mortality, whether or not
they receive oral rehydration fluids. Studies are not available in the
elderly or in other high-risk groups to determine the value of
continued feeding in bacterial diarrhea.
Water and Electrolytes
Rehydration and maintenance of water and electrolytes are primary
treatment goals until the diarrheal episode ends. If the patient is
volume depleted, rehydration should be directed at replacing water
and electrolytes to normal body composition. Then water and
electrolyte composition are maintained by replacing losses. Many
patients will not develop volume depletion and therefore will only
require maintenance fluid and electrolyte therapy. Parenteral and
enteral routes may be used for supplying water and electrolytes. If
vomiting and dehydration are not severe, enteral feeding is the less
costly and preferred method. In the United States, many commer-
cial oral rehydration preparations are available (Table 38–3).
Because of concerns about hypernatremia, physicians continue to
hospitalize patients and intravenously correct fluid and electrolyte
deficits in severe dehydration. Oral solutions are strongly recom-
mended.7,8 In developing countries, the World Health Organization
Oral Rehydration Solution (WHO-ORS) saves the lives of millions
of children annually.
During diarrhea, the small intestine retains its ability to actively
transport monosaccharides such as glucose. Glucose actively carries
sodium with water and other electrolytes. Because the WHO-ORS
has a high sodium concentration, physicians have been reluctant to
 620

Diarrhea
SECTION 4

History and physical

examination

Acute diarrhea Chronic diarrhea

( <3 days) ( >14 days)
Gastrointestinal Disorders

Go to Fig. 38–2
No fever or systemic Fever or systemic
symptoms symptoms

Symptomatic therapy Check feces for WBC/RBC/

a. Fluid/electrolyte ova and parasites
replacement
b. Loperamide,
diphenoxylate, Negative Positive
or absorbent
c. Diet
Symptomatic therapy Use appropriate antibiotic
and symptomatic therapy

FIGURE 38-1. Recommendations for treating acute diarrhea. Follow these steps: (a) Perform a complete history
and physical examination. (b) Is the diarrhea acute or chronic? If chronic diarrhea, go to Fig. 38–2. (c) If acute
diarrhea, check for fever and/or systemic signs and symptoms (i.e., toxic patient). If systemic illness (fever, anorexia,
or volume depletion), check for an infectious source. If positive for infectious diarrhea, use appropriate antibiotic/
anthelmintic drug and symptomatic therapy. If negative for infectious cause, use only symptomatic treatment. (d) If
no systemic findings, then use symptomatic therapy based on severity of volume depletion, oral or parenteral fluid/
electrolytes, antidiarrheal agents (see Table 38–4), and diet. (RBC, red blood cells; WBC, white blood cells.)

use it in well-nourished children. Yet controlled comparative studies
describe more favorable results with the WHO-ORS than with
parenteral fluids.9 The recommended WHO-ORS (see Table 38–3)
has now been reformulated to have a lower osmolarity, sodium
content, and glucose load. Rice-based oral solution is also a hypos-
motically active substrate that elutes glucose without increasing stool
or urine outflows. Rehydration of infants with acute diarrhea using a
rice-based solution is effective.9 Decreased stool output and greater
absorption and retention of fluid and electrolytes also results. In
summary, oral rehydration solution is a lifesaving treatment for
millions afflicted in developing countries. Acceptance in developed
countries is less enthusiastic; however, the advantage of this product
in reducing hospitalizations may prove its use as a cost-effective
alternative, saving millions of dollars in healthcare expenditures.
■ PHARMACOLOGIC THERAPY
Various drugs have been used to treat diarrheal attacks (Table 38–4).
These drugs are grouped into several categories: antimotility, adsor-
bents, antisecretory compounds, antibiotics, enzymes, and intestinal
microflora. Usually these drugs are not curative but palliative.
Opiates and Their Derivatives
Opiates and opioid derivatives (a) delay the transit of intraluminal
contents or (b) increase gut capacity, prolonging contact and
absorption. Enkephalins, which are endogenous opioid substances,
regulate fluid movement across the mucosa by stimulating absorp-
tive processes. Limitations to the use of opiates include an addiction
potential (a real concern with long-term use) and worsening of
diarrhea in selected infectious diarrhea.
Most opiates act through peripheral and central mechanisms
with the exception of loperamide, which acts only peripherally.
Loperamide is antisecretory; it inhibits the calcium-binding protein
calmodulin, controlling chloride secretion. Loperamide, available as
2-mg capsules or 1 mg/5 mL solution (both are nonprescription
products), is suggested for managing acute and chronic diarrhea.
The usual adult dose is initially 4 mg orally, followed by 2 mg after
each loose stool, up to 16 mg/day. Used correctly, this agent has rare
side effects, such as dizziness and constipation. If the diarrhea is
concurrent with a high fever or bloody stool, the patient should be
referred to a physician. Also, diarrhea lasting 48 hours beyond
initiating loperamide warrants medical attention. Loperamide can
also be used in traveler’s diarrhea. It is comparable to bismuth
subsalicylate for treatment of this disorder.10
Diphenoxylate is available as a 2.5-mg tablet and as a 2.5 mg/5mL
solution. A small amount of atropine (0.025 mg) is included in the
product to discourage abuse. In adults, when taken as 2.5 to 5 mg
three or four times daily, not to exceed a 20-mg total daily dose,
diphenoxylate is rarely toxic. Some patients may complain of
atropinism (blurred vision, dry mouth, and urinary hesitancy). Like
loperamide, it should not be used in patients who are at risk of
bacterial enteritis with E. coli, Shigella, or Salmonella.
Difenoxin, a diphenoxylate derivative also chemically related to
meperidine, is also combined with atropine and has the same uses,
precautions, and side effects. Marketed as a 1-mg tablet, the adult
dosage is 2 mg initially, followed by 1 mg after each loose stool, not
to exceed 8 mg/day.
Paregoric, tincture of opium, is marketed as a 2 mg/5 mL solution
and is indicated for managing both acute and chronic diarrhea. It is
not widely prescribed today because of its abuse potential.
Adsorbents
Adsorbents are used for symptomatic relief. These products, many
not requiring a prescription, are nontoxic, but their effectiveness
remains unproven. Adsorbents are nonspecific in their action; they
adsorb nutrients, toxins, drugs, and digestive juices. Polycarbophil
absorbs 60 times its weight in water and can be used to treat both
diarrhea and constipation. It is a nonprescription product and is
 621
marketed for indigestion, relieving abdominal cramps, and control-
Chronic diarrhea ling diarrhea, including traveler’s diarrhea. Bismuth subsalicylate

CHAPTER 38
dosage strengths are a 262-mg chewable tablet, 262 mg/5 mL liquid,
Lasting >14 days
and 524 mg/15 mL liquid. The usual adult dose is 2 tablets or 30 mL
every 30 minutes to 1 hour up to 8 doses per day.
Possible causes: History and
a. Intestinal infection physical examination  Bismuth subsalicylate contains multiple components that might
b. Inflammatory bowel be toxic if given excessively to prevent or treat diarrhea. For instance,
disease
c. Malabsorption an active ingredient is salicylate, which may interact with anticoagu-
d. Secretory hormonal lants or may produce salicylism (tinnitus, nausea, and vomiting).
tumor
e. Drug, factitious
Bismuth reduces tetracycline absorption and may interfere with select

Diarrhea, Constipation, and Irritable Bowel Syndrome

f. Motility disturbance gastrointestinal radiographic studies. Patients may complain of a
darkening of the tongue and stools with repeat administration.
Select appropriate Salicylate can induce gout attacks in susceptible individuals.
diagnostic studies
For example, Bismuth subsalicylate suspension has been evaluated in the treat-
a. Stool culture/ova/ ment of secretory diarrhea of infectious etiology as well. In a dose of
parasites/WBC/RBC/
fat
30 mL every 30 minutes for 8 doses, unformed stools decrease in the
b. Sigmoidoscopy first 24 hours. Bismuth subsalicylate may also be effective in pre-
c. Intestinal biopsy
venting traveler’s diarrhea.
Octreotide, a synthetic octapeptide analog of endogenous soma-
No diagnosis, Diagnosis
tostatin, is proven effective for the symptomatic treatment of carcinoid
symptomatic therapy a. Treat specific cause tumors and other peptide-secreting tumors, dumping syndrome, and
a. Replete hydration
b. Discontinue potential
chemotherapy-induced diarrhea.11 It has had limited success in
drug inducer patients with AIDS-associated diarrhea and short-bowel syndrome,
c. Adjust diet does not appear to have an advantage over various opiate derivatives
d. Loperamide or
absorbent in the treatment of chronic idiopathic diarrhea, and has the disadvan-
tage of being administered by injection.12 Metastatic intestinal carci-
FIGURE 38-2. Recommendations for treating chronic diarrhea. Follow noid tumors secrete excessive amounts of vasoactive substances,
these steps: (a) Perform a careful history and physical examination. (b) The including histamine, bradykinin, serotonin, and prostaglandins. Pri-
possible causes of chronic diarrhea are many. These can be classified into mary carcinoid tumors occur throughout the gastrointestinal tract,
intestinal infections (bacterial or protozoal), inflammatory disease (Crohn’s with most in the ileum. Predominant signs and symptoms experienced
disease or ulcerative colitis), malabsorption (lactose intolerance), secretory by patients with these tumors are attributable to excessive concentra-
hormonal tumor (intestinal carcinoid tumor or vasoactive intestinal peptide- tions of 5-hydroxytryptophan and serotonin. The totality of their
secreting tumor [VIPoma]), drug (antacid), factitious (laxative abuse), or clinical effects is termed the carcinoid syndrome. Paroxysmal vasomo-
motility disturbance (diabetes mellitus, irritable bowel syndrome, or hyper-
tor attacks characterize carcinoid syndrome, most notably sudden red
thyroidism). (c) If the diagnosis is uncertain, selected appropriate diagnostic
studies should be ordered. (d) Once diagnosed, treatment is planned for
to purple flushing of the face and neck. These attacks are often caused
the underlying cause with symptomatic antidiarrheal therapy. (e) If no by emotional outbursts or by ingestion of food or alcohol. Some
specific cause can be identified, symptomatic therapy is prescribed. (RBC, patients have a violent, watery diarrhea with abdominal cramping.
red blood cells; WBC, white blood cells.) Initially, diarrhea might be managed with various agents such as
codeine, diphenoxylate, cyproheptadine, methysergide, phenoxyben-
zamine, or methyldopa. But octreotide has more recently been consid-
sold as a 500-mg chewable tablet. This hydrophilic nonabsorbable
ered first-line therapy.
product is safe and may be taken four times daily, up to 6 g/day in
Octreotide blocks the release of serotonin and many other active
adults. See Table 38–4 for selected antidiarrheal preparations.
peptides, and has been effective in controlling diarrhea and flushing. It
is reported to have direct inhibitory effects on intestinal secretion and
Antisecretory Agents stimulatory effects on intestinal absorption. Non–gastrin-secreting
Bismuth subsalicylate appears to have antisecretory, antiinflamma- adenomas of the pancreas are tumors associated with profuse watery
tory, and antibacterial effects. As a nonprescription product, it is diarrhea. This condition has been referred to as Verner-Morrison’s

TABLE 38-3 Oral Rehydration Solutions

WHO-ORSa Pedialyteb (Ross) Rehydralyteb (Ross) Infalyte (Mead Johnson) Resolb (Wyeth)
Osmolality (mOsm/L) 311 249 304 200 269
Carbohydratesb (g/L) 13.5 25 25 30c 20
Calories (cal/L) 65 100 100 126 80
Electrolytes (mEq/L)
Sodium 75 45 75 50 50
Potassium 20 20 20 25 20
Chloride 65 35 65 45 50
Citrate — 30 30 34 34
Bicarbonate 30 — — — —
Calcium — — — — 4
Magnesium — — — — 4
Sulfate — — — — —
Phosphate — — — — 5
a
World Health Organization reduced osmolarity Oral Rehydration Solution.
b
Carbohydrate is glucose.
c
Rice syrup solids are carbohydrate source.
 622

TABLE 38-4 Selected Antidiarrheal Preparation

SECTION 4

Dose Form Adult Dose

Antimotility
Diphenoxylate 2.5 mg/tablet 5 mg four times daily; do not exceed 20 mg/day
2.5 mg/5 mL
Loperamide 2 mg/capsule Initially 4 mg, then 2 mg after each loose stool; do not exceed 16 mg/day
1 mg/5 mL
Paregoric 2 mg/5 mL (morphine) 5–10 mL one to four times daily
Opium tincture 5 mg/mL (morphine) 0.6 mL four times daily
Difenoxin 1 mg/tablet 2 tablets, then 1 tablet after each loose stool; up to 8 tablets/day
Gastrointestinal Disorders

Adsorbents
Kaolin–pectin mixture 5.7 g kaolin + 130.2 mg pectin/30 mL 30–120 mL after each loose stool
Polycarbophil 500 mg/tablet Chew 2 tablets four times daily or after each loose stool; do not exceed 12
tablets/day
Attapulgite 750 mg/15 mL 1200–1500 mg after each loose bowel movement or every 2 hours; up to
300 mg/7.5 mL 9000 mg/day
750 mg/tablet
600 mg/tablet
300 mg/tablet
Antisecretory
Bismuth subsalicylate 1050 mg/30 mL Two tablets or 30 mL every 30 min to 1 h as needed up to 8 doses/day
262 mg/15 mL
524 mg/15 mL
262 mg/tablet
Enzymes (lactase) 1,250 neutral lactase units/4 drops 3–4 drops taken with milk or dairy product
3,300 FCC lactase units per tablet 1 or 2 tablets as above
Bacterial replacement (Lactobacillus 2 tablets or 1 granule packet three to four times daily; give with milk, juice, or
acidophilus, Lactobacillus water
bulgaricus)
Octreotide 0.05 mg/mL Initial: 50 mcg subcutaneously
0.1 mg/mL One to two times per day and titrate dose based on indication up to 600 mcg/
0.5 mg/mL day in two to four divided doses

syndrome, WDHA (watery diarrhea, hypokalemia, and achlorhydria)
syndrome, pancreatic cholera, watery diarrhea syndrome, and vasoac-
tive intestinal peptide-secreting tumor (VIPoma). Excessive secretion
of VIP from a retroperitoneal or pancreatic tumor produces most of
the clinical features. Excessive VIP is isolated in about half of patients,
along with numerous other peptide hormones (peptide histidine
methionine [PHM], serotonin, somatostatin, gastrin, and glucagon).
Surgical tumor dissection is the treatment of choice. In nonsurgical
candidates, the profuse watery diarrhea and other symptoms com-
monly encountered are managed with octreotide.
The dose of octreotide varies with the indication, disease severity
and patient response.11 For managing diarrhea and flushing associated
with carcinoid tumors in adults, the initial dosage range is 100 to 600
mcg/day in two to four divided doses subcutaneously for 2 weeks. For
controlling secretory diarrhea of VIPomas, the dosage range is 200 to
300 mcg/day in two to four divided doses for 2 weeks. Some patients
may require higher doses for symptomatic control. Patients respond-
ing to these initial doses may be switched to Sandostatin LAR Depot, a
long-acting octreotide formulation. This product consists of micro-
spheres containing the drug. Initial doses consist of 20 mg given
intramuscularly intragluteally at 4-week intervals for 2 months. It is
recommended that during the first 2 weeks of therapy the short-acting
formulation also be administered subcutaneously. At the end of 2
months, patients with good symptom control may have the dose
reduced to 10 mg every 4 weeks, while those without sufficient
symptom control may have the dose increased to 30 mg every 4 weeks.
For patients experiencing recurrence of symptoms on the 10-mg dose,
dosage adjustment to 20 mg should be made. It is not uncommon for
patients with carcinoid tumors or VIPomas to experience periodic
exacerbation of symptoms. Subcutaneous octreotide for several days
should be reinstituted in these individuals. In so-called carcinoid crisis,
octreotide is given as an intravenous infusion at 50 mcg/h for 8 to 24
hours.
Because octreotide inhibits many other gastrointestinal hor-
mones, it has a variety of intestinal side effects. With prolonged use,
gallbladder and biliary tract complications such as cholelithiasis
have been reported. Approximately 5% to 10% of patients complain
of nausea, diarrhea, and abdominal pain. Local injection pain
occurs with about an 8% incidence. With high doses, octreotide
may reduce dietary fat absorption, leading to steatorrhea.
Two other somatostatin analogs, lanreotide and vapreotide, have
been studied.13 Lanreotide, not currently available in the United
States but available in Europe, is indicated for patients with carcinoid
tumors in a dose of 30 mg intramuscularly (as a depot) every 14 days.
If necessary the dose can be increased to 30 mg intramuscular every
7 to 10 days. Vapreotide is an orphan drug that is indicated for
pancreatic and gastrointestinal fistulas as well as esophageal variceal
bleeding.
Miscellaneous Products
Lactobacillus preparations such as Lactinex granules are considered
probiotics agents that contain bacteria or yeast, such as lactic acid
bacteria are dietary supplements that have been used for many years
in hopes of replacing colonic microflora. This supposedly restores
normal intestinal function and suppresses the growth of pathogenic
microorganisms. However, a dairy product diet containing 200 to 400
g of lactose or dextrin is equally effective in producing recolonization
of normal flora. The dosage of lactobacillus preparations varies
depending on the brand used and lactobacillus preparations should
be administered with milk, juice, water, or cereal. Intestinal flatus is
the primary patient complaint experienced with this modality.

Anticholinergic drugs such as atropine block vagal tone and
prolong gut transit time. Drugs with anticholinergic properties are
present in many nonprescription products. Their value in control-
ling diarrhea is questionable and limited because of side effects.
Angle-closure glaucoma, selected heart diseases, and obstructive
uropathies are relative contraindications to the use of anticholiner-
gic agents.
Lactase enzyme products are helpful for patients who are experi-
encing diarrhea secondary to lactose intolerance. Lactase is required
for carbohydrate digestion. When a patient lacks this enzyme, eating
dairy products causes an osmotic diarrhea. Several products are
available for use each time a dairy product, especially milk or ice
cream, is consumed.
CLINICAL CONTROVERSY
Long-term use of oral opiates is not routinely recommended for
several pharmacologic reasons. Some opioids such as morphine
and codeine have the tendency to cause constipation by slowing
down the peristaltic action of the bowels, which can also result
in a functional ileus. This effect can be minimized by administer-
ing laxatives and/or stool softeners in patients who require long-
term opiate therapy. Prokinetic agents may also be helpful in
treating opiate-related constipation.
Investigational Drugs
Several new classes of compounds are undergoing clinical trials for
efficacy in acute diarrhea.14 Enkephalins are endogenous opiate
compounds in the gut that have antisecretory and proabsorptive
activity in the small intestine. They promote sodium and chloride
reabsorption via stimulation of a nonadrenergic, noncholinergic
neurotransmitter. Enkephalinase inhibitors, compounds that slow
down the enzymatic (i.e., enkephalinase) breakdown of endoge-
nous enkephalins found in the small intestines. They exert an
antisecretory effect without affecting GI motility or CNS-related
effects/side effects. One specific compound, originally called acetor-
phan but now referred to as racecadotril, has been extensively tested
in humans and found to be equal to other opiate anti-diarrheals
such as loperamide, while causing less GI motility side effects such
as abdominal bloating, pain, and constipation.15,16 Racecadotril is
currently licensed only in France and a few other developing
countries with a high incidence of childhood diarrhea, but it is
expected to be approved by other countries as well in the near
future.
Vaccines are a new therapeutic frontier in controlling infectious
diarrheas, especially in developing countries.17,18 An oral vaccine for
cholera is licensed and available in other countries (Dukoral from
SBL Vaccines) appears to provide somewhat better immunity and
have fewer adverse effects than the previously available parenteral
vaccine. However, the CDC does not recommend cholera vaccines
for most travelers, nor is the vaccine available in the United States.
Oral Shigella vaccine, although effective under field conditions,
requires 5 weekly oral doses and repeat booster doses, thereby
limiting its practicality for use in developing nations. With about
1,500 serotypes for Salmonella, a vaccine is not currently available
for humans. There are two newer typhoid vaccine formulations, one
a parenteral inactivated whole-cell vaccine and the other an oral
live-attenuated (Ty21a) vaccine that is administered in 4 doses on
days 1, 3, 5, and 7, to be completed at least l week before exposure.
Rotavirus vaccine is effective in infants and children; and is admin-
istered as a three-oral-dose sequence. A rotavirus vaccine program
has been formed to reduce child morbidity and mortality from
diarrheal disease by accelerating the availability of rotavirus vaccines
appropriate for use in developing countries.
623
■ EVALUATION OF
THERAPEUTIC OUTCOMES
CHAPTER 38
General Outcomes Measures
Therapeutic outcomes are directed toward key symptoms, signs,
and laboratory studies. Constitutional symptoms usually improve
within 24 to 72 hours. Monitoring for changes in the frequency and
character of bowel movements on a daily basis in conjunction with
vital signs and improvement in appetite are of utmost importance.
Also, the clinician needs to monitor body weight, serum osmolality,
Diarrhea, Constipation, and Irritable Bowel Syndrome
serum electrolytes, complete blood cell counts, urinalysis, and
culture results (if appropriate).
Acute Diarrhea
Most patients with acute diarrhea experience mild to moderate
distress. In the absence of moderate to severe dehydration, high
fever, and blood or mucus in the stool, this illness is usually self-
limiting within 3 to 7 days. Mild to moderate acute diarrhea is
usually managed on an outpatient basis with oral rehydration,
symptomatic treatment, and diet. Elderly persons with chronic
illness and infants may require hospitalization for parenteral rehy-
dration and close monitoring.
Severe Diarrhea
In the urgent/emergent situation, restoration of the patient’s vol-
ume status is the most important outcome. Toxic patients (fever
dehydration, hematochezia, or hypotension) require hospitaliza-
tion, intravenous fluids and electrolyte administration, and empiric
antibiotic therapy while awaiting culture and sensitivity results.
With timely management, these patients usually recover within a
few days.
CONSTIPATION
Constipation is a commonly encountered medical condition in the
United States for which many patients initiate self-treatment. One
reason constipation continues to be a frequent problem in this
country is lack of adequate dietary fiber. Another unfortunate
problem is that many people have misconceptions about normal
bowel function, and think that daily bowel movements are required
for health and well being. Others believe that the lack of a daily
bowel movement contributes to the accumulation of toxic sub-
stances or is associated with various somatic complaints. These
misconceptions often lead to the inappropriate use of laxatives by
the general public.
Constipation does not have a single, generally agreed upon
definition. When using the term, the lay public or healthcare
professional may be referring to several difficult-to-quantify vari-
ables: bowel movement frequency, stool size or consistency, and
such symptoms as the sensation of incomplete defecation. Stool
frequency is most often used to describe constipation; however, the
frequency of bowel movements used to define constipation is not
well established.
Normal people pass at least 3 stools per week. Some of the
definitions of constipation used in clinical studies include (a) less than
3 stools per week for women and 5 stools per week for men despite a
high-residue diet, or a period of more than 3 days without a bowel
movement; (b) straining at stool greater than 25% of the time and/or
2 or fewer stools per week; or (c) straining at defecation and less than
1 stool daily with minimal effort. These varying definitions demon-
strate the difficulty in characterizing this problem. An international
committee defined and classified constipation on the basis of stool
frequency, consistency, and difficulty of defecation.19,20
 624
Functional constipation is defined as two or more of the follow- TABLE 38-5 Possible Causes of Constipation
ing complaints present for at least 12 months in the absence of
SECTION 4

Conditions Possible Causes

laxative use: (a) straining at least 25% of the time; (b) lumpy or hard
stools at least 25% of the time; (c) a feeling of incomplete evacua- GI disorders Irritable bowel syndrome
tion at least 25% of the time; or (d) two or fewer bowel movements Diverticulitis
in a week. Rectal outlet delay is defined as anal blockage more than Upper GI tract diseases
25% of the time and prolonged defecation or manual disimpaction Anal and rectal diseases
Hemorrhoids
when necessary.
Anal fissures
Ulcerative proctitis
EPIDEMIOLOGY Tumors
Gastrointestinal Disorders

Hernia
A systematic review of the epidemiology of constipation in North Volvulus of the bowel
America reported a prevalence range for constipation of 1.9% to 27%, Syphilis
with the most reported estimates ranging from 12% to 19%. Preva- Tuberculosis
lence estimates by gender were female-to-male ratio of 2.2:1.21 Results Helminthic infections
from 42,375 participants of the National Health Interview Survey on Lymphogranuloma venereum
Digestive Disorders demonstrated that there is not an age-related Hirschsprung’s disease
increased incidence of infrequent bowel movements; however, there Metabolic and endocrine disorders Diabetes mellitus with neuropathy
is an age-related increased incidence of laxative use.22 The frequency Hypothyroidism
Panhypopituitarism
of subjects reporting two or fewer bowel movements per week was
Pheochromocytoma
5.9% for those younger than 40 years of age; 3.8% for subjects 60 to
Hypercalcemia
69 years of age; and 6.3% for subjects older than 80 years of age. In a Enteric glucagon excess
prospective study of 3,166 people older than 65 years of age in a Pregnancy Depressed gut motility
Florida community,23 26% of women and 15.8% of men reported Increased fluid absorption from colon
recurrent constipation. Factors found to correlate with self-reported Decreased physical activity
constipation were age, sex (higher frequency in females), total num- Dietary changes
ber of drugs taken, abdominal pain, and hemorrhoids. Inadequate fluid intake
Low dietary fiber
Use of iron salts
PATHOPHYSIOLOGY
Neurogenic causes CNS diseases
 Constipation is not a disease, but a symptom of an underlying Trauma to the brain (particularly the medulla)
disease or problem. Approaches to the treatment of constipation Spinal cord injury
CNS tumors
should begin with attempts to determine its cause. Disorders of the GI
Cerebrovascular accidents
tract (irritable bowel syndrome or diverticulitis), metabolic disorders
Parkinson’s disease
(diabetes), or endocrine disorders (hypothyroidism) may be involved. Psychogenic causes Ignoring or postponing urge to defecate
Constipation commonly results from a diet low in fiber or from use of Psychiatric diseases
constipating drugs such as opiates. Finally, constipation may some- Drug induced See Table 38–6
times be psychogenic in origin.24 Each of these causes is discussed in
the following sections.
Constipation is a frequently reported problem in the elderly, than parenterally administered products. Orally administered
probably the result of improper diets (low in fiber and liquids), enkephalins (endogenous opiate-like polypeptides) are recognized
diminished abdominal wall muscular strength, and possibly dimin- to have antimotility properties.
ished physical activity. However, as previously stated, the frequency
of bowel movements is not decreased with normal aging. In addi- CLINICAL PRESENTATION
tion, diseases that may cause constipation, such as colon cancer and
diverticulitis, are more common with increasing age. Table 38–5 Table 38–7 shows the general clinical presentation of constipation.
lists common causes of constipation in specific disease states.
TABLE 38-6 Drugs Causing Constipation
Drug-Induced Constipation Analgesics
Use of drugs that inhibit the neurologic or muscular function of the GI Inhibitors of prostaglandin synthesis
Opiates
tract, particularly the colon, may result in constipation (Table 38–6).
Anticholinergics
The majority of cases of drug-induced constipation are caused by
Antihistamines
opiates, various agents with anticholinergic properties, and antacids AntiParkinsonian agents (e.g., benztropine or trihexyphenidyl)
containing aluminum or calcium. With most of the agents listed in Phenothiazines
Table 38–6, the inhibitory effects on bowel function are dose depen- Tricyclic antidepressants
dent, with larger doses clearly causing constipation more frequently. Antacids containing calcium carbonate or aluminum hydroxide
Opiates have effects on all segments of the bowel, but effects are Barium sulfate
most pronounced on the colon. The major mechanism by which Calcium channel blockers
opiates produce constipation has been proposed to be prolongation of Clonidine
intestinal transit time by causing spastic, nonpropulsive contractions. Diuretics (non–potassium-sparing)
An additional contributory mechanism may be an increase in electro- Ganglionic blockers
lyte absorption. Iron preparations
Muscle blockers (D-tubocurarine, succinylcholine)
All opiate derivatives are associated with constipation, but the
Nonsteroidal antiinflammatory agents
degree of intestinal inhibitory effects seems to differ between agents. Polystyrene sodium sulfonate
Orally administered opiates appear to have greater inhibitory effects
 625

TABLE 38-7 Clinical Presentation of Constipation TABLE 38-8 Constipation Treatment Algorithm

CHAPTER 38
Signs and symptoms History
• It is important to ascertain whether the patient perceives the problem as • Stool frequency
infrequent bowel movements, stools of insufficient size, a feeling of fullness, • Stool consistency
or difficulty and pain on passing stool. • Difficulty of defecation
• Signs and symptoms include hard, small, or dry stools, bloated stomach, Possible causes
cramping abdominal pain and discomfort, straining or grunting, sensation of • Diet deficient in high-fiber items and consisting mainly of highly refined foods
blockade, fatigue, headache, and nausea and vomiting. • GI disorders
Laboratory tests • Metabolic and endocrine disorders
• A series of examinations, including proctoscopy, sigmoidoscopy, colonoscopy, • Pregnancy

Diarrhea, Constipation, and Irritable Bowel Syndrome

and barium enema, may be necessary to determine the presence of colorectal
pathology.
• Thyroid function studies may be performed to determine the presence of
metabolic and endocrine disorders.
TREATMENT
Constipation
■ GENERAL APPROACH TO TREATMENT
The patient should be asked about the frequency of bowel move-
ments and the chronicity of constipation. Constipation occurring
recently in an adult may indicate significant colon pathology such as
malignancy; constipation present since early infancy may be indica-
tive of neurologic disorders. The patient also should be carefully
questioned about usual diet and laxative regimens. Does the patient
have a diet consistently deficient in high-fiber items and containing
mainly highly refined foods? What laxatives or cathartics has the
patient used to attempt relief of constipation? The patient should be
questioned about other concurrent medications, with interest
focused on agents that might cause constipation.
For most patients who complain of constipation, a thorough
physical examination is not required after it is established that
constipation (a) is not a chronic problem, (b) is not accompanied
by signs of significant GI disease (e.g., rectal bleeding or anemia),
and (c) does not cause severe discomfort. In these circumstances,
the patient may be referred directly to the first-line therapies for
constipation described in the next section (mainly bulk-forming
laxatives and dietary fiber with occasional use of saline or stimulant
laxatives). Table 38–8 presents a general treatment algorithm for the
management of constipation.
 The proper management of constipation requires a number of
different modalities; however, the basis for therapy should be dietary
modification. The major dietary change should be an increase in the
amount of fiber consumed daily. In addition to dietary management,
patients should be encouraged to alter other aspects of their lifestyles
if necessary. Important considerations are to encourage patients to
exercise (achieved even by brisk walking after dinner) and to adjust
bowel habits so that a regular and adequate time is made to respond
to the urge to defecate. Another general measure is to increase fluid
intake. This is generally recommended and believed beneficial,
although there is little objective evidence to support this measure.
If an underlying disease is recognized as the cause of constipation,
attempts should be made to correct it. GI malignancies may be
removed via surgical resection. Endocrine and metabolic derange-
ments should be corrected by the appropriate methods. For example,
when hypothyroidism is the cause of constipation, cautious institu-
tion of thyroid-replacement therapy is the most important treatment
measure.
As discussed earlier, many drug substances may cause constipa-
tion. If a patient is consuming medications well known to cause
constipation, consideration should be given to alternative agents.
For some medications (e.g., antacids), nonconstipating alternatives
• Neurogenic
• Psychogenic
• Drug induced
• Laxative abusers
Symptoms seen with chronic constipation
• Fluid and electrolyte imbalances (hypokalemia)
• Protein-losing gastroenteropathy with hypoalbuminemia
• Syndromes resembling colitis
Select appropriate diagnostic studies
• Proctoscopy
• Sigmoidoscopy
• Colonoscopy
• Barium enema
Diagnosis
1. Treat specific cause
2. No diagnosis, symptomatic therapy
A. Bulk-forming agents
B. Dietary modification
C. Alter lifestyle (exercise)
D. Increase fluid intake
E. Discontinue potential drug inducer
exist. If no reasonable alternatives exist to the medication thought
to be responsible for constipation, consideration should be given to
lowering the dose. If a patient must remain on constipating medica-
tions, then more attention must be given to general measures for
prevention of constipation, as discussed in the next section.
■ NONPHARMACOLOGIC THERAPY
Dietary Modification and
Bulk-Forming Agents
The most important aspect of therapy for constipation for the
majority of patients is dietary modification to increase the amount of
fiber consumed. Fiber, the portion of vegetable matter not digested in
the human GI tract, increases stool bulk, retention of stool water, and
rate of transit of stool through the intestine. The result of fiber
therapy is an increased frequency of defecation. Also, fiber decreases
intraluminal pressures in the colon and rectum, which is thought to
be beneficial for diverticular disease and for irritable bowel syndrome.
The specific physiologic effects of fiber are not well understood.
Patients should be advised to include at least 10 g of crude fiber in
their daily diets.26 Fruits, vegetables, and cereals have the highest fiber
content. Bran, a by-product of milling of wheat, is often added to
foods to increase fiber content and contains a high amount of soluble
fiber, which may be extremely constipating in larger doses. Raw bran
is generally 40% fiber. Medicinal products, often called “bulk-form-
ing agents,” such as psyllium hydrophilic colloids, methylcellulose, or
polycarbophil, have properties similar to those of dietary fiber and
may be taken as tablets, powders, or granules (Table 38–9).
A trial of dietary modification with high-fiber content should be
continued for at least 1 month before effects on bowel function are
determined. Most patients begin to notice effects on bowel function 3
to 5 days after beginning a high-fiber diet, but some patients may
require a considerably longer period of time. Patients should be
cautioned that abdominal distension and flatus may be particularly
 626

TABLE 38-9 Dosage Recommendations for Laxatives suppository; if neither is effective, the use of oral sorbitol, low doses
and Cathartics of bisacodyl or senna, or saline laxatives (e.g., milk of magnesia) may
SECTION 4

provide relief. If laxative treatment is required for longer than 1 week,

Agent Recommended Dose
the person should be advised to consult a physician to determine if
Agents that cause softening of feces in 1–3 days there is an underlying cause of constipation that requires treatment
Bulk-forming agents/osmotic laxatives with other modalities.
Methylcellulose 4–6 g/day For some bedridden or geriatric patients, or others with chronic
Polycarbophil 4–6 g/day
constipation, bulk-forming laxatives remain the first line of treat-
Psyllium Varies with product
ment, but the use of more potent laxatives may be required relatively
Polyethylene glycol 3350
Emollients
frequently. Fiber should be avoided in bedridden patients who are
Gastrointestinal Disorders

Docusate sodium 50–360 mg/day cognitively impaired.25 When other than bulk-forming laxatives are
Docusate calcium 50–360 mg/day used, they should be administered in the lowest effective dose and as
Docusate potassium 100–300 mg/day infrequently as possible to maintain regular bowel function (more
Lactulose 15–30 mL orally than 3 stools per week). Agents that may be used in these situations
Sorbitol 30–50 g/day orally include bisacodyl, senna, milk of magnesia, and sorbitol or lactulose.
Mineral oil 15–30 mL orally Mineral oil should be avoided, particularly in bedridden patients,
Agents that result in soft or semifluid stool in 6–12 h because of the risk of aspiration and lipoid pneumonia. Some patients
Bisacodyl (oral) 5–15 mg orally with chronic constipation may present with fecal impactions. Before
Senna Dose varies with formulation vigorous oral laxatives can be used, the impaction needs to be
Magnesium sulfate (low dose) <10 g orally
removed using mechanical methods, including tap-water or saline
Agents that cause watery evacuation in 1–6 h
Magnesium citrate 18 g 300 mL water
enemas and digital extraction.
Magnesium hydroxide 2.4–4.8 g orally In the hospitalized patient without GI disease, constipation may be
Magnesium sulfate (high dose) 10–30 g orally related to the use of general anesthesia and/or opiate substances. Most
Sodium phosphates Varies with salt used orally or rectally administered laxatives may be used in these situations.
Bisacodyl 10 mg rectally For prompt initiation of bowel evacuation, either a tap-water enema,
Polyethylene glycol-electrolyte preparations 4L glycerin suppository, or oral milk of magnesia are recommended.
With infants and children, constipation may occur commonly. In
patients with persistent problems, the underlying etiology may be
troublesome in the first few weeks of fiber therapy, particularly with neurologic, metabolic, or secondary to anatomic abnormalities.
high bran consumption. In most cases these problems resolve with Management of constipation in this age group should consist of
continued use. dietary modification with an emphasis on high-fiber foods.
Bulk-forming laxatives have few adverse effects. The only major For acute constipation in most age groups, a tap-water enema or
caution in the use of bulk-forming laxatives is that obstruction of glycerin suppository may be helpful. Occasional use of milk of
the esophagus, stomach, small intestine, and colon has been magnesia or an anthraquinone laxative in low doses is justified as well.
reported when the agents have been consumed without sufficient
fluid and in patients with intestinal stenosis. Drug Classes
The traditional classification system for laxatives and cathartics by
Surgery suspected mode of action is not very useful, as this is not clearly
In a small percentage of patients who present with complaints of understood for many agents. In general, most of these products induce
constipation, surgical procedures are necessary because of the pres- bowel evacuation by one or more of the mechanisms associated with
ence of colonic malignancies or GI obstruction from a number of the etiology of diarrhea, including active electrolyte secretion,
other causes. In each case, the involved segment of intestine may be decreased water and electrolyte absorption, increased intraluminal
resected or revised. Surgery may be required in some endocrine osmolarity, and increased hydrostatic pressure in the gut. Laxatives
disorders that cause constipation, such as pheochromocytoma, which convert the intestine from primarily an organ that absorbs water and
requires removal of a tumor. electrolytes to an organ that secretes these substances.
The various classes of laxatives are discussed in this section. These
Biofeedback agents are divided into three general classifications: (a) those causing
softening of feces in 1 to 3 days (bulk-forming laxatives, docusates, and
The majority of patients with constipation related to pelvic floor
lactulose); (b) those that result in soft or semifluid stool in 6 to 12
dysfunction can benefit from electromyogram-guided biofeedback
hours (diphenylmethane derivatives and anthraquinone derivatives);
therapy.25 The value of biofeedback in children with chronic consti-
and (c) those causing water evacuation in 1 to 6 hours (saline cathar-
pation has not been well demonstrated.26
tics, castor oil, and polyethylene glycol-electrolyte lavage solution).
■ PHARMACOLOGIC THERAPY
Emollient Laxatives
Drug Regimens of Choice Emollient laxatives are surfactant agents, docusate in its various salts,
Treatment and prevention of constipation should consist of bulk- which work by facilitating mixing of aqueous and fatty materials
forming agents in addition to dietary modifications that increase within the intestinal tract. They may increase water and electrolyte
dietary fiber.27 A variety of products are available that provide secretion in the small and large bowel. These products are generally
adequate bulk. Whichever agent is chosen, it should be used daily given orally, although docusate potassium has also been used rectally.
and continued indefinitely in most patients, particularly those with These products result in a softening of stools within 1 to 3 days of
chronic constipation. therapy.
For most persons with acute constipation, infrequent use (less than Emollient laxatives are ineffective in treating constipation, but are
every few weeks) of laxative products is acceptable. Acute constipa- used mainly to prevent this condition. They may be helpful in
tion may be relieved by the use of a tap-water enema or a glycerin situations in which straining at stool should be avoided, such as

after recovery from myocardial infarction, with acute perianal
disease, or after rectal surgery. It is unlikely that these agents would
be effective in preventing constipation if major causative factors
(e.g., heavy opiate use, uncorrected pathology, or inadequate dietary
fiber) are not concurrently addressed.
Although docusates are generally safe, a few adverse effects have
been noted. They may increase the intestinal absorption of agents
administered concurrently and alter toxic potential.
Lubricants
Mineral oil is the only lubricant laxative in routine use. This agent,
obtained from petroleum refining, acts by coating stool and allowing
for easier passage. It inhibits colonic absorption of water, thereby
increasing stool weight and decreasing stool transit time. Mineral oil
may be given orally or rectally in a dose of 15 to 45 mL. Generally, the
effect on bowel function is noted after 2 or 3 days of use.
Mineral oil is helpful in situations similar to those suggested for
docusates: to maintain a soft stool and to avoid straining for relatively
short periods of time (a few days to 2 weeks); however, it possesses a
much greater potential for adverse effects and its routine use should
be discouraged. Mineral oil may be absorbed systemically and can
cause a foreign-body reaction in lymphoid tissue. Also, in debilitated
or recumbent patients, mineral oil may be aspirated, causing lipoid
pneumonia.28 Mineral oil may decrease the absorption of fat-soluble
vitamins (A, D, E, and K) with chronic use by causing retention in the
GI tract. Finally, even when given orally, mineral oil may leak from
the anal sphincter, causing pruritus and soiling of clothing.
Lactulose and Sorbitol
Lactulose is a disaccharide that is used orally or rectally. It is metabo-
lized by colonic bacteria to low-molecular-weight acids, resulting in
an osmotic effect whereby fluid is retained in the colon.29 The fluid
retained in the colon lowers the pH and increases colonic peristalsis.
Lactulose is generally not recommended as a first-line agent for the
treatment of constipation because it is costly and not necessarily more
effective than such agents as sorbitol or milk of magnesia. It may be
justified as an alternative for acute constipation, and has been partic-
ularly useful in elderly patients. Occasionally, the use of lactulose may
result in flatulence, cramps, diarrhea, and electrolyte imbalances.30
Sorbitol, a monosaccharide, exerts its effect by osmotic action and has
been recommended as a primary agent in the treatment of functional
constipation in cognitively intact patients.25 It is as effective as lactulose
and much less expensive.
Diphenylmethane and
Anthraquinone Derivatives
Bisacodyl, the only remaining diphenylmethane derivative with the
withdrawal of phenolphthalein, exerts its therapeutic effect by
stimulating the mucosal nerve plexus of the colon. Bisacodyl exhib-
its significant interpatient variability in effective dose, with doses
that cause no effect in one patient resulting in excessive cramping
and fluid evacuation in others. Bisacodyl is not recommended for
regular daily use but can be used intermittently (every few weeks) to
treat constipation or as a bowel preparation before diagnostic
procedures in which cleansing of the colon is necessary. Bisacodyl
may sometimes cause severe abdominal cramping as well as signifi-
cant fluid and electrolyte imbalances with chronic use.
Senna or sennosoids are the only remaining anthraquinone deriv-
atives after removal of cascara sagrada and casanthrone (cascara
extracts). Laxative effects are limited to the colon, and stimulation of
the Auerbach plexus may be involved. As with bisacodyl, senna is
only recommended for intermittent use and daily use should be
strongly discouraged.
627
Saline Cathartics
CHAPTER 38
Saline cathartics are composed of relatively poorly absorbed ions
such as magnesium, sulfate, phosphate, and citrate, which produce
their effects primarily by osmotic action in retaining fluid in the GI
tract. Magnesium stimulates the secretion of cholecystokinin, a
hormone that causes stimulation of bowel motility and fluid secre-
tion. These agents may be given orally or rectally. A bowel move-
ment may result within a few hours after oral doses and in 1 hour or
less after rectal administration.
These agents should be used primarily for acute evacuation of the
Diarrhea, Constipation, and Irritable Bowel Syndrome
bowel, which may be necessary before diagnostic examinations,
after poisonings, and in conjunction with some anthelmintics to
eliminate parasites. Such agents as milk of magnesia (an 8% suspen-
sion of magnesium hydroxide) may be used occasionally (every few
weeks) to treat constipation in otherwise healthy adults. Saline
cathartics should not be used on a routine basis. The enema
formulations of these agents may be useful in fecal impactions.
As with most laxatives, these agents may cause fluid and electro-
lyte depletion. Also, magnesium or sodium accumulation may
occur when magnesium-containing cathartics are used in patients
with renal dysfunction or when sodium phosphate is used in
patients with congestive heart failure.
Castor Oil
Castor oil is metabolized in the GI tract to an active compound,
ricinoleic acid, which stimulates secretory processes, decreases glu-
cose absorption, and promotes intestinal motility, primarily in the
small intestine. Castor oil usually results in a bowel movement
within 1 to 3 hours of administration. Because the agent has such a
strong purgative action, it should not be used for the routine
treatment of constipation.
Glycerin
Glycerin is usually administered as a 3-g suppository and exerts its
effect by osmotic action in the rectum. As with most agents given as
suppositories, the onset of action is usually less than 30 minutes.
Glycerin is considered a very safe laxative, although it may occasion-
ally cause rectal irritation. Its use is acceptable on an intermittent
basis for constipation, particularly in children.
Polyethylene Glycol-Electrolyte
Lavage Solution
Whole-bowel irrigation with polyethylene glycol-electrolyte lavage
solution (PEG-ELS) has become popular for colon cleansing before
diagnostic procedures or colorectal operations.
Four liters of this solution is administered over 3 hours to obtain
complete evacuation of the GI tract. The solution is not recom-
mended the routine treatment of constipation and its use should be
avoided in patients with intestinal obstruction.
Lubiprostone
The FDA recently approved the first new drug in a class called
“chloride channel activators,” which are designed to act locally in the
gut to open chloride channels on the GI luminal epithelium, which,
in turn, stimulates chloride-rich intestinal fluid secretion and acceler-
ates GI transit time and delays gastric emptying.31 Lubiprostone
(Amitiza), is approved for “chronic idiopathic constipation in adults”
at a recommended dose of one 24-mg capsule twice daily with food.
Clinical trials have shown a significant increase in spontaneous bowel
movements versus placebo.32 Common adverse effects include head-
ache (13%), diarrhea, and nausea, as a result of delayed gastric
emptying, which were more prominent with twice-daily dosing.
 628
Other Agents
Tap-water enemas may be used to treat simple constipation. The
SECTION 4
administration of 200 mL of tap water by enema to an adult often
results in a bowel movement within 30 minutes. Soap-suds enemas
are no longer recommended as their use may result in proctitis or
colitis.
Prevention
For certain groups of patients, such as those recovering from myocar-
Gastrointestinal Disorders
dial infarction or rectal surgery, straining at defecation is to be
avoided. The basis of preventive therapy in these patients should be
bulk-forming laxatives. Additionally, the use of docusate is popular,
although its effectiveness is debated. In pregnant patients, constipa-
tion may result because of alterations in anatomy or iron supplemen-
tation. As described earlier, bulk-forming laxatives and docusates
should be the first line of prevention.
LAXATIVE ABUSE SYNDROME
Misconceptions about normal bowel patterns and the effect of
laxatives have contributed to a syndrome of laxative abuse that is
relatively common in the United States. The availability of laxatives
as chocolates or gums conveys to the public that the use of these
agents is without adverse consequences. Abuse of laxatives has
occurred traditionally in persons trying to maintain daily bowel
function, but more recently has extended to others who use
laxatives for the purpose of controlling weight. In either case, the
consistent abuse of strong laxatives and cathartics may lead to
serious illness.
Laxative abuse for the purpose of maintaining daily bowel func-
tion begins with misconceptions about the frequency, quantity, or
consistency of stools. With the use of strong purgatives, the colon
may be so thoroughly cleansed that a bowel movement may not
occur normally until a few days later. This delay reinforces the need
for more purgatives and the cycle of laxative dependence is begun.
Eventually the patient may require daily laxatives to maintain bowel
function. A variation of laxative abuse is seen in persons who use
them as a means of weight loss.
The laxative abuser may present with contradictory findings of
diarrhea and weight loss. In addition, long-term abusers of laxatives
lend to have vomiting, abdominal pain, lassitude, weakness, thirst,
edema, and bone pain (caused by osteomalacia). With prolonged
use of laxatives a number of serious illnesses may arise, including
fluid and electrolyte imbalances (including acid–base imbalances
and hypokalemia), protein-losing gastroenteropathy with hypoal-
buminemia, and syndromes resembling colitis.
The determination of laxative abuse syndrome can be difficult
because many laxative abusers vigorously deny laxative use. Middle-
aged women tend to be the most common laxative abusers. The
chronic laxative abuse problem should be addressed by a combina-
tion of measures, including psychiatric evaluation, dietary modifi-
cation with reliance on bulk-forming laxatives, and specific guidelines
to the patient for the withdrawal of stimulant laxatives.
EVALUATION OF THERAPEUTIC OUTCOMES
The ultimate goal of treatment for constipation is alteration of
lifestyle (particularly diet) to prevent further episodes of constipa-
tion. Short-term goals include alleviation of acute constipation with
relief from symptoms. For patients with chronic constipation, the
goals are more long-term and include use of proper diet and
decreased reliance on laxatives. Effective treatment of constipation
requires the patient to become more knowledgeable about the
causes of constipation, proper diet, and appropriate use of laxatives.
IRRITABLE BOWEL SYNDROME
Irritable bowel syndrome (IBS) is a gastrointestinal syndrome
characterized by chronic abdominal pain and altered bowel habits
in the absence of any organic cause. It is the most commonly
diagnosed gastrointestinal condition.
EPIDEMIOLOGY
The prevalence of IBS is approximately 10% to 15% based on North
American and European population-based studies; however, there
is a wide variation in prevalence by individual country.33–36 IBS
affects men and women, young patients, and the elderly. However,
younger patients and women are more likely to be diagnosed with
IBS. A systematic review estimated that there is an overall 2:1 female
predominance in North America.34 Although only 15% of those
affected actually seek medical attention, IBS is the cause of between
25% and 50% of all referrals to gastroenterologists.37
PATHOPHYSIOLOGY
Although the exact pathophysiologic abnormalities with IBS are still
being actively investigated, it is currently thought that IBS results from
altered somatovisceral and motor dysfunction of the intestine from a
variety of causes. Abnormal central nervous system processing of
afferent signals may lead to visceral hypersensitivity, with the specific
nerve pathway affected determining the exact symptomatology
expressed. This visceral hypersensitivity is a neuroenteric phenome-
non that is independent of motility and psychological disturbances.27
Factors known to contribute to these alterations include genetics,
motility factors, inflammation, colonic infections, mechanical irrita-
tion to local nerves, stress, and other psychological factors.
Serotonin-Type Receptors
The enteric nervous system contains a significant percentage of the
body’s 5-hydroxytryptamine (serotonin, 5-HT).38 Two types of
serotonin exists within the gut: serotonin type 3 (HT3) and seroto-
nin type 4 (HT4), which are responsible for secretion, sensitization,
and motility.39 Previous studies show that there is an increase in the
postprandial levels of 5-HT in those who suffer from diarrhea
predominant IBS when compared with nonsufferers.38 Therefore,
stimulation and antagonism of these serotonin receptors has
become a focused area for research on new drug therapies for both
diarrhea- and constipation-predominant disease.
CLINICAL PRESENTATION
 Irritable bowel syndrome presents as either diarrhea-predominant
or constipation-predominant disease and can be defined as lower
abdominal pain, disturbed defecation (constipation, diarrhea, or an
alternating pattern of both), and bloating in the absence of struc-
tural or biochemical factors that might explain these symptoms
(Table 38–10). Because IBS can consist of a variable number of signs
and symptoms, two diagnostic criteria “check lists” are commonly
used to aid in the workup of a patient suspected of having IBS. The
Manning criteria was first proposed in 1978, whereas the Rome
criteria was initially proposed in 1999 and revised as recently as 2006
by an international working group in an effort to help standardize the
diagnostic criteria used in clinical research protocols. Table 38–11
shows the symptom criteria for both of the Manning40 and Rome III41
symptom-based criteria.
Additional diagnostic steps that can be taken include sigmoidos-
copy or colonoscopy; examination of the stool for occult blood and
ova and parasites; complete blood cell count; erythrocyte sedimen-
 629

TABLE 38-10 Clinical Presentation of Irritable Bowel Syndrome TABLE 38-11 Symptom-Based Criteria for Irritable

CHAPTER 38
Bowel Syndrome
Signs and symptoms
• Lower abdominal pain The Manning criteria40
• Abdominal bloating and distension Chronic or recurrent abdominal pain for at least 6 months and two or more of
• Diarrhea symptoms, >3 stools/day the following:
• Extreme urgency 1. Abdominal pain relieved with defecation
• Mucus passage 2. Abdominal pain associated with more frequent stools
• Constipation symptoms, <3 stools/wk, straining, incomplete evacuation 3. Abdominal pain associated with looser stools
• Psychological symptoms such as depression and anxiety 4. Abdominal distension
Nongastrointestinal symptoms 5. Feeling of incomplete evacuation after defecation

Diarrhea, Constipation, and Irritable Bowel Syndrome

• Urinary symptoms 6. Mucus in stools
• Fatigue Rome III diagnostic criteria for irritable bowel syndrome41
• Dyspareunia Recurrent abdominal pain or discomfort at least 3 days per month in the last 3
Other concurrent conditions months associated with 2 or more of the following:
• Fibromyalgia 1. Relieved with defecation
• Functional dyspepsia 2. Onset associated with a change in frequency of stool
• Chronic fatigue syndrome 3. Onset associated with a change in form (appearance) of stool
Reduced health-related quality of life

tation rate; and serum electrolytes. In some cases, radiographic
imaging studies, such as computed tomography scans or barium
swallows or enemas, may also be necessary if the findings of the
above assessment are not typical for IBS.42
TREATMENT
Irritable Bowel Syndrome
■ CONSTIPATION-PREDOMINANT DISEASE
In the constipation-predominant patient, dietary fiber may be
beneficial. Patients should be instructed to begin with 1 tablespoon-
ful of fiber with 1 meal daily and gradually increase the dose to
include fiber with 2 and 3 meals a day until the desired outcome is
achieved. End points that the patient should aim for include bulkier
and more easily passed stools. For patients unable to tolerate dietary
Diagnosis of irritable bowel syndrome

■ GENERAL APPROACH TO TREATMENT

The treatment approach to IBS is based upon the predominant
symptoms and their severity (Fig. 38–3). Milder, less frequent
Symptomatic treatment including stress
episodes can be managed with dietary restrictions and a higher-fiber management and patient education
diet, with addition of bulk-forming laxatives, if necessary. More
persistent disease may require as-needed uses of various antispas-
modic or antidiarrheal agents such as loperamide. Lastly, the most-
severe forms of this disease may call for pharmacologic agents
directed specifically at the underlying neurohormonal imbalance, Constipation predominant Diarrhea predominant
such as the 5-HT4 agonists, such as tegaserod, or the 5-HT3 receptor
antagonists, such as alosetron.

Increase dietary fiber and fluid Lactose-free, caffeine-free diet.

intake Counsel patient on other diarrhea-
inducing foods and drugs to
CLINICAL CONTROVERSY avoid
The newer serotonin receptor agonists and antagonists tegaserod
and alosetron act on GI-specific serotonin receptors to treat
constipation-predominant and diarrhea predominant IBS, Add bulk-forming laxatives and Add loperamide or other
respectively. However, both drugs are currently only indicated consider antispasmodic antispasmodic
agents
for women. Efficacy and safety in men has not been established
because the initial manufacturer’s sponsored clinical trials con-
tained insufficient numbers of men with IBS to provide the
Add serotonin-4 Add serotonin-3 antagonists
necessary statistical power to prove efficacy and safety. Ongoing
agonist (e.g., (e.g., alosetron)a
studies should determine if these drugs are indicated in men. tegaserod)a

Alosetron, a 5-HT3 receptor antagonist, was withdrawn from the

U.S. market in 2000 as a result of serious adverse effects, including
severe constipation and ischemic colitis that did not appear in the
initial clinical trials. It was reintroduced in 2002 and is now limited
to an FDA-approved restricted-use program in lower initial doses,
and requires extensive postmarketing surveillance. Results of these
trials are necessary to definitively determine alosetron’s true safety
profile, especially with regard to its association with or causation of
fatal ischemic colitis.
Add psychotherapeutic behavior
modifications, including stress reduction,
and consider antidepressants for
associated pain symptoms
FIGURE 38-3. A general stepwise approach to the management of both
constipation- and diarrhea-predominant irritable bowel syndrome. aCon-
sider manufacturer sponsored patient access program.
 630
bran, bulking agents such as psyllium may be substituted.30 Laxative
use is not encouraged in these patients, and it should only be used
SECTION 4
in the smallest dose for the least amount of time in cases of severe
constipation.
The 5-HT4 partial agonist tegaserod was the first therapy approved
by the FDA specifically for short-term, intermittent treatment of
constipation-predominant IBS.42 Tegaseride was suspended from
marketing in early 2007 at the request of the FDA due to an analysis
of clinical trial data showing a small, yet significant, increase in
ischemia events (MI < CVA, and unstable angina) in patients with
Gastrointestinal Disorders
pre-existing cardiovascular disease and/or cardiovascular risk factors.
In July 2007, the drug’s manufacturer, Novartis, began tegaseride
(Zelnorm®) restricted access program to patients in the United States
via either a manufacturer sponsored FDA-approved investigational
new drug (IND) protocol or through the FDA via an emergency INID
Select patients with IBS suffer significant pain associated with their
protocol. Tegaserod is a serotonin derivative that activates 5-HT4
receptors on the neurons in the gastrointestinal tract, increasing GI
motility and decreasing visceral sensations. It is approved as 2-mg or
6-mg doses given twice daily 30 minutes prior to a meal with water for
up to 12 weeks.43 Stimulation of the 5-HT4 receptors by tegaserod
increases gastric secretions and promotes motility, with improvement
in symptoms generally occurring within the first week of therapy.
Currently this therapy is only approved for use in women, as efficacy
and safety in men has not been established because of inadequate
numbers of men enrolled in clinical trials to date.44 In addition, length
of effective therapy has only been approved for 12 weeks 45; however,
tegaserod may provide safe and effective therapy for up to 12
months.44,46 Diarrhea was the most common adverse effect, resulting
in drug discontinuation in 1.6% of study subjects.
■ DIARRHEA-PREDOMINANT DISEASE
For patients in whom diarrhea is the primary complaint, avoid-
ance of certain food products may be necessary. Caffeine, alcohol,
and artificial sweeteners (sorbitol, fructose, and mannitol) are
known to irritate the gut and produce a laxative effect. Lactose
intolerance should be considered in certain patients; however, the
prevalence of this condition may be exaggerated.
Herbal medicines or teas often contain senna, which may produce
diarrhea. In patients with disease persistence following dietary modi-
fication, loperamide may be used for episodic management of urgent
diarrhea, or in situations in which the patient wishes to avoid the
possibility of an acute onset of symptoms.43 This drug decreases
intestinal transit, enhances water and electrolyte absorption, and
strengthens rectal sphincter tone. Some patients may require contin-
uous therapy, and careful dosage titration can usually be undertaken
to prevent the development of constipation. Bile acid sequestrants
such as cholestyramine may be useful in patients with diarrhea related
to idiopathic bile acid malabsorption or following cholecystectomy.42
Diarrhea-predominant IBS caused by excessive stimulation of the
5-HT3 receptor can be relieved by the drug alosetron. Alosetron was
the first truly effective treatment for diarrhea-predominant IBS.
However, in November 2000 it was voluntarily withdrawn from the
market because of severe GI adverse effects, including 113 reported
cases of serious constipation and 8 cases of possible ischemic colitis
and death. This decision was met with a great public outcry, as many
who had suffered for years had experienced relief for the first time.
Because this drug was highly effective in many patients, the FDA
approved restricted use of alosetron in June 2002. Alosetron is now
available via an FDA-approved restricted-use program in conjunction
with GlaxoSmithKline as detailed at http://www.lotronex.com. It is
now indicated, in lower initial doses of 0.5 mg twice daily, for women
with diarrhea-predominant symptoms of longer than 6 months’
duration that are not relieved by conventional therapy. Healthcare
providers must use extreme caution in therapy with this drug, and
must follow strict FDA-mandated guidelines.
Use of Antidepressants in IBS
Tricyclic antidepressants have shown some benefit in treatment of
diarrhea-predominant IBS associated with moderate to severe
abdominal pain, by modulating perception of visceral pain, altering
GI transit time, and treating underlying comorbidities.47,48 Selective
serotonin reuptake inhibitors are less-well studied, with only one
report with paroxetine showing some improvement in stool passage
and “well being” but no decrease in abdominal pain.49
Figure 38–3 shows a general stepwise approach to the manage-
ment of both constipation and diarrhea-predominant irritable
bowel syndrome.
■ PAIN IN IBS
disease. Data supporting the use of antispasmodic agents in these
patients are conflicting.50,51 In these cases, a trial of low-dose antide-
pressant therapy is indicated, especially if pain is associated with
eating. Both tricyclic antidepressants and serotonin reuptake inhibi-
tors produce analgesia, and may relieve depressive symptoms if
present. Preprandial doses of drugs containing anticholinergic proper-
ties may suppress pain (and/or diarrhea) associated with an overactive
postprandial gastrocolonic response. Tricyclic antidepressants should
be avoided in patients with pain and constipation. In addition, psycho-
therapy, including cognitive behavioral therapy, relaxation therapy,
and hypnotherapy, has been shown to decrease IBS symptoms.52
■ DRUG CLASSES CURRENTLY UNDER
INVESTIGATION FOR THE TREATMENT
OF IBS
Probiotics (see Diarrhea above) such as Lactobacillus and Bifidobacte-
rium reduced IBS symptoms in several investigation trials.53,54 Another
5-HT3 antagonist, cilansetron, has demonstrated similar efficacy to that
of alosetron in phase II trials and enrolled enough male patients to
show benefit in males as well. This drug is currently in phase III trials.
In addition, other compounds being evaluated include neurokinin1
(NK1) and neurokinin3 (NK3) receptor antagonists, gut-selective cal-
cium channel blockers, cholecystokinin receptor antagonists, and
agents capable of stimulating motilin receptors (motilin mimetics).55
■ EVALUATION OF
THERAPEUTIC OUTCOMES
IBS is usually classified as constipation-predominant, diarrhea-
predominant, or IBS with abdominal pain and bloating. Therapeutic
goals in IBS should focus on the patient’s primary complaint. Dietary
and drug therapy goals should focus on end-organ treatment to relieve
abdominal pain (antispasmodic drugs) or disturbed bowel habits
(antidiarrheals and bulk-forming agents). Additionally, severe symp-
toms from central nervous system dysregulation should be treated
with antidepressants, psychotherapy, relaxation/stress management,
cognitive behavior treatment, and/or hypnosis aimed at specific affec-
tive disorders.55 Lastly, the serotonin receptor agonists and antagonists
can be used in carefully selected patients whose symptoms are not
adequately controlled with other agents. The American Gastroenterol-
ogy Association recommends that patients with severe IBS consider
psychological treatments such as psychotherapy, relaxation/stress
management, and/or cognitive behavior treatment.
ABBREVIATIONS
5-HT: serotonin
IBS: irritable bowel syndrome
ORS: oral rehydration solution

PEG-ELS: polyethylene glycol-electrolyte lavage solution
PHM: peptide histidine methionine
VIP: vasoactive intestinal peptide
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