40
563
C H AP TER
KEY CONCEPTS
 Patients with peptic ulcer disease (PUD) should reduce
psychological stress, cigarette smoking, and nonsteroidal
Critically ill patients at the highest risk of developing stress-
antiinflammatory drug (NSAID) use and avoid foods and
beverages that exacerbate ulcer symptoms.
 Eradication is recommended for all Helicobacter pylori
(H. pylori)positive patients with an active ulcer, a docu- 
mented history of a prior ulcer, or a history of ulcer-related
complications.
 The selection of an H. pylori eradication regimen should
be based on efficacy, safety, antibiotic resistance, cost, and
the likelihood of medication adherence. Treatment should be
initiated with a proton pump inhibitor (PPI)based three-drug
regimen. If a second course of H. pylori therapy is required,
the regimen should contain different antibiotics.
 PPI cotherapy reduces the risk of NSAID-related gastric and
duodenal ulcers and is at least as effective as recommended
dosages of misoprostol and superior to the histamine-2 recep-
tor antagonists (H2RA).
 Standard PPI dosages and a nonselective NSAID are as
effective as a selective cyclooxygenase-2 (COX-2) inhibitor
in reducing the risk of NSAID-induced ulcers and upper
gastrointestinal (GI) complications.
 The eradication of H. pylori improves clinical outcomes and
decreases the use of healthcare resources when compared
with conventional antisecretory therapy. The cost effective-
ness of misoprostol cotherapy is greatest for patients with
the highest risk for GI complications. Cotherapy with PPIs
and NSAIDs or selective COX-2 inhibitors is cost effective
even in low-risk patients especially if the least costly PPI is
used.
 Patients with PUD, especially those receiving H. pylori eradi-
cation or misoprostol cotherapy, require patient education
regarding their disease and drug treatment to successfully
achieve a positive therapeutic outcome.
The recommended treatment for severe peptic ulcer bleed-
ing after appropriate endoscopic treatment is the intravenous
Learning objectives, review questions,
and other resources can be found at
www.pharmacotherapyonline.com.
Peptic Ulcer Disease
ROSEMARY R. BERARDI AND RANDOLPH V. FUGIT
administration of a PPI loading dose followed by a 72-hour
continuous infusion with a goal of maintaining an intragastric
pH of 6 or greater.
related mucosal bleeding (SRMB) who require prophylactic
drug therapy include those with respiratory failure on
mechanical ventilation or those with coagulopathy.
There are limited data to support the selection of a PPI over an
intravenous H2RA for SRMB prophylaxis. The decision should
be based upon appropriate individual patient characteristics
(e.g., nothing by mouth, presence of nasogastric tube, renal
failure).
PEPTIC ULCER DISEASE
Acid-related diseases (gastritis, erosions, and peptic ulcer) of the
upper gastrointestinal (GI) tract require gastric acid for their
formation.13 Peptic ulcer disease (PUD) differs from gastritis and
erosions in that ulcers typically extend deeper into the muscularis
mucosa.1 There are three common forms of peptic ulcers: Helicobacter
pylori (H. pylori)-positive, nonsteroidal antiinflammatory drug
(NSAID)-induced, and stress ulcers (Table 401). The term stress-
related mucosal damage (SRMD) is preferred to stress ulcer or stress
gastritis, because the mucosal lesions range from superficial gastritis
and erosions to deep ulcers.
H. pyloripositive and NSAID-induced ulcers are chronic
peptic ulcers that differ in etiology, clinical presentation, and
tendency to recur (see Table 401). These ulcers develop most
often in the stomach and duodenum of ambulatory patients
(Fig. 401). Occasionally, ulcers develop in the esophagus,
jejunum, ileum, or colon. The natural course of chronic PUD is
characterized by frequent ulcer recurrence. The most important
factors that influence ulcer recurrence are H. pylori infection
and NSAID use. Other factors include cigarette smoking, alcohol
use, ulcer-related complications, gastric acid hypersecretion, and
patient noncompliance. The cause of ulcer recurrence is most
likely multifactorial.
Peptic ulcers are also associated with Zollinger-Ellison syndrome
(ZES), radiation, chemotherapy, vascular insufficiency, and other
chronic diseases (Table 402).1,3 Although a strong association
exists between chronic pulmonary diseases, chronic renal failure,
and cirrhosis, the pathophysiologic mechanisms of these associa-
tions remain unclear.1 In contrast, SRMD occurs primarily in the
stomach in critically ill patients (see Table 401).1
This chapter focuses on chronic PUD associated with H. pylori
and NSAIDs. A brief discussion of ZES and upper GI bleeding
related to PUD and SRMD is included.
564
TABLE 40-1 Comparison of Common Forms of Peptic Ulcer
SECTION 4
Characteristic H. pylori Induced
Condition Chronic
Site of damage Duodenum > stomach
Intragastric pH More dependent
Symptoms Usually epigastric pain
Ulcer depth Superficial
GI bleeding Less severe, single vessel
H. pylori, Helicobacter pylori; NSAID, nonsteroidal antiinflammatory drug; SRMD, stress-related mucosal damage.
Gastrointestinal Disorders
EPIDEMIOLOGY
The epidemiology of PUD is complicated and difficult to estimate
given the variablity in the prevalence of H. pylori infection,
NSAID use, and cigarette smoking as well as the various methods
used to detect ulcers, e.g., endoscopy, radiology, symptoms, or
complications.1,4 The prevalence and incidence of PUD in the United
States also reflects improvements in drug therapy, the dramatic shift
to ambulatory management, and changes in the criteria and coding
system for mortality and hospitalization data.1 Recent trends suggest
a shift from predominance in men to a similar occurrence in men
and women with increasing rates of disease in older individuals and
a decrease in the younger population.1,4 Despite a modest decline in
mortality, hospitalizations, and office visits, PUD remains one of the
most common GI diseases, resulting in impaired quality of life, work
loss, and high-cost medical care.
ETIOLOGY AND RISK FACTORS
Most peptic ulcers occur in the presence of acid and pepsin when
H. pylori, NSAIDs, or other factors (see Table 402) disrupt the
normal mucosal defense and healing mechanisms.1 Hypersecretion
of acid is the primary pathogenic mechanism in hypersecretory
states such as ZES.3 Benign gastric ulcers can occur anywhere in
the stomach, although most are located on the lesser curvature,
just distal to the junction of the antral and acid-secreting mucosa
(see Fig. 401). Most duodenal ulcers occur in the first part of the
duodenum (duodenal bulb).
HELICOBACTER PYLORI
H. pylori infection causes chronic gastritis in infected individuals
and is causally linked to PUD, mucosa-associated lymphoid tissue
FIGURE 40-1. Anatomic structure of the stomach and duodenum and
most common locations of gastric and duodenal ulcers.
NSAID Induced SRMD
Chronic Acute
Stomach > duodenum Stomach > duodenum
Less dependent Less dependent
Often asymptomatic Asymptomatic
Deep Most superficial
More severe, single vessel More severe, superficial mucosal capillaries
(MALT) lymphoma, and gastric cancer (Fig. 402).1,2,58 The
majority of infected individuals remain asymptomatic, but 10%
to 20% will develop PUD during their lifetime and about 1% will
develop gastric cancer.1,2,8 Host-specific cofactors and H. pylori
strain variability play an important role in the pathogenesis of PUD
and gastric cancer.2,8 Although an association between H. pylori
and PUD bleeding is less clear, there is evidence that eradication of
H. pylori decreases recurrent bleeding.5,9 No specific link has been
established between H. pylori and dyspepsia, nonulcer dyspepsia
(NUD), or gastroesophageal reflux disease (GERD).5,911 However,
some patients with dyspepsia and NUD may benefit from H. pylori
eradication.5,9 Although eradication of H. pylori may worsen GERD
symptoms in some patients, eradication should not be withheld.5,10
An association between H. pylori infection and iron deficiency ane-
mia has been established, but cause and effect has not been proven,
and whether H. pylori eradication is beneficial is uncertain.5,11
There are insufficient data to support a link between H. pylori and
extragastric manifestations including cardiovascular, hematologic,
respiratory, hepatobiliary, and neurologic diseases.5,11
The prevalence of H. pylori varies by geographic location, socio-
economic conditions, ethnicity, and age. In developing countries,
H. pylori prevalence is more common than in industrialized coun-
tries and correlates with lower socioeconomic levels.2,5,6 The preva-
lence of H. pylori in the United States is 30% to 40% but is much
higher in individuals over 60 years (50% to 60%) than in children
under 12 years (10% to 15%) of age.2,5 Although most individuals in
the United States acquire H. pylori in childhood, the rate of acquisi-
tion in children is declining and most likely will continue to fall as
a consequence of improved socioeconomic conditions.2 Caucasians
are infected with H pylori less frequently than African Americans
and Hispanic persons, but this is thought to be related to lower
socioecomonic status and living conditions. Infection rates do not
differ with gender or smoking status.
TABLE 40-2 Potential Causes of Peptic Ulcer
Common causes
Helicobacter pylori infection
Nonsteroidal antiinflammatory drugs
Critical illness (stress-related mucosal damage)
Uncommon causes of chronic peptic ulcer
Idiopathic (non-H. pylori, non-NSAID peptic ulcer)
Hypersecretion of gastric acid (e.g., Zollinger-Ellison syndrome)
Viral infections (e.g., cytomegalovirus)
Vascular insufficiency (e.g., crack cocaine associated)
Radiation therapy
Chemotherapy (e.g., hepatic artery infusions)
Infiltrating disease (e.g., Crohn disease):
Diseases and medical conditions associated with chronic peptic ulcer
Cirrhosis
Chronic renal failure
Chronic obstructive pulmonary disease
Cardiovascular disease
Organ transplantation

Normal gastric mucosa
Acquisition of
Helicobacter pylori
Acute gastritis
Asymptomatic or symptomatic acquisition
Chronic active gastritis
Corpus-predominant gastritis
Antral-predominant gastritis
with multifocal atrophy
Environmental
Factors
Duodenal Gastric Gastric
MALT lymphoma
ulcer ulcer cancer
FIGURE 40-2. The natural history of Helicobacter pylori infection in the
pathogenesis of gastric ulcer and duodenal ulcer, mucosa-associated
lymphoid tissue (MALT) lymphoma, and gastric cancer.
The most common route of H. pylori transmission is person to
person either by gastrooral (vomitus) or fecaloral (diarrhea) contact
which occurs primarily during childhood.2 Members of the same
household are likely to become infected when someone in the
same household is infected.2 H. pylori can also be transmitted by
the use of inadequately sterilized endoscopes.
NONSTEROIDAL ANTIINFLAMMATORY DRUGS
NSAIDs (Table 403) are widely used in the United States,
particularly in individuals over 60 years of age, to treat chronic
pain and inflammation.1 These agents include prescription and
nonprescription medications and low-dose aspirin used for car-
diovascular and cerebrovascular risk reduction.1,1214 There is
overwhelming evidence linking chronic NSAID (including aspi-
rin) use to a variety of upper GI tract injuries.1,1216 NSAIDs cause
superficial (topical) mucosal damage consisting of petechiae (intra-
mucosal hemorrhages) within minutes of ingestion, and progress
to erosions with continued use.1 These lesions typically heal within
a few days and rarely cause ulcers or acute upper GI bleeding.
Gastroduodenal ulcers develop in about 25% of chronic NSAID
users with continued use.12 Gastric ulcers are most common, occur
primarily in the antrum, and are of greater concern because of
their potential to cause ulcer-related upper GI complications (see
Table 401). As many as 2% to 4% of patients with an NSAID
ulcer will bleed or perforate.12 Each year, NSAIDs account for at
least 100,000 hospitalizations and between 7,000 and 10,000 deaths
TABLE 40-3 Selected Nonsteroidal Antiinflammatory Drugs
(NSAIDs) and Cyclooxygenase-2 (COX-2) Inhibitors
Nonsalicylatesa
Nonselective (traditional) NSAIDs: indomethacin, piroxicam, ibuprofen,
naproxen, sulindac, ketoprofen, ketorolac, flurbiprofen
Partially selective NSAIDs: etodolac, nabumetone, meloxicam, diclofenac, celocoxib
Selective COX-2 inhibitors: rofecoxib,b valdecoxibb
Salicylates
Acetylated: aspirin
Nonacetylated: salsalate, trisalicylate
a
Based on COX-1/COX-2 selectivity ratio.
b
Withdrawn from U.S. market.
565
TABLE 40-4 Risk Factors Associated with Nonsteroidal
CHAPTER 40
Antiinflammatory Drug (NSAID)Induced Ulcers
and Upper Gastrointestinal Complicationsa
Age >65
Previous peptic ulcer
Previous ulcer-related upper GI complication
High-dose NSAIDs
Multiple NSAID use
Selection of NSAID (e.g., COX-1 vs COX-2 inhibition)
NSAID-related dyspepsia
Peptic Ulcer Disease
Aspirin (including cardioprotective dosages)
Concomitant use of NSAID plus low-dose aspirin
Concomitant use of oral bisphosphonates (e.g., alendronate)
Concomitant use of corticosteroids
Concomitant use of anticoagulant or coagulopathy
Concomitant use of antiplatelet drugs (e.g., clopidogrel)
Concomitant use of selective serotonin reuptake inhibitor
Chronic debilitating disorders (e.g., cardiovascular disease, rheumatoid arthritis)
Helicobacter pylori infection
Cigarette smoking
Alcohol consumption
a
Combinations of risk factors are additive.
Data from references 1, 12 to 15, 20, and 29.
in the United States.12 NSAID-induced ulcers occur less frequently
in the esophagus, small bowel, and colon.16,17 How NSAIDs damage
the lower GI tract is unclear, but the enteropathy is associated with
lower GI bleeding.
Table 404 lists the risk factors associated with NSAID-induced
ulcers and upper GI complications. Combinations of factors confer
an additive risk.1216,18 Advanced age is an independent risk factor,
and the incidence of NSAID-induced ulcers increases linearly with
the age of the patient.1 The high incidence of ulcer complications
in older individuals may be explained by age-related changes in
gastric mucosal defense. The relative risk of NSAID complications
is increased for patients with a previous peptic ulcer and may be as
high as 14-fold in those with a history of an ulcer-related complica-
tion.1,16 The risk of adverse events is greatest during the first month
after initiating continuous therapy and remains the same through-
out treatment.1
NSAID ulcers and related complications are dose-dependent,
but may occur with low doses of nonprescription NSAIDs and low
cardioprotective dosages of aspirin (81 to 325 mg/day).1,1216 Factors
such as NSAID potency, longer duration of effect, and a greater
propensity to inhibit cyclooxygenase-1 (COX-1) versus COX-2
isoezymes are associated with increased risk (see Table 403).1,16,18,19
NSAID-related dyspepsia, in itself, does not correlate directly with
mucosal injury or clinical events. However, new-onset dyspepsia,
changes in severity, or dyspepsia not relieved by antiulcer medica-
tions may suggest an ulcer or ulcer complication.1 Nonacetylated
salicylates (e.g., salsalate) may be associated with decreased GI
toxicity.1 Buffered or enteric-coated aspirin confers no added pro-
tection from upper GI events.13
NSAID ulcer and GI complication risk are increased with the use
of multiple NSAIDs or the concomitant use of low-dose aspirin,
oral bisphosphonates, corticosteroids, anticoagulants, antiplatelet
drugs, and selective serotonin reuptake inhibitors.1,1216,20 The risk
of an ulcer-related GI complication is greater when a NSAID or
COX-2 inhibitor (see Table 403) is coadministered with low-dose
aspirin than when either drug is taken alone.1,13,16 The NSAID may
also reduce the antiplatelet effects of aspirin, although NSAIDs vary
in their effects on platelet function.1315 Corticosteroids, when used
alone, do not potentiate the risk of ulcer or complications, but the
relative risk is increased twofold in corticosteroid users who are
566
also taking concurrent NSAIDs.1,16 The relative risk of GI bleeding
increases up to 20-fold when NSAIDs are taken concomitantly with
SECTION 4
anticoagulants (e.g., warfarin) and up to sixfold with the concurrent
use of serotonin reuptake inhibitors.16,17 When clopidogrel is taken
in combination with aspirin, an NSAID, or an anticoagulant, the
risk of GI bleeding is increased compared with when these agents
are taken alone.13,15,16 Even when prescribed as monotherapy, clopi-
dogrel increases the risk of rebleeding for patients with history of a
bleeding ulcer.13,15,16
H. pylori and NSAIDs act independently to increase ulcer risk
Gastrointestinal Disorders
and ulcer-related bleeding and appear to have additive effects.5,16
Thus, the incidence of peptic ulcer is higher in H. pyloripositive
NSAID users. Whether H. pylori infection is actually a risk factor
for NSAID ulcers remains controversial.1,5,16 However, eradication
is reported to reduce the incidence of peptic ulcer if undertaken
prior to starting the NSAID but does not reduce the risk for patients
who were previously taking an NSAID.1,5,16
CIGARETTE SMOKING
Epidemiologic evidence links cigarette smoking to PUD, but it is
uncertain whether smoking causes peptic ulcers.1 Ulcer risk is pro-
portional to the number of cigarettes smoked and is modest when
fewer than 10 cigarettes are smoked per day. Cigarette smoking
impairs ulcer healing, promotes ulcer recurrence, and increases
ulcer risk.1 The exact mechanism by which cigarette smoking
contributes to PUD remains unclear. Possible mechanisms include
inhibition of pancreatic bicarbonate secretion and increases in
gastric acid secretion, but these effects are inconsistent. Whether
nicotine or other components of smoke are responsible for these
physiologic alterations is unknown.
PSYCHOLOGICAL STRESS
The importance of psychological factors in the pathogenesis of
PUD remains controversial.1 Clinical observation suggests that ulcer
patients are adversely affected by stressful life events. However, results
from controlled trials are conflicting and have failed to document a
cause-and-effect relationship.1 Emotional stress may induce behav-
ioral risks such as smoking and the use of NSAIDs or alter the inflam-
matory response or resistance to H. pylori infection. The role of stress
and how it affects PUD is complex and probably multifactorial.
DIETARY FACTORS
The role of diet and nutrition in PUD is uncertain.1 Coffee, tea, cola
beverages, beer, milk, and spices may cause dyspepsia but do not
increase the risk for PUD. Beverage restrictions and bland diets do not
alter the frequency of ulcer recurrence. Although caffeine is a gastric
acid stimulant, constituents in decaffeinated coffee or tea, caffeine-
free carbonated beverages, beer, and wine may also increase gastric
acid secretion. In high concentrations, alcohol ingestion is associated
with acute gastric mucosal damage and upper GI bleeding; however,
there is insufficient evidence to confirm that alcohol causes ulcers.1
PATHOPHYSIOLOGY
A physiologic imbalance between aggressive (gastric acid and
pepsin) and protective factors (mucosal defense and repair) remain
important issues in the pathophysiology of gastric and duodenal
ulcers.1,21 Gastric acid is secreted by the parietal cells, which contain
receptors for histamine, gastrin, and acetylcholine.21 Acid (as well
as H. pylori infection and NSAID use) is an independent factor
that contributes to the disruption of mucosal integrity.1 Increased
acid secretion has been observed for patients with duodenal
ulcers and may be a consequence of H. pylori infection.2,22 Patients
with Zollinger-Ellison syndrome (ZES) (described in the section
Zollinger-Ellison Syndrome) have profound gastric acid hyper-
secretion resulting from a gastrin-producing tumor.3 In contrast,
patients with gastric ulcer usually have normal or reduced rates of
acid secretion (hypochlorhydria).
Acid secretion is expressed as the amount of acid secreted under
basal or fasting conditions, basal acid output (BAO); after maxi-
mal stimulation, maximal acid output (MAO); or in response to a
meal.21 Basal, maximal, and meal-stimulated acid secretion varies
according to time of day and the individuals psychological state,
age, gender, and health status. The BAO follows a circadian rhythm,
with the highest acid secretion occurring at night and the lowest in
the morning. An increase in the BAO:MAO ratio suggests a basal
hypersecretory state such as ZES. A review of gastric acid secretion,
and its regulation can be found elsewhere.21
Pepsin is an important cofactor that plays a role in the proteolytic
activity involved in ulcer formation.21 Pepsinogen, the inactive pre-
cursor of pepsin, is secreted by the chief cells located in the gastric
fundus (see Fig. 401). Pepsin is activated by acid pH (optimal
pH of 1.8 to 3.5), inactivated reversibly at pH 4, and irreversibly
destroyed at pH 7.
Mucosal defense and repair mechanisms (mucus and bicarbonate
secretion, intrinsic epithelial cell defense, and mucosal blood flow)
protect the gastroduodenal mucosa from noxious endogenous and
exogenous substances.1,21 The viscous nature and near-neutral pH of
the mucus-bicarbonate barrier protect the stomach from the acidic
contents in the gastric lumen. Mucosal repair after injury is related
to epithelial cell restitution, growth, and regeneration. The mainte-
nance of mucosal integrity and repair is mediated by the production
of endogenous prostaglandins. The term cytoprotection is often used
to describe this process, but mucosal defense and mucosal protection
are more accurate terms, as prostaglandins prevent deep mucosal
injury and not superficial damage to individual cells. Gastric hy-
peremia and increased prostaglandin synthesis characterize adaptive
cytoprotection, the short-term adaptation of mucosal cells to mild
topical irritants. This phenomenon enables the stomach to initially
withstand the damaging effects of irritants. Alterations in mucosal
defense that are induced by H. pylori or NSAIDs are the most
important cofactors in the formation of peptic ulcers.
HELICOBACTER PYLORI
H. pylori is a spiral-shaped, pH-sensitive, gram-negative, microaero-
philic bacterium that resides between the mucus layer and surface
epithelial cells in the stomach, or any location where gastric-type
epithelium is found.2,22 The combination of its spiral shape and
flagellum permits it to move from the lumen of the stomach, where
the pH is low, to the mucus layer, where the local pH is neutral.
H. pylori produces large amounts of urease, which hydrolyzes urea
in the gastric juice and converts it to ammonia and carbon dioxide.2
The local buffering effect of ammonia creates a neutral microenvi-
ronment within and surrounding the bacterium, which protects it
from the lethal effect of gastric acid. H. pylori also produces acid-
inhibitory proteins, which allows it to adapt to the low-pH environ-
ment of the stomach.2
H. pylori binds to specific regions within the stomach. It attaches
to gastric-type epithelium by adherence pedestals, which prevent the
organism from being shed during cell turnover and mucus secre-
tion.2 Colonization of the antrum and corpus (body) of the stomach
is associated with gastric ulcer and cancer.1,2,22 Antral organisms
colonize gastric metaplastic tissue (gastric tissue that develops in
the duodenum secondary to changes in gastric acid or bicarbonate
secretion) leading to duodenal ulcer (see Fig. 402).1,2 Although
H. pylori causes chronic gastric mucosal inflammation in all infected
 567
individuals, only a minority actually develop an ulcer or gastric can-
Membrane phospholipids
cer.1,2,8 The difference in the diverse clinical outcomes is related to

CHAPTER 40
Phospholipase A2
variations in bacterial pathogenicity and host susceptability.2,22
Arachidonic acid
Mucosal injury is produced by (1) elaborating bacterial enzymes NSAIDs
ASA
(urease, lipases, and proteases), (2) adherence, and (3) H. pylori
Lipoxygenase Cyclooxygenase
virulence factors.2,22 Lipases and proteases degrade gastric mucus,
ammonia produced by urease may be toxic to gastric epithelial cells, PG endoperoxide
and bacterial adherence enhances the uptake of toxins into gastric 15-HPETE 5-HPETE
epithelial cells. H. pylori induces gastric inflammation by altering the
host inflammatory response and damaging epithelial cells directly Lipoxin A1B Leukotrienes A4-E4 Thromboxane A2 PGE2
PG1 (prostacyclin)

Peptic Ulcer Disease

by cell-mediated immune mechanisms or indirectly by activated
neutrophils or macrophages attempting to phagocytose bacteria
or bacterial products.2,22 However, H. pylori strains are genetically
diverse and account for differences in adaptation within the human
host. Two of the most important are cytotoxin-associated gene
protein (CagA) and vacuolating cytotoxin (VacA). About 60% of H.
pylori strains in the United States possess CagA, but CagA-positive
strains increase the risk for severe PUD, gastritis, and gastric cancer
compared with CagA-negative strains.2,22 The VacA gene codes
for the Vac-A cytotoxin, a vacuolizating toxin. Although VacA is
present in most all H pylori strains, strains vary in cytotoxicity and
increased risk for peptic ulcer and gastric cancer.2,22 Host polymor-
phisms are important markers of disease susceptibility and may
identify high-risk patients.2,22 Polymorphisms of interleukin (IL)-1
and its receptor antagonist, as well as tumor necrosis factor (TNF-)
and IL-10, may be associated with increased gastric acid secretion and
duodenal ulcer or acid suppression and gastric cancer.2,22
NONSTEROIDAL ANTIINFLAMMATORY DRUGS
NSAIDs, including aspirin (see Table 403), cause gastric mucosal
damage by two important mechanisms: (1) direct or topical irrita-
tion of the gastric epithelium and (2) systemic inhibition of endog-
enous mucosal prostaglandin synthesis.1,13 Although the initial
injury is initiated topically by the acidic properties of many of the
NSAIDs, systemic inhibition of the protective prostaglandins limits
the ability of the mucosa to defend itself against injury and thus
plays the predominant role in the development of gastric ulcer.1,13
Topical irritant properties are predominantly associated with
acidic NSAIDs (e.g., aspirin) and their ability to decrease the
hydrophobicity of the mucous gel layer in the gastric mucosa. Most
nonaspirin NSAIDs have topical irritant effects, but aspirin is the
most damaging. Although NSAID prodrugs, enteric-coated aspirin
tablets, salicylate derivatives, and parenteral or rectal preparations
are associated with less-acute topical gastric mucosal injury, they
can cause ulcers and related GI complications as a result of their
systemic inhibition of endogenous PGs.1
Cyclooxygenase (COX) is the rate-limiting enzyme in the
conversion of arachidonic acid to prostaglandins and is inhibited
by NSAIDs (Fig. 403). Two similar COX isoforms have been
identified: cyclooxygenase-1 (COX-1) is found in most body
tissue, including the stomach, kidney, intestine, and platelets;
cyclooxygenase-2 (COX-2) is undetectable in most tissues under
normal physiologic conditions, but its expression can be induced
during acute inflammation and arthritis (Fig. 404).1,13 COX-1
produces protective prostaglandins that regulate physiologic
processes such as GI mucosal integrity, platelet homeostasis, and
renal function. COX-2 is induced (unregulated) by inflammatory
stimuli such as cytokines and produces prostaglandins involved
with inflammation, fever, and pain. COX-2 is also constitution-
ally expressed in organs such as the brain, kidney, and reproduc-
tive tract. Adverse effects (e.g., GI or renal toxicity) of NSAIDs
are primarily associated with the inhibition of COX-1, whereas
antiinflammatory actions result primarily from NSAID inhibi-
tion of COX-2.1,13
PGD2
12-HPETE PGF2
FIGURE 40-3. Metabolism of arachidonic acid after its release from
membrane phospholipids. Broken arrow indicates inhibitory effects. (ASA,
aspirin; HPETE, hydroperoxyeicosatetraenoic acid; NSAIDs, nonsteroidal
antiinflammatory drugs; PG, prostaglandin.)
The COX-1-to-COX-2 inhibitory ratio determines the relative
GI toxicity of a specific NSAID. Nonselective NSAIDs, including
aspirin (see Table 403), inhibit both COX-1 and COX-2 to vary-
ing degrees and are associated with an increased propensity to cause
gastric ulcers.1,13 In contrast, the selective COX-2 inhibitors are
associated with a reduction in ulcers and related GI complications,
but the benefit of celecoxib, is less that that of rofecoxib and valde-
coxib (see Table 403). The addition of aspirin to a selective COX-2
inhibitor reduces its ulcer-sparing benefit and increases ulcer
risk.1,13 Aspirin and nonaspirin NSAIDs irreversibly inhibit platelet
COX-1, resulting in decreased platelet aggregation and prolonged
bleeding times, thereby increasing the potential for upper and lower
GI bleeding.1,13,15 Coadministration of selected NSAIDs may reduce
the antiplatelet effects of aspirin.1315 Clopidogrel and other medica-
tions that impair angiogenesis do not cause ulcers, per se, but may
impair healing of gastric erosions leading to ulceration.13,15
COMPLICATIONS
Upper GI bleeding, perforation, and obstruction occur with
H. pyloriassociated and NSAID-induced ulcers and constitute
the most serious, life-threatening complication of chronic PUD.1,23
Bleeding is caused by the erosion of an ulcer into an artery. It
may be occult (hidden) and insidious or may present as melena
Cyclooxygenase
COX-1 COX-2
Constitutively expressed Induced at inflammation site
Selective
Nonselective
COX-2
NSAID/ASA
inhibitor
Macrophages
Stomach
Leukocytes
Kidney
Platelets
Fibroblasts
Endothelial cells
Intestinal endothelium
Other
FIGURE 40-4. Tissue distribution and actions of cyclooxygenase (COX)
isoenzymes. Nonselective nonsteroidal antiinflammatory drugs (NSAIDs)
including aspirin (ASA) inhibit COX-1 and COX-2 to varying degrees; COX-2
inhibitors inhibit only COX-2. Broken arrow indicates inhibitory effects.
568
(black-colored stools) or hematemesis (vomiting of blood). The
use of NSAIDs (especially in older adults) is the most important
SECTION 4
risk factor for upper GI bleeding. Deaths occur primarily in
patients who continue to bleed or in those patients who rebleed
after the initial bleeding has stopped (see Upper Gastrointestinal
Bleeding).
Ulcer-related perforation into the peritoneal cavity is generally
considered a surgical emergency.1,23 About one third to one half
of perforated ulcers are associated with the use of NSAIDs, with
the highest mortality reported in the elderly.23 The pain of perfo-
Gastrointestinal Disorders
ration is usually sudden, sharp, and severe, beginning first in the
epigastrium, but quickly spreading over the entire abdomen. Most
patients experience ulcer symptoms prior to perforation. However,
older patients who experience perforation in association with
NSAID use may be asymptomatic. Penetration occurs when an
ulcer burrows into an adjacent structure (pancreas, biliary tract, or
liver) rather than opening freely into a cavity.
Gastric outlet obstruction is related to mechanical obstruction
caused by scarring, muscular spasm or edema of the duodenal bulb
usually resulting from chronic ulcercation.1,23 Symptoms occur over
several months and include early satiety, bloating, anorexia, nausea,
vomiting, and weight loss. Perforation, penetration, and gastric out-
let obstruction occur most often with long-standing PUD.
Treatment of PUD has improved so that even the most virulent
ulcers can be managed with medication. Intractability to drug
therapy is an infrequent manifestation of PUD and an infrequent
indication for surgery.
SIGNS AND SYMPTOMS
The clinical presentation of PUD varies depending on the severity
of epigastric pain and the presence of complications (Table 405).1
Ulcer-related pain in duodenal ulcer often occurs 1 to 3 hours after
meals and is usually relieved by food, but this is variable. In gas-
tric ulcer, food may precipitate or accentuate ulcer pain. Antacids
usually provide immediate pain relief in most ulcer patients. Pain
usually diminishes or disappears during treatment; however, recur-
rence of epigastric pain after healing often suggests an unhealed or
recurrent ulcer.
The presence or absence of epigastric pain does not define an ulcer.1
Ulcer healing does not necessarily render the patient asymptomatic.
Why symptoms remain is unclear, but it may relate to sensitization
of afferent nerves in response to mucosal injury.1 Conversely, the
absence of pain does not preclude an ulcer diagnosis especially in
the elderly who may present with a silent ulcer complication. The
reasons for this are unclear, but may relate to differences in the way
the elderly perceive pain or the analgesic effect of NSAIDs.
Dyspepsia in itself is of little clinical value when assessing subsets
of patients who are most likely to have an ulcer. Patients taking
NSAIDs often report dyspepsia, but dyspeptic symptoms do not
directly correlate with an ulcer. Individuals with dyspeptic symp-
toms may have either uninvestigated (no upper endoscopy) or
investigated (underwent upper endoscopy) dyspepsia. If an ulcer
is not confirmed in a patient with ulcer-like symptoms at the time
of endoscopy, the disorder is referred to as nonulcer dyspepsia.9
Ulcer-like symptoms may occur in the absence of peptic ulceration
in association with H. pylori gastritis or duodenitis. There is no one
sign or symptom that differentiates between H. pyloripositive and
NSAID-induced ulcer.
DIAGNOSIS
Routine laboratory tests are not helpful in establishing the diagnosis
of PUD (see Table 405).1
TABLE 40-5 Clinical Presentation of Peptic Ulcer Disease
General
Mild epigastric pain or acute life-threatening upper gastrointestinal
complications
Symptoms
Abdominal pain that is often epigastric and described as burning but may
present as vague discomfort, abdominal fullness, or cramping
A typical nocturnal pain that awakens the patient from sleep (especially
between 12 AM and 3 AM)
The severity of ulcer pain varies from patient to patient and may be
seasonal, occurring more frequently in the spring or fall; episodes of
discomfort usually occur in clusters, lasting up to a few weeks and followed
by a pain-free period or remission lasting from weeks to years
Changes in the character of the pain may suggest the presence
of complications
Heartburn, belching, and bloating often accompany the pain
Nausea, vomiting, and anorexia are more common for patients with gastric
ulcer than with duodenal ulcer but may also be signs of an ulcer-related
complication
Signs
Weight loss associated with nausea, vomiting, and anorexia
Complications including ulcer bleeding, perforation, penetration,
or obstruction
Laboratory tests
Gastric acid secretory studies
The hematocrit and hemoglobin are low with bleeding, and stool hemoccult
tests are positive.
Tests for Helicobacter pylori (see Table 406).
Diagnostic tests
Fiberoptic upper endoscopy (esophagogastroduodenoscopy) detects more
than 90% of peptic ulcers and permits direct inspection, biopsy, visualization
of superficial erosions, and sites of active bleeding.
Upper gastrointestinal radiography with barium has been replaced with
upper endoscopy as the diagnostic procedure of choice for supsected
peptic ulcer.
TESTS FOR HELICOBACTER PYLORI
The diagnosis of H. pylori infection can be made using endoscopic
or nonendoscopic tests (Table 406).2,5,24 The tests that require
upper endoscopy are invasive, more expensive, and usually require
a mucosal biopsy for histology, culture, or detection of urease activ-
ity. At least three tissue samples are taken from specific areas of the
stomach, as patchy distribution of H. pylori infection can lead to
false-negative results. Because certain medications may decrease the
sensitivity of rapid urease test, antibiotics and bismuth salts should
be withheld for 4 weeks and proton pump inhibitors (PPIs) for 1 to
2 weeks prior to endoscopic testing.2,5 If the patient has been taking
these medications, then a gastric biopsy for histology should be
performed.5
Two types of nonendoscopic tests are available: tests that identify
active infection and tests that detect antibodies (see Table 406).
Antibody tests do not differentiate between active infection and
previously eradicated H. pylori. The nonendoscopic tests include
the urea breath test (UBT), serologic antibody detection tests, and
the fecal antigen test. These tests are less invasive, more convenient,
and less expensive than the endoscopic tests.2,5,24
The UBT is the most accurate noninvasive test and is based on
H. pylori urease activity.5 The 13carbon (nonradioactive isotope) and
14
carbon (radioactive isotope) tests require that the patient ingest
radiolabeled urea, which is then hydrolyzed by H. pylori (if present
in the stomach) to ammonia and radiolabeled bicarbonate. The
radiolabeled bicarbonate is absorbed in the blood and excreted in
the breath. A mass spectrometer is used to detect 13Carbon whereas
14
Carbon is measured using a scintillation counter. The fecal antigen
test is less expensive and easier to perform than the UBT, and may

TABLE 40-6 Tests for Detection of Helicobacter pylori
Test Description
Endoscopic tests
Histology Microbiologic examination using
various stains
Culture Culture of biopsy
Biopsy (rapid) urease H. pylori urease generates ammonia,
which causes a color change
Polymerase chain H. pylori DNA detected gastric tissue
reaction
Nonendoscopic tests
Antibody detection Detects antibodies to H. pylori in
(laboratory based) serum using laboratory-based
enzyme-linked immunosorbent
assay (ELISA) tests and latex
agglutination techniques
Antibody detection (can Detects IgG antibodies to H. pylori
be performed in office in whole blood or finger stick
or near patient)
Urea breath test H. pylori urease breaks down
ingested labeled C-urea, patient
exhales labeled CO2
Fecal antigen Identifies H. pylori antigen in stool
by enzyme immunoassay using
polyclonal anti-H. pylori antibody
H2RA, H2-receptor antagonist; PPI, proton pump inhibitor.
Data from references 2, 5, and 25.
be useful in children. Although comparable to the UBT in the initial
detection of H. pylori, the fecal antigen test is less accurate when
used to confirm H. pylori eradication posttreatment and is consid-
ered an alternative to the UBT.
Serologic tests are a cost-effective alternative for the initial diag-
nosis of H. pylori infection in the untreated patient.2,5 Antibodies to
H. pylori usually develop about 3 weeks after infection and remain
present after successful eradication.5 Therefore, serology should not
be used to confirm H. pylori eradication.2,5 Office-based tests are less
expensive, widely available and provide rapid results, but the results
are less accurate and more variable than the laboratory-based tests.
Salivary and urine antibody tests are under investigation.2
Testing for H. pylori is only recommended if eradication is
planned. Serologic antibody testing is a reasonable choice if endos-
copy is not planned. The diagnostic accuracy of H. pylori tests for
patients with an active bleeding ulcer has been questioned because
of the potential for false-negative results. However, endoscopic
biopsy-based tests such as the rapid urease test have a high degree of
specificity in these patients (see Peptic Ulcer-Related Bleeding).5
Confirmation of eradication is indicated posttreatment of active
ulcers, previous ulcers, MALT lymphoma, endoscopic resection
of gastric cancer, and uninvestigated dyspepsia, but routine test-
ing for all patients is neither cost-effective nor practical.5 The
decision to test posttreatment should be patient specific and take
into consideration the patients diagnosis, age, and ulcer history.
The UBT is the preferred nonendoscopic test to confirm H. pylori
eradication but must be delayed at least 4 weeks after the comple-
tion of treatment to avoid confusing bacterial suppression with
eradication. The term eradication or cure is used when posttreat-
ment tests conducted 4 weeks after the end of treatment do not
detect the organism. Quantitative antibody tests are impractical for
posttreatment as antibody titers remain elevated for long periods
569
CHAPTER 40
Comments
Gold standard; >95% sensitive and specific; permits classification of gastritis; results are not immediate; not
recommended for initial diagnosis; tests for active H. pylori infection
Enables sensitivity testing to determine appropriate treatment or antibiotic resistance; 100% specific; results
are not immediate; not recommended for initial diagnosis; used after failure of second-line treatment;
tests for active H. pylori infection
Test of choice at endoscopy; >90% sensitive and specific; easily performed; rapid results (usually within
24 hours); tests for active H. pylori infection
Peptic Ulcer Disease
Test is highly specific and sensitive; high rate of false positives and false negatives; positive DNA does not
directly equate top presence of the organism; considered a research technique
Quantitative; less sensitive and specific than endoscopic tests; more accurate than in office; unable to determine
if antibody is related to active or cured infection; antibody titers vary markedly among individuals and take
6 months to 1 year to return to the uninfected range; not affected by PPIs or bismuth; antibiotics given for
unrelated indications may cure the infection, but antibody test will remain positive
Qualitative; quick (within 15 minutes); unable to determine if antibody is related to active or cured
infection; most patients remain seropositive for at least 6 months to 1 year after H. pylori eradication;
not affected by PPIs, bismuth, or antibiotics
Tests for active H. pylori infection; 95% sensitive and specific; results take about 2 days; antibiotics,
bismuth, PPIs, and H2RAs may cause false-negative results; withhold PPIs or H2RAs (12 weeks)
and bismuth or antibiotics (4 weeks) prior to testing; recommended test to confirm posttreatment
eradication of H. pylori
Tests for active H. pylori infection; sensitivity and specificity comparable to urea breath test when used for
initial diagnosis; antibiotics, bismuth, and PPIs may cause false-negative results, but to a lesser extent
than with the urea breath test; may be used posttreatment to confirm eradication, but patients may
have a reluctance to obtain stool samples
of time. A negative posttreatment antibody test, however, is con-
sidered reliable.
IMAGING AND ENDOSCOPY
The diagnosis of PUD depends on visualizing the ulcer crater either
by upper GI radiography or upper endoscopy (see Table 405).1 In
the past, radiograpy was the initial diagnostic procedure of choice
because of its lower cost, greater availability, and greater safety. Today,
upper endoscopy has replaced radiography because it provides a more
accurate diagnosis and permits direct visualization of the ulcer.
CLINICAL COURSE AND PROGNOSIS
The natural history of PUD is characterized by periods of exacerba-
tions and remissions.1 Ulcer pain is usually recognizable and epi-
sodic, but symptoms are variable, especially in older adults and for
patients taking NSAIDs. Antiulcer medications, including the hista-
mine-2 receptor antagonists (H2RAs), PPIs, and sucralfate, relieve
symptoms, accelerate ulcer healing, and reduce the risk of ulcer
recurrence, but they do not cure the disease. Both duodenal and gas-
tric ulcers recur unless the underlying cause (H. pylori or NSAID) is
removed. Successful H. pylori eradication markedly decreases ulcer
recurrence and complications. Prophylactic cotherapy or a COX-2
inhibitor decreases the risk of upper GI events for patients who are
taking NSAIDs. GI bleeding, perforation, or obstruction remain
troublesome complications of chronic PUD. Mortality for patients
with gastric ulcer is slightly higher than in duodenal ulcer and the
general population. The development of gastric cancer in H. pylori
infected individuals is a slow process that occurs over 20 to 40 years
and is associated with a lifetime risk of less than 1%.2,8
570

TREATMENT  GENERAL APPROACH TO TREATMENT

SECTION 4

The eradication of H. pylori infection with antimicrobials such as

 DESIRED OUTCOME
The treatment of chronic PUD varies depending on the etiology of
the ulcer (H. pylori or NSAID), whether the ulcer is initial or recur-
rent, and whether complications have occurred (Fig. 405). Overall
treatment is aimed at relieving ulcer pain, healing the ulcer, prevent-
ing ulcer recurrence, and reducing ulcer-related complications. The
goal of therapy for H. pyloripositive patients with an active ulcer, a
Gastrointestinal Disorders
clarithromycin, metronidazole, amoxicillin, bismuth salts, and anti-
secretory drugs (PPIs or H2RAs) relieve ulcer symptoms, heal the
ulcer, and eradicate H. pylori infection. PPIs are preferred to H2RAs
or sucralfate for healing H. pylorinegative NSAID-induced ulcers
because they accelerate ulcer healing and provide more effective
relief of symptoms. Treatment with a PPI should be extended to 8
to 12 weeks if the NSAID must be continued. A PPI-based H. pylori
eradication regimen is recommended when the patient with an active

previously documented ulcer, or a history of an ulcer-related compli-
cation, is to eradicate H. pylori, heal the ulcer, and cure the disease.
Successful eradication heals ulcers and reduces the risk of recurrence
for most patients. The goal of therapy for a patient with a NSAID-
induced ulcer is to heal the ulcer as rapidly as possible. Patients
who are at high risk of developing NSAID ulcers should receive
prophylactic cotherapy or be switched to a selective COX-2 inhibitor
NSAID (if available) to reduce ulcer risk and related complications.
When possible, the most cost-effective drug regimen should be used.
ulcer is taking an NSAID and is H. pyloripositive. Prophylactic
cotherapy with either a PPI or misoprostol decreases ulcer risk and
upper GI complications for patients taking nonselective NSAIDs.
Selective COX-2 inhibitor NSAIDs (if available) may be used as an
alternative to a nonselective NSAID, but their beneficial GI effect
when taken with low-dose aspirin is negated and their association
with adverse cardiovascular effects reduce their usefulness.
Dietary modifications are important for patients who are unable to
tolerate certain foods and beverages. Lifestyle modifications such as

Patient presents with ulcer-like symptoms

Dyspepsia, no alarm symptoms Alarm symptoms present, e.g.,

bleeding, anemia, weight loss

On NSAID?
Endoscopy to assess
ulcer status
Yes No

Ulcer present Ulcer absent

Previously
Stop NSAID: if not treated for
Test for H. pylori Consider other
possible, decrease dose H. pylori?
etiologies for
symptoms, e.g.,
No Yes Positive Negative GERD, NUD

Symptoms Symptoms
Perform Continue
resolve persist
serology Treat with PPI- On NSAID? NSAID or
based H. pylori switch to
No further eradication Discontinue COX-2
Initiate
treatment regimen NSAID inhibitor, if
H2RA Negative
available
or PPI

Positive Treat with PPI

Treat ulcer with

No further Signs/symptoms 12
No PPI followed by
treatment weeks posttreatment?
cotherapy with
Symptoms Symptoms PPI or
Yes misoprostol
resolve persist

Consider NSAID use,

antibiotic resistance,
Consider continuation of nonadherence, other
PPI or H2RA diagnosis

FIGURE 40-5. Algorithm. Guidelines for the evaluation and management of a patient who presents with dyspeptic or ulcer-like symptoms. (COX-2,
cyclooxygenase-2; GERD, gastroesophageal reflux disease; H. pylori, Helicobacter pylori; H2RA, H2-receptor antagonist; PPI, proton pump inhibitor; NSAID,
nonsteroidal antiinflammatory drug; NUD, nonulcer dyspepsia.)
 571
reducing stress and stopping cigarette smoking is encouraged. Surgery TABLE 40-7 Guidelines for the Eradication of Helicobacter
may be necessary for patients with ulcer-related complications.

 NONPHARMACOLOGIC THERAPY
 Patients with PUD should eliminate or reduce psychological
stress, cigarette smoking, and the use of NSAIDs (including
aspirin). Although there is no antiulcer diet, the patient should
avoid foods and beverages (e.g., spicy foods, caffeine, and alcohol)
that cause dyspepsia or that exacerbate ulcer symptoms. If possible,
CHAPTER 40
pylori Infection
Indications for treatment of H. pylori infection
Established indications for the treatment of H. pylori include gastric or duodenal
ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma, after endoscopic
resection of gastric cancer, and uninvestigated dyspepsia
Controversial indications for the treatment of H. pylori infection include nonulcer
dyspepsia, gastroesophageal reflux disease, individuals taking nonsteroidal
antiinflammatory drugs (NSAIDs), individuals at high risk for gastric cancer, and
unexplained iron deficiency anemia.

Peptic Ulcer Disease

alternative agents such as acetaminophen or nonacetylated salicylate
(e.g., salsalate) should be used for relief of pain. Elective surgery for
PUD is rarely performed today because of highly effective medical
management. A subset of patients, however, may require emer-
gency surgery for bleeding, perforation, or obstruction. In the past,
surgical procedures were performed for medical treatment failures
and included vagotomy with pyloroplasty or vagotomy with ant-
rectomy.23 Vagotomy (truncal, selective, or parietal cell) inhibits
vagal stimulation of gastric acid. A truncal or selective vagotomy
frequently results in postoperative gastric dysfunction and requires
a pyloroplasty or antrectomy to facilitate gastric drainage. When an
antrectomy is performed, the remaining stomach is anastomosed
with the duodenum (Billroth I) or with the jejunum (Billroth II).
A vagotomy is unnecessary when an antrectomy is performed for
gastric ulcer. Postoperative consequences include postvagotomy
diarrhea, dumping syndrome, anemia, and recurrent ulceration.
 PHARMACOLOGIC THERAPY
Recommendations
 Table 407 presents guidelines for the eradication of infection
in H. pyloripositive individuals. Table 408 lists regimens used to
eradicate H. pylori infection.
 First-line therapy is usually initiated with a PPI-based three-
drug regimen for 10 to 14 days. If a second course of treatment
is required, the PPI-based three-drug regimen should contain
different antibiotics or a four-drug regimen with a bismuth salt,
metronidazole, tetracycline, and a PPI should be used.
Initial treatment of H. pylori infection
Use only those eradication regimens that are of proven effectiveness in the
United States
In the United States, first-line treatment should include a proton pump inhibitor
(PPI), clarithromycin, and either amoxicillin or metronidazole (PPI-based triple
therapy) for 1014 days
The PPI-based triple therapy amoxicillin-containing regimen is preferred
initially because bacterial resistance to amoxicillin is almost absent, it has
fewer adverse effects, and it leaves metronidazole as a backup agent for
second-line therapy
In penicillin allergic patients, metronidazole should be substituted for amoxicillin
in the PPI- based triple therapy regimen and yields similar results when
combined with clarithromycin
An alternate initial strategy includes a PPI or H2RA, bismuth salt, tetracycline, and
metronidazole (bismuth-based quadruple therapy) for 1014 days.
Sequential therapy consisting of a PPI and amoxicillin for 5 days followed
by a PPI, clarithromycin, and metronidazole for 5 days is an alternative
to PPI-based triple therapy or PPI-based quadruple therapy, but requires
further validation before it can be recommended as first-line therapy in the
United States.
Eradication of H. pylori after initial treatment failure
Avoid antibiotics that have been used in previous eradication regimens.
Bismuth-based quadruple therapy with a bismuth salt, tetracycline,
metronidazole, and a PPI or H2RA for 1014 days is an acceptable treatment
regimen for persistent H. pylori infections.
PPI-based triple therapy with levofloxacin and amoxicillin for 10 days may be
more effective and better tolerated than PPI-based quadruple therapy with a
bismuth salt, tetracycline, and metronidazole, but it requires further validation
in the United States.
Data from references 5, 25 to 29.

TABLE 40-8 Drug Regimens Used to Eradicate Helicobacter pylori

Drug #1 Drug #2 Drug #3 Drug #4

Proton pump inhibitorbased triple therapya

PPI once or twice dailyb
Bismuth-based quadruple therapya
PPI or H2RA once or twice dailyb,c
e
Sequential therapy
PPI once or twice daily on days 110b
Second-line (salvage) therapy for persistent infections
PPI or H2RA once or twice dailyb,c
PPI once or twice dailyb,f
Clarithromycin 500 mg twice daily
Bismuth subsalicylated 525 mg 4 times daily
Amoxicillin 1 g twice daily on days 15
Bismuth subsalicylated 525 mg 4 times daily
Amoxicillin 1 g twice daily
Amoxicillin 1 g twice daily
or metronidazole 500 mg twice daily
Metronidazole 250500 mg 4 times daily Tetracycline 500 mg 4 times daily
Metronidazole 250500 mg twice daily Clarithromycin 250500 mg twice
on days 610 daily on days 610
Metronidazole 250500 mg 4 times daily Tetracycline 500 mg 4 times daily
Levofloxacin 250 mg twice daily

H2RA, H2-receptor antagonist; PPI, proton pump inhibitor.

a
Although treatment is minimally effective if used for 7 days, 1014 days is recommended. The antisecretory drug may be continued beyond antimicrobial treatment for patients with a history of a
complicated ulcer, e.g., bleeding, or in heavy smokers.
b
Standard PPI peptic ulcer healing dosages given once or twice daily (see Table 409).
c
Standard H2RA peptic ulcer healing dosages may be used in place of a PPI (see Table 409).
d
Bismuth subcitrate potassium (biskalcitrate) 140 mg, as the bismuth salt, is contained in a prepackaged capsule (Pylera), along with metronidazole 125 mg and tetracycline 125 mg; three capsules are taken
with each meal and at bedtime; a standard PPI dosage is added to the regimen and taken twice daily. All medications are taken for 10 days.
e
Requires validation as first-line therapy in the United States.
f
Requires validation as rescue therapy in the United States.
Data from references 5, 25 to 29.
572
TABLE 40-9 Oral Drug Regimens Used to Heal Peptic Maintenance therapy with a PPI or H2RA should be limited
Ulcers and Maintain Ulcer Healing to high-risk patients with ulcer complications, patients who fail
SECTION 4

eradication, and those with H. pylorinegative ulcers. Treatment

Duodenal Maintenance
failure is associated with poor medication adherence, antimicrobial
or Gastric of Ulcer
Prescription Ulcer Healing Healing
resistance, NSAID use, cigarette smoking, acid hypersecretion, or
Generic Name Brand Name (mg/dose) (mg/dose) tolerance to the antisecretory effects of an H2RA.
Proton pump inhibitors
Omeprazole Prilosec, various 2040 daily 2040 daily Treatment of Helicobacter
Omeprazole sodium Zegerid 2040 daily 2040 daily PyloriPositive Ulcers
bicarbonate
This chapter focuses on the eradication of H. pylori in adults.2529
Gastrointestinal Disorders

Lansoprazole Prevacid, various 1530 daily 1530 daily

Rabeprazole Aciphex 20 daily 20 daily A discussion of the treatment of H. pylori infection in children is
Pantoprazole Pantoprazole, 40 daily 40 daily found elsewhere.30,31
various The treatment of H. pyloripositive PUD should be effective, well
Esomeprazole Nexium 2040 daily 2040 daily tolerated, easy to adhere to, and cost-effective. Historically, none
Dexlansoprazole Dexilant 3060 daily 30 daily of these factors have been addressed in a systematic way making
H2-receptor antagonists it difficult to identify the best evidence-based treatment regimens.1
Cimetidine Tagamet, various 300 four times daily 400800 at Successful eradication depends on the drug regimen, resistance to
400 twice daily bedtime
the antibiotics used, duration of therapy, medication adherence,
800 at bedtime
Famotidine Pepcid, various 20 twice daily 2040 at bedtime
and genetic polymorphism.2529 H. pylori regimens should have
40 at bedtime eradication (cure) rates of at least 80% based on intention-to-treat
Nizatidine Axid, various 150 twice daily 150300 at analysis or at least 90% based on per-protocol analysis, and they
300 at bedtime bedtime should minimize the potential for antimicrobial resistance.1,25,29 Not
Ranitidine Zantac, various 150 twice daily 150300 at one antibiotic, bismuth salt, or antiulcer drug achieves this goal,
300 at bedtime bedtime but clarithromycin is the single most effective antibiotic. Two-drug
Promote mucosal defense regimens that combine a PPI and either amoxicillin or clarithro-
Sucralfate Carafate, various 1 g 4 times daily 12 g twice daily mycin have yielded marginal and variable eradication rates in the
2 g twice daily 1 g 4 times daily United States and are not recommended.1,5 In addition, the use of
only one antibiotic is associated with a higher rate of antimicrobial
resistance.
Patients with NSAID-induced ulcers should be tested to deter- Drug regimens (see Table 408) that combine an antisecretory
mine their H. pylori status. If H. pyloripositive, treatment should drug with two antibiotics (triple therapy) or with two antibiotics and a
be initiated with a PPI-based three-drug regimen. If H. pylori bismuth salt (quadruple therapy) usually increase eradication rates to
negative, the NSAID should be discontinued, and the patient acceptable levels and reduce the risk of antimicrobial resistance.5,2529
treated with either a PPI, H2RA, or sucralfate (see Table 409). If When selecting an initial eradication regimen, an antibiotic combi-
the NSAID is continued, treatment should be initiated with a PPI nation should be used that permits second-line treatment (if neces-
(if H. pylori negative) or with a PPI-based three-drug regimen (if sary) with different antibiotics. The antibiotics that have been most
H. pylori positive). Cotherapy with a PPI or misoprostol or switch- extensively studied and found to be effective in various combinations
ing to a selective COX-2 inhibitor (if available) is recommended include clarithromycin, amoxicillin, metronidazole, and tetracycline.1
for patients at risk of developing an ulcer-related complication Because of insufficient data, ampicillin should not be substituted for
(see Table 4010). amoxicillin, doxycycline should not be substituted for tetracycline,

TABLE 40-10 Guidelines for Reducing Gastrointestinal Risk for Patients Receiving Chronic NSAID Therapy
Gastrointestinal risk factors (see Table 404)

Cardiovascular Risk No or Low GI Risk Moderate GI Risk High GI Risk

No or low CV risk (patient
does not require
low-dose aspirin)
High CV risk (patient
requires low-dose
aspirin, no NSAID
High CV risk (patient
requires low-dose
aspirin) and NSAID
(No risk factors) (12 risk factors) (> 2 risk factors or prior ulcer or ulcer-related complication)
Age < 65 years) Age 65 years Age 65 years
High-dose NSAIDs Concomitant use of aspirin corticosteroids, or anticoagulants
Concomitant use of aspirin, Dual antiplatelet therapy
corticosteroids, or anticoagulants
Nonselective NSAID or Nonselective NSAID or partially selective Avoid NSAID or selective COX-2 inhibitor, if possible; use alternative therapy
partially selective NSAID NSAID + PPI or misoprostol Nonselective NSAID or partially selective NSAID + PPI or misoprostol
(see Table 403) Selective COX-2 inhibitor NSAID (if available) Selective COX-2 inhibitor NSAID (if available) + PPI or misoprostol
No prophylaxis required PPI or misoprostol PPI or misoprostol
Naproxen + PPI or Naproxen + PPI or misoprostol Avoid NSAID or selective COX-2 inhibitor, if at all possible; use
misoprostol alternative therapy
If antiinflammatory drug is needed and CV risk is >GI risk, use
naproxen and aspirin + PPI or misoprostol
If antiinflammatory drug and aspirin are needed and GI risk is
>CV, use selective COX-2 inhibitor + PPI or misoprostol

COX-2, cycloxygenase-2 inhibitor; NSAID, nonsteroidal antiinflammatory drug; PPI, proton pump inhibitor; CV, cardiovascular; GI, gastrointestinal.
Data from references 12 to 15, 18, 19, and 59.

and azithromycin or erythromycin should not be substituted for
clarithromycin. Antisecretory drugs enhance antibiotic activity and
stability by increasing intragastric pH and by decreasing intragastric
volume thereby enhancing the topical antibiotic concentration.27
Proton Pump InhibitorBased
Three-Drug Regimens
PPI-based triple therapy (see Table 408) is the initial treatment of
choice for eradicating H. pylori (see Table 407).5,2529 The regimens
that combine either clarithromycin and amoxicillin or clarithro-
mycin and metronidazole are more effective than the amoxicillin-
metronidazole regimen. In most cases, increasing the antibiotic dosage
does not improve eradication rates. The clarithromycin-amoxicillin
regimen is preferred initially (see Table 407), but metronidazole
should be substituted for amoxicillin for penicillin-allergic patients
unless alcohol is consumed.5,2527 Unfortunately, eradication rates
for PPI-based triple therapy have declined substantially in recent
years in North America and Europe due primarily to an increase
in clarithromycin-resistant H. pylori strains (see the section Factors
that Contribute to Unsuccessful Eradication).5.2527 Other antibiot-
ics and antibiotic combinations have been investigated, but these
regimens should not be used as initial treatment in the United States
until well-designed trials confirm their effectiveness.5,27
The recommended duration of therapy in the United States is
10 to 14 days, but the 14-day regimen is preferred in light of the
decreasing eradication rate with the PPI-based triple therapy regi-
mens containing clarithomycin.5 Although a 7-day course has been
approved by the FDA and is used in Europe, the longer treatment
periods favor higher eradication rates and are less likely to be asso-
ciated with antimicrobial resistance.5,2527
CLINICAL CONTROVERSY
Some clinicians favor an initial 7-day H. pylori regimen even
though clinical guidelines suggest a longer treatment course.
These clinicians believe that the shorter treatment period
enhances the compliance of a complicated drug regimen.
Others adhere to clinical guidelines and recommend a 10- or
14-day treatment period that favors higher eradication rates in
the compliant patient and is less likely to contribute to antimi-
crobial resistance.
The PPI is an integral part of the three-drug regimen and should be
taken 30 to 60 minutes before a meal along with the two antibiotics (see
Table 408).5,32 Prolonged PPI treatment beyond 2 weeks after eradi-
cation is usually not necessary for ulcer healing. A single daily dose of
a PPI may be less effective than a twice daily dose.33 Substitution of
one PPI for another is acceptable and does not enhance or diminish
H. pylori eradication.32,34 An H2RA should not be substituted for a PPI,
as H2RA is associated with lower eradication rates.35,36 Pretreatment
with a PPI does not influence H. pylori eradication.37
Bismuth-Based Four-Drug Regimens
Bismuth-based quadruple therapy (see Table 408) is recommended
as an alternative first-line eradication therapy (see Table 407) for
those allergic to penicillin.5,2529 Although this regimen may be used
initially, it is often reserved as a second-line therapy after treatment
failure with the PPI-based clarithromycin-amoxicillin regimen (see
the section Eradication of H. Pylori After Initial Treatment Failure).
Eradication rates for bismuth-based quadruple therapy (bismuth
salicylate, metronidazole, tetracycline, and either a PPI or H2RA)
are similar to those achieved with PPI-based triple therapy.5,27,38
573
Eradication rates are comparable when bismuth subcitrate potas-
sium (biskalcitrate) is substituted for bismuth subsalicylate (see
CHAPTER 40
Table 408).39 Substitution of amoxicillin for tetracycline lowers the
eradication rate and is usually not recommended.38 Substitution of
clarithromycin 250 to 500 mg four times a day for tetracycline yields
similar results but increases adverse effects. Bismuth salts have a
topical antimicrobial effect.1 The antisecretory drug hastens ulcer
healing and relives pain in patients with an active ulcer. All medica-
tions except the PPI should be taken with meals and at bedtime.
The original bismuth-based regimens contained an H2RA in place of
Peptic Ulcer Disease
a PPI, but a recent metaanalysis indicated that quadruple therapy with
a PPI provides greater efficacy and permits a shorter treatment dura-
tion (7 days) when compared with the H2RA-based regimens (10 to
14 days).40 However. a 10- to 14-day duration is recommended in the
United States as it generally provides higher eradication rates.5 When
treating an active ulcer, the antisecretory drug is usually continued for
2 (PPI) to 4 (H2RA) weeks after stopping bismuth and antibiotics.
Bismuth-based quadruple therapy is the treatment of choice when
medication costs are of overriding importance. However, major
concerns include a 4-time-a-day dosing regimen (see Table 408),
poor medication adherence, and frequent adverse effects. Although
minor adverse effects are more common, the frequency of moderate
or severe adverse effects is similar to those reported for the PPI-
based triple therapy.41
Sequential Therapy Sequential therapy is a new form of eradica-
tion therapy whereby the antibiotics are administered in a sequence
rather than all together.5,26,29 The rationale for sequential therapy
is to initially treat with antibiotics that rarely promote resistance
(e.g., amoxicillin) to reduce the bacterial load and preexisting resis-
tant organisms and then to follow with different antibiotics (e.g.,
clarithromycin and metronidazole) to kill the remaining organisms.1
Treatment consists of a PPI and amoxicillin for 5 days followed by
a PPI, clarithromycin, and metronidazole for an additional 5 days
(see Table 408).5,26,42 Although this regimen has achieved eradica-
tion rates that are superior to the PPI-based three-drug regimens
containing clarithromycin,42 the regimen requires a change in medi-
cation mid-treatment, which may contribute to nonadherence.43
The advantages of sequential therapy need to be confirmed in the
United States before it can be recommended as a first-line H. pylori
eradication therapy (see Table 407).5,26,27
Eradication of H. Pylori After
Initial Treatment Failure
H. pylori eradication is often more difficult after initial treatment
fails and successful eradication after retreatment is extremely
variable.5,44 Treatment failures should be referred to a gastroen-
terologist for further diagnostic evaluation. Second-line (salvage)
treatment should (a) use antibiotics that were not previously used
during initial therapy; (b) use antibiotics that are not associated
with resistance; (c) use a drug that has a topical effect such as
bismuth; and (d) extend the duration of treatment to 14 days.5,44,45
The most commonly used second-line therapy, after unsuc-
cessful initial treatment with a PPI-amoxicillin-clarithromycin
regimen, is a 14-day course of the PPI-based quadruple therapy
(see Table 408).5,26,27,45 A levofloxacin-containing regimen (see
Table 408) may be an alternative second-line eradication regimen
and may be better tolerated than PPI-based quadruple therapy (see
Table 407).46 Additionally, the levofloxacin regimen may serve as
an alternative to PPI-clarithromycin-metronidazole usually recom-
mended in penicillin allergic patients.47 However, concerns about
using fluoroquinolones for H. pylori eradication are related to the
development of resistance and adverse effects such as tendonitis
and hepatoxicity.26 Other second-line regimens which include
rifabutin and furazolidone are discussed elsewhere.5,2527
574
Factors That Predict H. Pylori
Eradication Outcomes
SECTION 4
Factors that predict H. pylori eradication outcomes include anti-
biotic resistance, poor medication adherence, short duration of
therapy, CagA status, high bacterial load, low intragastric pH, and
genetic polymorphism.5,45,4850 Medication adherence decreases with
multiple medications, increased frequency of administration, intol-
erable adverse effects, and costly drug regimens. One metaanalysis
reported that CYP2C19 polymorphism may alter the effect of PPIs
on gastric acid secretion thereby influencing eradication outcomes.49
Gastrointestinal Disorders
Tolerability varies with different regimens.1,5 Common adverse
effects include nausea, vomiting, abdominal pain, diarrhea and taste
disturbances (metronidazole and clarithromycin). Adverse effects
with metronidazole are dose-related (especially when >1 g/day) and
include a disulfiram-like reaction with alcohol. Tetracycline may
cause photosensitivity and should not be used in children because
of possible tooth discoloration. Bismuth salts may cause darkening
of the stool and tongue. Antibiotic-associated colitis occurs occa-
sionally. Oral thrush and vaginal candidiasis may also occur.
An important predictor of H. pylori eradication is the pres-
ence or absence of resistant microrganisms.5,5052 United States
data from 1993 to 1999 report resistance rates among H. pylori
strains for metronidazole (37%), clarithromycin (10%), and
amoxicillin (1.4%).51 Data from 1998 to 2002 reveal rates of
25% for metronidazole, 13% for clarithromycin, and 0.9% for
amoxicillin.52 It is possible that the increased rate of clarithomycin
resistance partially explains the decrease in efficacy of clarithomy-
cin-containing regimens. The clinical importance of metronida-
zole resistance remains uncertain, as resistance can be overcome
by using higher dosages and combining metronidazole with
other antibiotics.5 Resistance to tetracycline and amoxicillin is
uncommon.5 Resistance to bismuth has not been reported. The role
of antibiotic sensitivity testing prior to initiating H. pylori treatment
has not been established.
Probiotics
Probiotics (e.g., strains of Lactobacillus and Bifidobacterium) and
foodstuffs (e.g., cranberry juice and some milk proteins) with bio-
active components have been used proactively to control H. pylori
colonization in at-risk individuals and, when taken as a supplement
to eradication therapy, may have a role in improving H. pylori
eradication and reducing the adverse effects of PPI-based triple
therapy.5355 However, the administration of probiotics alone does
not eradicate H. pylori infection. In the future, the regular intake
of probiotics may constitute a low-cost alternative for individuals
who are at-risk for H. pylori infection and, in combination with
antibiotics, augment eradication rates. These preliminary data are
encouraging and warrants more research in this area.
Treatment of NSAID-Induced Ulcers
Nonselective NSAIDs should be discontinued (when possible) upon
confirmation of an active ulcer. If the NSAID is stopped, most
uncomplicated ulcers heal with standard regimens of an H2RA,
PPI, or sucralfate (see Table 409).1,13,29 However, the PPIs are
usually preferred because they provide more rapid symptom relief
and ulcer healing. If the NSAID is continued despite ulceration,
consideration should be given to reducing the NSAID dose, switch-
ing to acetaminophen or a nonacetylated salicylate or to using a
more selective COX-2 inhibitor (see Table 403). The PPIs are the
drugs of choice when the NSAID is continued, as potent acid sup-
pression is required to accelerate ulcer healing.1,13,29 If the ulcer is
H. pyloripositive, eradication should be initiated with a regimen
that contains a PPI.1,13,29
Strategies to Reduce the Risk of NSAID Ulcer and GI
Complications There are three therapeutic approaches to reduc-
ing the risk of NSAID ulcers and related upper GI complications
(see Table 4010). Medical cotherapy with either a PPI or miso-
prostol decreases ulcer risk and GI complications in high-risk
patients.1214,16,19,29 The use of a selective COX-2 inhibitor instead
of a nonselective NSAID also decreases risk of ulcers and upper GI
events.1214,16,18,19,29 Unfortunately, these strategies do not completely
eliminate ulcers and complications for patients at the highest risk.
When selecting a gastroprotective strategy, the GI benefits be must
be balanced against the cardiovascular risks associated with selec-
tive COX-2 inhbitor NSAIDs, nonselective NSAIDs, and concomit-
tant antiplatelet therapy.1216 Strategies aimed at reducing the topical
irritant effects of nonselective NSAIDs, e.g., prodrugs, slow-release
formulations, and enteric-coated products, do not prevent ulcers or
GI complications.
Misoprostol Cotherapy Misoprostol, 200 mcg orally 4 times
per day, reduces the risk of NSAID-induced gastric and duo-
denal ulcer, and related upper GI complications, but diarrhea
and abdominal cramping limit its use.12,16,56 Because a dosage of
200 mcg 3 times per day is comparable in efficacy to 800 mcg/
day, the lower dosage should be considered for patients unable to
tolerate the higher dose.12,16 Reducing the misoprostol dosage to
400 mcg per day or less to minimize diarrhea compromises its gas-
troprotective effects. A fixed combination of misoprostol 200 mcg
and diclofenac (50 mg or 75 mg) may enhance compliance, but the
flexibility to individualize drug dosage is lost. A large clinical trial
in rheumatoid arthritis patients provided the most compelling evi-
dence that misoprostol reduces the risk of upper GI complications
for high-risk patients.57
Proton Pump Inhibitor Cotherapy  PPI cotherapy reduces
NSAID-related gastric and duodenal ulcer risk and is better toler-
ated than misoprostol.1214,16,56 All PPIs are effective when used
in standard dosages (see Table 409). Although head-to-head
comparative trials are few, there are limited data to indicate that
PPIs are superior to standard H2RA dosages.12,13,16, When lanso-
prazole (15 or 30 mg/day) was compared with misoprostol 800
mcg/day or placebo, both dosages of lansoprazole and misoprostol
effectively reduced ulcer recurrence, although the PPI was bet-
ter tolerated.58 A greater proportion of those in the misoprostol
group reported treatment-related adverse events and withdrew
early from the study. Results from observational studies and
metaanalyses indicate the PPIs reduce the risk of NSAID-related
ulcer bleeding.12,16,19,59
H2-Receptor Antagonist Cotherapy Standard H2RA dosages
(e.g., famotidine 40 mg/day) are effective in reducing NSAID-
related duodenal ulcer but not gastric ulcer (the most frequent
type of ulcer associated with NSAIDs).12,13,16 Higher dosages (e.g.,
famotidine 40 mg twice daily, ranitidine 300 mg twice daily) may
reduce the risk of gastric and duodenal ulcer, but studies compar-
ing double dosages with PPIs or misoprostol are not available.12,13
One study suggests that famotidine 20 mg twice daily may be
an alternative to PPIs for patients taking low cardioprotective
dosages of aspirin, but additional studies are required to confirm
these findings.60 The H2RAs are not recommended as prophylactic
cotherapy because it is likely that they are not as effective as the
PPIs or misoprostol in preventing NSAID-induced gastric ulcer
and related GI complications.16 An H2RA, however, may be used to
relieve NSAID-related dyspepsia.
Cyclooxygenase-2 Inhibitors Two large outcome trials have
compared celecoxib61 and rofecoxib62 to nonselective NSAIDs.
Patients in the Celecoxib Long-term Arthritis Safety Study (CLASS)
trial who were taking celecoxib and required cardioprotection

(antiplatelet effects of aspirin) were permitted to take low-dose aspi-
rin.61 Although a 6-month analysis found a nonsignficant reduc-
tion in ulcer complications with celecoxib when compared with
ibuprofen and diclofenac, results after 1 year found no difference
between the groups. Today, celecoxib is not considered a selective
COX-2 inhibitor (Table 403) by the FDA as it contains the same
GI warnings as the nonselctive and patially selective NSAIDs.63 A
post hoc analysis confirmed that any gastroprotective benefits of
celecoxib were negated in aspirin users. Similar effects have been
observed with rofecoxib.
The Vioxx Gastrointestinal Outcomes Research (VIGOR) trial
excluded aspirin users and found that ulcers and ulcer-related
complications were significantly reduced with rofecoxib when com-
pared with naproxen.62 However, there was an increased number
of nonfatal myocardial infarctions observed in the rofecoxib group
compared with those taking naproxen. It was initially suggested
that the lack of antiplatelet effects from rofecoxib, in contrast to the
platelet inhibition associated with naproxen, was responsible for
the increased thrombotic events observed in the rofecoxib group.
Rofecoxib was later withdrawn from the market following an
interim analysis of a study to prevent colorectal adenomas that
revealed an increased risk of myocardial infarction and thrombotic
stoke with rofecoxib when compared with placebo.64 Subsequently,
valdecoxib was withdrawn from the market amid concerns about
cardiovascular risk.
Cardiovascular safety was also evaluated in the CLASS trial, but
serious cardiovascular thromboembolic events were no different
between celecoxib and the comparative nonselective NSAIDs.
In contrast, the results of a metaanalysis of randomized trials of
COX-2 inhbitor NSAIDs reported a dose-dependent increase in
cardiovascular events with all COX-2 inhibitor NSAIDs, including
celecoxib.65 Increased cardiovascular risk appears to be dependent
on a number of factors including increased COX-2 selectivity,
higher dosages, and a longer duration of treatment.12,18,19 Thus, the
lowest effective celecoxib dose should be used for the shortest dura-
tion of time. Dyspepsia and abdominal pain, fluid retention, hyper-
tension, and renal toxicity are associated with the COX-2 inhibitors
and nonselective NSAIDs.1
COX-2 Inhibitor Versus NSAID plus PPI  There are limited
data that suggest that for high-risk, H. pylorinegative patients,
a COX-2 inhibitor NSAID may be as beneficial as a nonselective
NSAID plus a PPI in reducing NSAID-related ulcer complica-
tions.12,18,19 However, neither the COX-2 inhibitor NSAID nor the
NSAID plus a PPI will eliminate upper GI events for these patients.
Combining a COX-2 inhibitor NSAID with a PPI may be consid-
ered for very high-risk patients, but this regimen is likely to be of
modest benefit.12,18
Gastrointestinal and
Cardiovascular Safety Issues
There is no difference in cardiovascular risk between the selective
COX-2 inhitor NSAIDs and the nonselective or partially selective
NSAIDs, with the exception of naproxen12,18,65 Thus, individual
patient risk factors for NSAID-related GI bleeding and cardiovas-
cular events must be weighed when determining treatment (see
Table 4010). Naproxen is preferred to nonnaproxen NSAIDs and
COX-2 inhbitors because of its comparative cardiovascular safety
and not because of its GI safety profile. There is insufficient evi-
dence regarding the preferred NSAID for patients also taking low-
dose aspirin.14 Clopidogrel should not be substituted for low-dose
aspirin in order to reduce recurrent GI bleeding as it is inferior to
a PPI plus low-dose aspirin.13 Despite limited evidence to suggest
an interaction via the hepatic cytochrome P450 (CYP450) pathway,
combining a PPI and clopidogrel with or without low-dose aspirin
575
results in less GI bleeding.13 Ongoing studies for patients with
cardiovascular disease should provide the necessary information to
CHAPTER 40
help resolve these issues. The lowest possible daily dose of a COX-2
inhibitor should be used as the cardiovascular risk may be dose
dependent. However, no studies, to date, have evaluated the safety
of low-dose COX-2 inhibitor NSAIDs for patients with or at risk for
cardiovascular disease. In the future, there will be new formulations
and classes of NSAIDs and COX-2 inhibitors with an improved GI
and cardiovascular safety profile.66 Until then patients who take
NSAIDs or COX-2 inhibitors should be counseled about the signs
Peptic Ulcer Disease
and symptoms of upper GI bleeding and major cardiovascular
events and what they should do if they occur.
Treatment of non-H. Pylori,
non-NSAID Ulcers
Very few individuals have non-H. pylori, non-NSAID (idiopathic)
ulcers.29,67,68 Patients should be double-checked to verify that they
are H. pylori negative and that they are not taking ulcerogenic
medications. Possible explanations for non-H.pylori, non-NSAID
ulcers include gastric hypersecretion, gastric outlet obstruction,
genetic predisposition, concomitant diseases (see Table 402), and
heavy tobacco use. Treatment should be initiated with conventional
ulcer healing therapy (see Table 409). Although standard H2RA
or sucralfate dosage regimens heal the majority of gastric and duo-
denal ulcers in 6 to 8 weeks, PPIs provide comparable ulcer healing
rates in 4 weeks.32 A higher daily dose or a longer treatment dura-
tion is sometimes needed to heal larger gastric ulcers. Antacids are
not used as single agents to heal ulcers because of the high volume
and frequent doses required. When conventional antiulcer therapy
is discontinued after ulcer healing, most patients develop a recur-
rent ulcer within 1 year.32 Maintenance therapy may be required to
prevent ulcer recurrence.
Long-Term Maintenance of Ulcer Healing
Continuous antiulcer therapy is aimed at the long-term mainte-
nance of ulcer healing and the prevention of ulcer-related compli-
cations. Because H. pylori eradication dramatically decreases ulcer
recurrence, continuous maintenance therapy is primarily used to
treat high-risk patients who failed H. pylori eradication, have a his-
tory of ulcer-related complications, have frequent recurrences of H.
pylorinegative ulcers, and are heavy smokers or NSAID users. For
most patients, standard maintenance dosages (see Table 409) are
effective.32
Treatment of Refractory Ulcers
Ulcers are considered refractory to therapy when symptoms,
ulcers, or both persist beyond 8 to 12 weeks despite conventional
treatment or when several courses of H. pylori eradication fail.1,45
Poor patient compliance, antimicrobial resistance, cigarette smok-
ing, NSAID use, gastric acid hypersecretion, or tolerance to the
antisecretory effects of an H2RA (see the section Antiulcer Agents)
may contribute to refractory PUD. Patients with refractory
ulcers should undergo upper endoscopy to confirm a nonhealing
ulcer, exclude malignancy, and assess H. pylori status. H. pylori
positive patients should receive eradication therapy (see the secton
Treatment of Helicobacter pyloriAssociated Ulcers). In H. pylori
negative patients, higher PPI dosages (e.g., omeprazole 40 mg/
day) heal the majority of ulcers. Continuous treatment with a PPI
is often necessary to maintain healing, as refractory ulcers recur
when therapy is discontinued or the dose is reduced. Switching
from one PPI to another is not beneficial. Patients with refrac-
tory gastric ulcer may require surgery because of the possibility
of malignancy.
576
Antiulcer Agents 24-hour control of intragastric pH. A dosage reduction is unneces-
sary for patients with renal impairment or in older adults but should
SECTION 4

Proton Pump Inhibitors The PPIs (omeprazole, esomepra-

be considered in severe hepatic disease.32 The short-term adverse
zole, lansoprazole, dexlansoprazole, rabeprazole, and pantoprazole)
effects of the PPIs are similar to those observed with the H2RAs
dose-dependently inhibit basal and stimulated gastric acid secre-
and include headache, nausea, and abdominal pain.32 Because
tion.32 When PPI therapy is initiated, the degree of acid suppression
the immediate-release formulations contain sodium bicarbonate,
increases over the first 3 to 4 days of therapy, as more proton pumps
they are contraindicated for patients with metabolic alkalosis and
are inhibited.32 Because PPIs inhibit only those proton pumps that
hypocalemia.72 The sodium should also be taken into consideration
are actively secreting acid, they are most effective when taken 30
for patients who are on sodium-restricted diets, e.g., congestive
to 60 minutes before meals.32 The duration of acid suppression
heart failure.
is a function of binding to the H+/K+-adenosine triphosphatase
Gastrointestinal Disorders

(ATPase) enzyme and is longer than their elimination half-lives.32
Symptomatic acid rebound upon withdrawal of a PPI has been
reported in healthy volunteers after 8 weeks of treatment.1,69
Various PPI dosage forms and formulations exist and (see
Table 4011) include the delayed-release enteric-coated dos-
age forms that have pH-sensitive granules contained in gelatin
capsules (omeprazole, esomeprazole, prescription and nonpre-
scription lansoprazole, and dexlansoprazole), rapidly disintegrat-
ing tablets (lansoprazole), and delayed release enteric-coated
tablets (rabeprazole, pantoprazole, and nonprescription omepra-
zole).32 The pH-sensitive enteric coating prevents degradation and
premature protonation of the drug in stomach acid but dissolves
at a higher pH in the duodenum where the drug is absorbed.
Dexlansoprazole is formulated with a dual release mechanism
that results in inhibition of proton pumps that become activated
after initial release of the medication.70,71 Omeprazole is also
available as an immediate release formulation (oral suspension,
oral capsule) containing sodium bicarbonate, which raises intra-
gastric pH and protects omeprazole from acid degradation in the
stomach thus permitting rapid absorption from the duodenum.72
Intravenous products available in the United States include pan-
toprazole and esomeprazole.
Five of the PPIs provide similar rates of ulcer-healing (dexlanso-
prazole has not been labeled at this time for these indications),
maintenance of ulcer healing, and symptom relief when used in
recommended dosages (see Table 409). When higher dosages are
indicated, the daily dose should be divided in order to obtain better
Drug Interactions All PPIs increase intragastric pH and may
alter the bioavailability of orally administered drugs, such as
ketoconazole (weak bases) and digoxin, or pH-dependent dosage
forms.32,73 This interaction is especially important with atazanavir,
a protease inhibitor. Concomitant use with a PPI can significantly
reduce the oral bioavailability of atazanavir and potentially lead
to therapeutic failure and viral resistance in patients infected with
HIV.74 Omeprazole and esomeprazole selectively inhibit the hepatic
CYP2C19 pathway and may decrease the elimination of phenytoin,
warfarin, diazepam, and carbamazepine.32 The PPIs may increase
the metabolic clearance and decrease the GI absorption of levothy-
roxine resulting in increased thyroid-stimulating hormone levels
and a corresponding increase in the levothyroxine dose.75 A review
of the FDA database for the years 1997 to 2001 reveals that drug
interactions with PPIs are rare and usually do not constitute a major
clinical risk.76
One of the most perplexing potential PPI drug interactions is
with the antiplatelet drug clopidogrel. This interaction is especially
important given recent consensus guidelines that recommend
the use of a PPI for high-risk patients on antiplatelet therapies to
prevent ulcers and related GI bleeding.13 Clopidogrel, a prodrug, is
converted to its active form through CYP2C19. PPIs may attenuate
the antiplatelet effect of clopidogrel by inhibiting or competing for
this metabolic pathway. FDA safety guidelines recommend that
the coadministration of omeprazole, omeprazole/sodium bicar-
bonate, or esomeprazole with clopidogrel be avoided because they
reduce the effectiveness of clopidogrel.7779 Details of new studies

TABLE 40-11 Proton Pump Inhibitor Formulations and Options for Administration
Omeprazole Esomeprazole Lansoprazole Pantoprazole Rabeprazole Dexlansoprazole
Commercially available oral formulations
Capsule Xa X X Xe
Tablet Xb X X
Oral disintegrating tablet X
Packet for oral suspension Xc Xc
Extemporaneous oral preparations
Pellets from capsule in water X
Pellets from capsule in applesauce X X X
Pellets from capsule in juice X Xd X
Extemporaneous preparation of delayed-release X X X
PPI in bicarbonate
Parenteral formulations
Intravenous Not available in the X X
United States

X, product is available.
a
Omeprazole is available as delayed-release enteric-coated pellets in a capsule or as immediate-release capsule that contains 20 or 40 mg of omeprazole with 1100 mg sodium bicarbonate (equivalent to 304 mg
of sodium). Because 20 and 40 mg dosages contain the same amount of bicarbonate, two 20 mg capsules should not be substituted for the 40 mg immediate-release omeprazole-bicarbonate capsule.
b
Omeprazole oral tablets are available as 20 mg delayed-release nonprescription tablets.
c
Omeprazole oral suspension is available as 20 or 40 mg omeprazole with 1,680 mg sodium bicarbonate (equivalent to 460 mg of soidum). Because 20 and 40 mg dosages contain the same amount of
bicarbonate, two 20 mg packets should not be substituted for the 40 mg immediate-release omeprazole-bicarbonate packet.
d
No published information; based on omeprazole data.
e
Dexlansoprazole is available as a dual delayed-release formulation in capsules for oral administration. The capsule contains dexlansoprazole in a mixture of two types of enteric-coated granules with different
pH-dependent dissolution profiles.
Data from references 32, 70, and 72.

performed by the manufacturer and submitted to the FDA, as
well as warnings regarding omeprazole, esomeprazole, and other
interacting drugs (e.g., cimetidine) are contained in the clopidogrel
package insert.80 A reduced antiplatelet effect of clopidogrel may
also result from genetic polymorphisms of the CYP2C19 pathway
leading to decreased biotransformation of the drug to its active
form.81,82 Whether the use of other PPIs such as pantoprazole,
lansoprazole, dexlansoprazole, and rebeprazole interact with clopi-
dogrel remains uncertain as the capacity to inhibit CYP2C19 varies
among these PPIs.83,84 While some reports suggest a class effect
among the different PPIs, other pharmacodynamic studies suggest
an interaction with omeprazole and esomeprazole but not with
pantoprazole.83,84 Because of the uncertainty of the effect of the
PPI-clopidogrel interaction on clinical outcomes and the extent
to which other PPIs may interact with clopidogrel, caution is war-
ranted. Until more compelling data becomes available, patients
should have an acceptable indication for a PPI recognizing that
risk versus benefit must be weighed on an individual basis. If a PPI
is absolutely necessary, the use of omeprazole and esomeprazole
should be avoided.
CLINICAL CONTROVERSY
Some clinicians believe that the antiplatelet effect of clopidogrel
is attenuated by omeprazole and that there is an increased risk
of adverse cardiac events when these medications are taken
concomitantly. Strategies to avoid this interaction for patients
at risk of NSAID-related GI events include switching omepra-
zole to another PPI or substituting an H2RA for the PPI. Others
believe that the use of a PPI (if indicated) and clopidogrel is not
a safety concern and that it is not necessary to switch omepra-
zole to another PPI.
Potential Risks and Long-Term Safety Issues Numerous
potential risks and safety issues (see Table 4012) have been
associated with the long-term use of PPIs as a consequence of
prolonged hypergastrinemia and chronic hypochlorhydria.32,8588
In most cases, causality is difficult to ascertain because of the
study design, confounding variables, and subject selection. All
of the PPIs dose-dependently increase serum gastrin concentra-
tions two- to fourfold as a function of their potent acid-inhibitory
effect.32,85 Fasting gastrin elevations are usually within the normal
range and return to baseline within 1 month of discontinuing the
drug. In humans, PPIs may lead to enterochromaffin-like (ECL)
hyperplasia as a result of the hypergastrinemia, but there is no evi-
dence that these changes result in dysplasia, carcinoid tumors, or
gastric adenocarcinoma.85,86 Although long-term PPI therapy in H.
pyloripositive individuals is associated with progressive atrophic
gastritis, there is insufficient data to link chronic PPI use with
gastric cancer in H. pyloripositive patients.85,86 Despite theoretical
and in vitro data, there is no evidence to support an association
between PPIs and colonic polyps or colorectal cancer.85,86 Bacterial
overgrowth occurs in the stomach as a consequence of hypochlo-
rhydria and may lead to carcinogenic N-nitroso compounds in
animals but is unlikely to result in significant gastric nitrosation
in humans.85,88
Chronic PPI therapy may be associated with an increased risk
of infection and nutritional deficiences.8587 Gastric acid (low
stomach pH) plays an important role in the defense against bacte-
rial colonization of the stomach and in nutrient absorption. Acid
suppression has been implicated as a risk factor for community
acquired pneumonia (CAP) and enteric infections (Clostridium
577
TABLE 40-12 Potential Risks and Safety Issues Associated
CHAPTER 40
with the Proton Pump Inhibitors
Gastric cancers or malignancy
Carcinoid tumors
Atrophic gastritis
Adenocarcinoma
Bacterial overgrowth
Increase in N-nitroso compounds from ingested nitrates (carcinogenic)
Enteric infections (Clostridium difficile, Salmonella typhimurium, and
Campylobacter jejuni)
Community acquired pneumonia
Peptic Ulcer Disease
Decreased nutrient absorption:
Iron
Calcium
Cyanocobalamin (vitamin B12)
Osteoporosis and related fractures
Data from references 32, 85 to 88.
difficile, Salmonella, Campylobacter).86 Three case-controlled
studies demonstrate a higher adjusted relative risk of CAP for
patients currently using PPIs compared with controls.8991 The
results of these retrospectively designed studies, however, need
to be interpreted cautiously because of the variability in the
length of therapy for current PPI users and the inclusion of older
(>60 years of age) patients with concomitant comorbidities. A
systematic review of the literature has linked PPIs with various
enteric infections, but the most convincing data was with C.
difficile.92 It is likely that sustained elevations in intragastric pH
facilitate the survival of C. difficile spores. However, the magni-
tude of risk varies and causality is difficult to establish. The risk of
various infections associated with PPI therapy can not be firmly
established until the results of large prospective studies are made
available.
The absorption of Vitamin B12, dietary iron, and calcium
requires an acidic environment and may be adversely affected by
PPI-induced prolonged hypochlorhydria.86 Although a few stud-
ies have investigated the long-term use of PPIs on Vitamin B12
and iron absorption, the clinical importance of their effect on
absorption has not been established, and monitoring of B12
and iron levels cannot be recommended.86 However, adequate
supplementation and monitoring should be considered in high
risk populations (e.g., older patients, vegetarians, alcoholism)
who may be already depleted.85,86 High PPI dosage and long-term
therapy have been associated with an increased risk of hip, wrist
and spine fractures related to reduction in calcium absorption.26,93
Although the results of the studies vary, the FDA has revised the
warnings and precautions of prescription and nonprescription
PPIs to reflect this potential risk.93 Bone density tests for osteo-
porosis screening, calcium supplementation, or other precautions
cannot be recommended solely based on chronic PPI therapy.94
However, it is appropriate to screen and treat older patients for
osteoporosis regardless of whether they are receiving long-term
PPI therapy.
H2-Receptor Antagonists Ulcer healing is comparable among
H2RAs (cimetidine, famotidine, nizatidine, and ranitidine) with
equipotent multiple daily doses or a single full dose given after
dinner or at bedtime (see Table 409), but tolerance to their
antisecretory effect may occur.95 Twice-daily administration sup-
presses daytime acid and benefits patients with daytime ulcer
pain. Cigarette smokers may require higher doses or a longer
duration of treatment. H2RAs are eliminated renally and therefore
a dosage reduction is recommended for patients with moderate
to severe renal failure.96 The short- and long-term safety of all
four H2RAs is similar.1 Thrombocytopenia, the most common
578
hematologic adverse effect, is reversible and occurs with all four preparations. Aluminum-containing antacids (except aluminum
H2RAs. However, the propensity for H2RAs to cause thrombo- phosphate) form insoluble salts with dietary phosphorus and inter-
SECTION 4

cytopenia is likely overestimated.97 Cimetidine inhibits several
CYP450 isoenzymes, resulting in numerous drug interactions
(e.g., theophylline, lidocaine, phenytoin, warfarin, and clopi-
dogrel).77,96 Ranitidine has less potential for hepatic CYP450 drug
interactions, while famotidine and nizatidine do not interact with
drugs metabolized by the hepatic CYP450 pathway.96 The H2RAs
decrease acid secretion and may alter the bioavailability of orally
administered drugs, similar to that seen with the PPIs.
Gastrointestinal Disorders
fere with phosphorus absorption. Hypophosphatemia occurs most
often for patients with low dietary phosphate intake (e.g., malnu-
trition or alcoholism). Combined treatment with sucralfate may
amplify the hypophosphatemia and aluminum toxicity.
Magnesium-containing antacids should not be used for patients
with a creatinine clearance of less than 30 mL/min because
magnesium excretion is impaired, which may lead to toxicity.
Hypercalcemia may occur for patients with normal renal function

taking more than 20 g/day of calcium carbonate and for patients

Sucralfate Sucralfate heals peptic ulcers, but is not widely used
with renal failure who are taking more than 4 g/day. The milk
today for this indication.1 Deterrents to its use include the require-
alkali syndrome (hypercalcemia, alkalosis, renal stones, increased
ment for multiple doses per day, large tablet size, and the need to
blood urea nitrogen, and increased serum creatinine concentra-
separate the drug from meals and potentially interacting medica-
tion) occurs with high calcium intake for patients with systemic
tions. Drug interactions can be minimized by giving the interact-
alkalosis produced by either ingestion of absorbable antacids
ing drug at least 2 hours before sucralfate. Alternative therapy is
(sodium bicarbonate) or prolonged vomiting. Antacids may alter
warranted for patients taking oral fluoroquinolones. Constipation
the absorption and excretion of drugs when administered con-
may be troublesome especially in older individuals. Seizures may
comitantly.96,98 Drug interactions may occur when antacids are
occur in dialysis patients taking aluminum-containing antacids.
administered with iron, warfarin, tetracycline, digoxin, quinidine,
Hypophosphatemia may develop with long-term treatment. Gastric
isoniazid, ketoconazole, or the fluoroquinolones. Most interac-
bezoar formation has also been reported.
tions can be avoided by separating the antacid from the oral drug
Prostaglandins Misoprostol, a synthetic prostaglandin E1 analog, by at least 2 hours.
moderately inhibits acid secretion and enhances mucosal defense.1,98
Antisecretory effects are dose dependent over the range of 50 to Pharmacoeconomic Considerations
200 mcg; cytoprotective effects occur in humans at doses of greater
 The eradication of H. pylori improves clinical outcomes and
than 200 mcg. Because protective effects occur at higher doses,
decreases the use of healthcare resources when compared with
it is difficult to establish the protective effect independent of the
conventional antisecretory therapy.99 Thus the costs of contin-
antisecretory action. Although not recommended in the United
ued treatment and recurrence far outweigh the cost of H. pylori
States, a dose of 200 mcg 4 times daily or 400 mcg twice daily heals
drug regimens. The cost-effectiveness of misoprostol cotherapy is
duodenal ulcers and gastric ulcers comparable to standard H2RA
greatest for patients with the highest risk for NSAID-related GI
or sucralfate regimens. Diarrhea, the most troublesome adverse
complications.100 The addition of a PPI to both nonselective and
effect, is dose dependent and develops in 10% to 30% of patients.1,98
partially selective NSAIDs or selective COX-2 inhibitor NSAIDs (if
Abdominal cramping, nausea, flatulence, and headache typically
available) is highly cost-effective even for patients with low GI risk
accompany the diarrhea. Taking the drug with or after meals and
especially when the least expensive PPI is used.101
at bedtime may minimize the diarrhea. Misoprostol is contraindi-
cated in pregnant women because it is uterotropic and produces
uterine contractions that may endanger pregnancy.98 If misoprostol EVALUATION OF THERAPEUTIC OUTCOMES
is prescribed to women in their childbearing years, contraceptive
measures must be confirmed and a negative serum pregnancy  Table 4013 lists the recommendations for treating and
test should be documented within 2 weeks of initiating treatment. monitoring patients with PUD. Relief of epigastric pain should be
Patients should be counseled about the GI effects and the need to monitored throughout the course of treatment for patients with
avoid magnesium antacids, as they may increase the propensity for either H. pylori or NSAID-related ulcers. Ulcer pain typically
GI adverse effects. resolves in a few days when NSAIDs are discontinued and within
7 days upon initiation of antiulcer therapy. Most patients with
Bismuth Preparations Bismuth subsalicylate and bismuth
uncomplicated PUD will be symptom free after treatment with
subcitrate potassium (biskalcitrate) are the only available bismuth
any one of the recommended antiulcer regimens. The persistence,
salts in the United States.1,96 Possible ulcer-healing mechanisms
or recurrence, of symptoms within 14 days after the end of treat-
include an antibacterial effect, a local gastroprotective effect, and
ment suggests failure of ulcer healing or H. pylori eradication
stimulation of endogenous prostaglandins. Bismuth salts do not
or an alternative diagnosis such as GERD. Most patients with
inhibit or neutralize acid. Bismuth subsalicylate is regarded as safe
uncomplicated H. pyloripositive ulcers do not require confirma-
and has few adverse effects when taken in recommended dosages.
tion of ulcer healing or H. pylori eradication. However, eradica-
Because renal insufficiency may decrease bismuth elimination,
tion should be confirmed after treatment in individuals who are
bismuth salts should be used with caution in older patients and
at risk for complications, for example, individuals who had a prior
in renal failure. Bismuth subsalicylate may cause salicylate sen-
bleeding ulcer. The UBT is the preferred test to confirm H. pylori
sitivity or bleeding disorders and should be used with caution
eradication when endoscopy is not indicated. Medication adher-
for patients receiving concurrent salicylate therapy. Bismuth
ence should be assessed for patients who fail therapy. Because
salts impart a black color to stool and possibly the tongue (liquid
a large number of at-risk patients treated with NSAIDs do not
preparations).
receive adequate prophylaxis for GI complications, therapeutic
Antacids Antacids neutralize gastric acid, inactivate pepsin, and outcomes can be improved by advocating preventive strategies.
bind bile salts.96,98 Aluminum-containing antacids also suppress Patients on NSAIDs should be closely monitored for signs or
H. pylori and enhance mucosal defense. The GI adverse effects are symptoms of bleeding, obstruction, penetration, or perforation.
most common and are dose dependent. Magnesium salts cause A follow-up endoscopy is justified for patients with frequent
an osmotic diarrhea, whereas aluminum salts cause constipa- symptomatic recurrence, refractory disease, complications, or
tion. Diarrhea usually predominates with magnesium/aluminum suspected hypersecretory states.

TABLE 40-13 Recommendations for Treating and Monitoring
Patients with Helicobacter pyloriAssociated
and Nonsteroidal Antiinflammatory Drug
(NSAID)Induced Ulcers
Helicobacter pylori-associated ulcer
1. Recommend drug treatment as presented in the chapter text. See Tables
407 and 408.
2. Assess patient allergies to determine if allergic to penicillin (or other
antibiotics) so that drug regimens that contain penicillin (or other antibiotics)
can be avoided. Avoid regimens that contain tetracycline in children.
3. Assess patient use of alcohol or alcohol-containing products with metronidazole
and oral birth control medications with antibiotics and counsel appropriately.
4. Assess likelihood of nonadherence to the drug regimen as a cause of
treatment failure.
5. Recommend a different antibiotic combination if H. pylori eradication fails and
a second treatment is planned.
6. Inform the patient of change in stool color when bismuth salicylate is included
in an H. pylori eradication regimen.
7. Assess and monitor patients for potential adverse effects, especially those
associated with metronidazole, clarithromycin, and amoxicillin.
8. Assess and monitor patients for potential drug interactions, especially those
receiving metronidazole, clarithromycin, or cimetidine.
9. Monitor patients for salicylate toxicity, especially patients receiving cotherapy
with other salicylates and anticoagulants and patients with renal failure.
10. Monitor patients for persistent or recurrent symptoms within 14 days after
completion of a course of H. pylori eradication therapy.
11. Provide patient education to patients who are receiving H. pylori eradication
therapy and include why antibiotic and antiulcer combinations are used;
when and how to take medications; adverse effects; alarm symptoms; the
importance of adherence to the entire course of drug treatment; and contact
their healthcare provider if alarm symptoms develop (e.g., blood in the stools,
black tarry stools, vomiting, severe abdominal pain), or if symptoms persist or
return after H. pylori eradication.
NSAID-induced ulcer
1. Recommend drug treatment as presented in the chapter text.
2. Assess risk factors for NSAID-induced ulcers and ulcer-related complications and
recommend appropriate strategies for reducing ulcer risk (see Table 4010).
3. Weigh patient risk factors for NSAID-related GI bleeding and cardiovascular
events when selecting a strategy to reduce ulcer risk.
4. Recommend eradication treatment for H. pylori-positive patients taking NSAIDs.
5. Monitor patients for signs and symptoms of NSAID-related upper GI complications.
6. Assess and monitor patients for potential drug interactions and adverse effects
(especially misoprostol).
7. Provide patient education to patients who are at risk of NSAID-induced
ulcers or GI-related complications and include why cotherapy is used with
nonselective NSAIDs; when and how to take medications; adverse effects;
alarm symptoms; when to contact their healthcare provider; and the
importance of adherence to drug treatment.
ZOLLINGER-ELLISON SYNDROME (ZES)
ZES is characterized by gastric acid hypersecretion and recurrent
peptic ulcers that result from a gastrin-producing tumor (gastri-
noma).21,45 In the United States, ZES accounts for 0.1% to 1% of
patients with duodenal ulcer; however, this may be an underestima-
tion of the true incidence because of the heterogeneity of clinical
manifestations.21 Gastrinomas are classified as those associated
with multiple endocrine neoplasia type 1 (MEN 1) or sporadic
tumors, which have a greater tendency to behave as malignant
tumors. In more than 80% of cases, gastrinomas are localized in
an area referred to as the triangle of gastrinomas, which includes
the convergence of the cystic duct and the common bile duct, the
junction of the second and third portion of the duodenum, and the
junction of the head and body of the pancreas.21 More than 50% of
the gastrinomas malignant, often with metastases to regional lymph
nodes, liver, and bone.21
579
Zollinger-Ellison syndrome is suspected for patients with mul-
tiple ulcers and recurrent or refractory PUD, often accompanied
CHAPTER 40
by esophagitis or ulcer complications.21,45 Ulcers occur most
often in the duodenum but may involve the stomach or jejunum.
Diarrhea occurs in about 50% of patients, and results from high
concentrations of acid that overwhelm the duodenums buffer-
ing capacity and damage to the mucosa.21 Intraluminal acid also
causes steatorrhea by inactivating pancreatic lipase and pre-
cipitating bile acids. Vitamin B12 malabsorption may result from
reduced intrinsic factor activity. The diagnosis is established
Peptic Ulcer Disease
when the serum gastrin is higher than 1,000 pg/mL and the BAO
15 mEq/h for patients with an intact stomach (BAO 5 mEq/h
for patients with previous gastric surgery) or when hypergas-
trinemia is associated with a gastric pH value of 2.21 In situations
in which the serum gastrin is between 100 and 1,000 pg/mL and
gastric pH is 2, a secretin or calcium proactive test is used to aid
the diagnosis.21 Identification of the location of the tumor with
imaging techniques is essential, as early surgical resection prior
to liver metastases is often curative.21 The widespread use of PPIs,
although effective in reducing symptoms, may mask the clinical
presentation and PPI-related hypergastrinemia may further com-
plicate the diagnosis.21
Treatment is based on the presence or absence of peptic ulcers,
esophagitis, diarrhea, and a gastrinoma, which may be malignant.
The PPIs are the oral drugs of choice for managing gastric acid
hypersecretion. Treatment should be instituted with omeprazole
60 mg/day (or an equivalent dose of the available PPIs) and should
be adjusted based on individual patient response.21 Dividing the
daily dose and giving the PPI every 8 to 12 hours is most effective
in controlling acid output and relieving symptoms. The goal of
therapy for uncomplicated patients is to maintain BAO between
1 and 10 mEq/h, in the hour preceding the next dose of the PPI. In
complicated cases, such as patients with MEN 1, GERD, or those
who are undergoing partial gastrectomy, the BAO should be main-
tained below 5 mEq/h. A gradual reduction in PPI dose is recom-
mended after the adequate control of gastric acid hypersecretion is
achieved. Intravenous PPIs are used to suppress gastric acid secre-
tion in patients who are unable to take oral PPIs. The somatostatin
analogues, octreotide and lanreotide, directly inhibit the release
of gastrin and gastric acid secretin and have been used with vary-
ing degrees of success.21 However, these drugs are not considered
first-line therapy as they are only available in the injectable form.
Preliminary studies have found the long-acting depot formation of
octreotide to be efficacious in the treatment of GI neuroendocrine
tumors.21 Patients with metastatic gastrinoma require tumor resec-
tion or treatment with chemotherapeutic agents.
UPPER GASTROINTESTINAL BLEEDING
There are about 160 cases of upper GI bleeding per 100,000 adults
annually in the United States.102 Despite a decreased incidence of
PUD and improvements in the management of upper GI bleed-
ing, the mortality rate associated with acute hemorrhage remains
between 5% and 15%.102104 Upper GI bleeding is categorized as
variceal or nonvariceal bleeding. Two common types of nonvariceal
bleeding are bleeding from chronic peptic ulcers and bleeding
from SRMD (stress gastritis, stress ulcer, or stress erosions), both
of which are acidpeptic complications.102106 Upper GI bleeding
associated with chronic PUD usually precedes hospital admission,
whereas bleeding associated with SRMD develops in severely ill
patients during hospitalization.102,106
The underlying pathophysiology of bleeding from a peptic
ulcer or from SRMD is similar in that impaired mucosal defense
in the presence of gastric acid and pepsin leads to mucosal
580
damage. In chronic PUD, H. pylori infection and NSAID use are
the most important etiologic factors, whereas the primary patho-
SECTION 4
genic factor of SRMD in critically ill patients is thought to be
mucosal ischemia which is a result of reduced gastric blood flow
(decreased oxygen and nutrient delivery) resulting from splanch-
nic hypoperfusion.1,102,106108 Defense mechanisms are normally in
place to protect the gastric mucosa against the damaging effects
of gastric acid, pepsin, and bile (see the section Pathophysiology
of Chronic PUD). However, these defense mechanisms become
diminished in the face of the overwhelming physiologic stress
Gastrointestinal Disorders
from critical illness and coupled with mucosal ischemia and subse-
quent reperfusion injury along with gastric acid result in the rapid
development of mucosal lesions.106107 In contrast to chronic PUD,
stress-related mucosal lesions are characteristically asymptomatic,
numerous, located in the proximal stomach, and are unlikely to
perforate.107 Bleeding from SRMD occurs from superficial mucosal
capillaries, whereas bleeding associated with chronic PUD usually
results from a single vessel.107
The mortality rate associated with clinically important SRMB
is approximately 50% and is related to the underlying severity of
disease and comorbidities in this patient population.105,107,109 In
contrast, the mortality associated with chronic PUD-related bleeding
is approximately 10% but can increase dramatically in select patient
populations.103,110,111 Although the initial management of acute
upper GI bleeding focuses on aggressive resuscitative measures and
ensuring hemodynamic stability, the medical management of PUD-
related bleeding and SRMB is distinctly different.102,103,106,107
PEPTIC ULCER-RELATED BLEEDING
The most common presenting signs and symptoms of PUD-related
bleeding are hematemasis (vomiting up blood) or melena (dark,
tarry stools) or possibly both. When evaluating patients with PUD-
related bleeding, the degree of risk for adverse outcomes must be
rapidly assessed in order to determine if the patients condition
constitutes a medical emergency.102,103 Two risk-stratification tools
exist for early assessment and triage.112,113 The Blatchford score is a
newer risk-stratification scale and is used to evaluate the need for
urgent endoscopic intervention for patients presenting with PUD-
related bleeding.112 The scale values range from 0 to 23, with higher
scores indicating higher risk. The most well-known scale, however,
is the Rockall Score.113 This validated risk-assessment instrument is
composed of two assessments: the clinical score, which is performed
prior to endoscopy, and the endoscopic score. The use of these risk-
stratification tools can reduce the requirement of endoscopic proce-
dures and lead to early discharge for low-risk patients while ensuring
rapid intervention for patients at higher risk.102 These data will also
allow the pharmacist to make appropriate pharmacotherapy decisions
based on the patients assessed level of risk. When considering the risk
of death due to PUD-bleeding, the following patients generally have
poorer prognoses and usually require more aggressive intervention
including admission to an intensive care unit (ICU).102,103,106,107
Older than 60 years of age
Comorbid conditions (e.g., ischemic heart disease, congestive
heart failure, renal failure, hepatic failure, metastatic cancer)
High transfusion requirements
Ongoing blood loss
Presence of hypovolemic shock (i.e. tachycardia with a pulse of
100 beats per minute, hypotension with a systolic blood pres-
sure of <100 mmHg with concomitant orthostatic changes,
such as an increase in the heart rate of 20 beats per minute or
decrease in systolic blood pressure of 20 mmHg upon stand-
ing from a sitting position)
Prolonged prothrombin time [or increased international nor-
malized ratio (INR)]
Erratic mental status
Initial therapy for patients with defined hemostatic instability
should focus on correcting fluid volume loss though appropriate
volume resuscitative measures. This is usually accomplished with
a continuous 0.9% sodium chloride infusion (or blood products if
clinically indicated) through two large bore peripheral intravenous
catheters (i.e., 16 to 18 gauge).102,104 The use of nasogastric (NG)
tubes remains controversial but may aid in early assessment and
gastric lavage.102
Diagnostic endoscopy is usually performed as early as possible
(preferably within 24 hours of presentation) to identify the source of
the bleeding, assess the potential risk for rebleeding, and, if appropri-
ate, employ therapeutic interventions to promote hemostasis.102,104
Several endoscopic treatment approaches (e.g., thermocoagulation,
laser therapy, injection sclerotherapy, hemoclipping, and ligation) can
be used; however, to maximize the likelihood of positive outcomes,
patients are usually treated with a combination of thermocoagulation
and injection of lesions with epinephrine.102104 The appearance of
the ulcer at the time of endoscopy is a prognostic indicator for the
risk of rebleeding.102,104,110 Clean-based and flat spot (pigmented)
ulcers are most commonly seen and are associated with a low
risk of rebleeding (5% and 10%, respectively).104,110 In most cases,
patients with clean base ulcers can be immediately discharged after
endoscopy on antiulcer therapy (usually twice daily PPI), while
patients with flat spot ulcers may be admitted to the general hospi-
tal ward for a brief observation period. Patients with an adherent
clot overlying the ulcer base are at intermediate risk of rebleeding
(22%), and controversy exists as to the appropriate management
of these patients.104,110 Adherent clots can be removed, and then
the lesion be reclassified based on what is observed following clot
removal.104,110 Patients with a visible vessel or active bleeding are
at the highest risk of rebleeding (43% and 55%, respectively) and
should be managed within an ICU for at least 24 hours and then
monitored on a general medical/surgical service for an additional
48 hours (total of 72 hours), as rebleeding significantly increases
mortality.102,103,110
Antisecretory therapy is often used as adjuvant therapy to
endoscopic procedures to prevent PUD rebleeding in high-risk
patients because acid impairs clot stability.102 However, endoscopic
hemostatis techniques remain the treatment of choice for patients
with life-threatening bleeding, as this has been associated with better
outcomes when compared with either placebo or pharmacotherapy
alone.102104,109 H2-Receptor antagonists are ineffective in preventing
PUD rebleeding because they do not achieve an intragastric pH of 6
(which is needed to promote hemostatis and clot stability) and tol-
erance to their antisecretory effect develops rapidly (especially with
high dose or intravenous therapy).102104,108,114,115 In contrast, PPIs
reduce the incidence of rebleeding and need for surgery but have
no significant impact on overall mortality.102,103,114,115 Interestingly,
subgroup analysis from two differing metaanalyses has suggested a
mortality benefit with high-dose intravenous PPIs in a subpopula-
tion of patients with the highest risk of rebleeding (i.e., nonbleeding
visible vessel or active bleeding).114,116
The precise route (oral or intravenous) and the dose of PPI
should be based on the clinical situation, risk of rebleeding, endo-
scopic identification of the lesion, and patient risk.114,115 Because
of the theoretical goal of maintaining intragastric pH values >6,
and data from randomized, controlled trials, practice guidelines
recommend that high-dose continuous infusion PPI (equivalent to
omeprazole 80 mg given intravenously as a loading dose, followed
by 8 mg/h continuous infusion for 72 hours) be used to reduce
the risk of rebleeding in high-risk patients who have undergone

endoscopy hemostasis.102,103,114,115 Because intravenous omeprazole is
not available in the United States and three small randomized,
controlled trials have not demonstrated any evidence of improved
outcomes between the available intravenous PPIs and omeprazole,
most clinicians consider intravenous pantoprazole and esomprazole
to be equivalent to intravenous omeprazole on a milligram-per-
milligram basis. Thus, intravenous pantoprazole and esomeprazole
can be interchanged as there is currently no evidence to suggest that
one PPI is superior to another.115,117 The administration of high-
dose continuous-infusion PPIs given prior to endoscopy hastens
resolution of bleeding stigmata.118 However, PPI therapy is not a
replacement for interventional endoscopy for patients who are at
high risk of rebleeding, as data demonstrate that the combination of
a high-dose PPI continuous intravenous infusion with therapeutic
endoscopy is superior to either strategy alone.115,119 High-dose oral
PPI therapy (omeprazole 80 mg/day for 5 days) is also effective;
however, concerns exist as to whether critically ill patients will
absorb the medication.109,114 The risk of rebleeding is greatest within
the first 72 hours (especially the first 24 hours), and it is during this
time that antisecretory therapy to prevent rebleeding in high-risk
patients should be employed.102,103 Patients should be transitioned to
an oral PPI upon completion of intravenous therapy. Somatostatin
or octreotide have not demonstrated any significant benefit in
treating nonvariceal bleeding and are not recommended at this
time.102,103
Patients with upper GI bleeding should be tested for H. pylori at
the time of endoscopy (see Tests for Helicobacter Pylori). However,
the tests are associated with an increased rate of false-negatives
when obtained during acute bleeding episodes.120 If the initial
results of the rapid urease test and/or histology are negative, a
confirmatory test (14C-urea breath test or serology) should be per-
formed following the acute bleeding episode. There is no rationale
for using intravenous therapy to eradicate H. pylori. Ulcer treat-
ment, including H. pylori eradication, if appropriate, should be ini-
tiated after the acute bleeding episode has resolved (see Treatment
of Helicobacter PyloriAssociated Ulcers and Treatment of NSAID-
Induced Ulcers).
STRESS-RELATED MUCOSAL BLEEDING
Critically ill patients may develop SRMD leading to SRMB because
of the homeostatic compromise that is associated with severe
illness.106,107 More than 75% (some studies suggesting up to 100%)
of critically ill patients develop SRMD within the first 1 to 3 days of
admission to an ICU, but the incidence of clinically important SRMB
(defined as overt bleeding with concomitant hemodynamic instabil-
ity and likely requirement for blood products) is 1% to 4%.106,107,121
Clinically important bleeding increases the length of ICU stay by
up to 11 days, results in excessive healthcare costs and is associated
with increased mortality.106,107,122 Thus, attempts to prevent SRMB
are warranted in high-risk patients. Prophylactic therapy to prevent
bleeding is most effective if initiated early in the patients course.
Patients who are at risk for SRMB include those with respi-
ratory failure (need for mechanical ventilation for longer than
48 hours), coagulopathy (INR >1.5, platelet count <50,000 mm3),
hypotension, sepsis, hepatic failure, acute renal failure, high-dose
corticosteroid therapy (>250 mg/day hydrocortisone or equivalent),
multiple trauma, severe burns (>35% of body surface area), head
injury, traumatic spinal cord injury, major surgery, prolonged ICU
admission (>7 days), or history of GI bleeding.105107,122 The rela-
tive importance of the various risk factors remains controversial,
but most clinicians concur that patients with respiratory failure or
coagulopathy should receive prophylaxis, as these two factors are
independent risk factors for SRMB.105,106 In the absence of these risk
factors, some clinicians only administer prophylaxis to patients who
581
have two of the aforementioned risk factors.105 Since not all patients
in a hospital or ICU are at increased risk of SRMB, a cost-effective
CHAPTER 40
approach should be developed to target prophylactic therapy at
high-risk patients.
CLINICAL CONTROVERSY
Some clinicians feel that stress-related mucosal bleeding pro-
phylaxis is indicated for all critically ill patients given the asso-
Peptic Ulcer Disease
ciated mortality and increased length of stay for patients who
develop this complication. Others adhere to clinical guidelines
that suggest only high-risk patients such as those with respira-
tory failure requiring ventilation or patients with coagulopathy
and perhaps those patients with two or more other risk factors
will benefit from prophylaxis.
Prevention of SRMB includes resuscitative measures that restore
mucosal blood and pharmacotherapy that either maintains an
intragastric pH of >4 or provides gastric mucosal protection.105107
Although the benefits of enteral nutrition to patient outcome
(e.g., improved nutritional status enhances mucosal integrity) are
of overall clinical importance, its precise role as a sole modality to
prevent SRMB remains controversial.106107 Therapeutic options for
the prevention of SRMB include antacids (which are of historical
interest, as they are no longer used because of cumbersome dosage
schedules and side effects), antisecretory drugs (H2RAs and PPIs),
and sucralfate (mucosal protectant).105107,109,122
Antisecretory therapy is generally preferred for SRMB prophy-
laxis for several reasons. First, a large landmark study demonstrated
that intravenous ranitidine was superior to oral sucralfate in pre-
venting SRMB.123 Second, ranitidine did not increase the risk for
nosocomial pneumonia, as the incidence of pneumonia was not
different between the two treatment groups.123 Third, although
sucralfate is an evidence based option, it is cumbersome, requiring
multiple daily dosage administration (up to 4 times daily), which
may occlude nasogastric tubes, cause constipation, interact with
several medications, and/or increase the potential for aluminum
toxicity in patients with renal dysfunction. Finally, sucralfate
does not have any appreciable effect on reducing intragastric pH.
Although data published in 2004 indicated that H2RAs were the
most commonly prescribed antisecretory agents used to prevent
SRMB,124 it is now estimated that PPIs have become the mainstay
of therapy.106 Regardless, numerous studies and years of experience
support the use of H2RAs, and they remain a recommended option
for the prevention of SRMB.105107,124
Parenteral H2RAs may be administered as either continu-
ous infusions or intermittent bolus doses (see Table 4014).
Cimetidine, given as a continuous intravenous infusion, is the
only FDA-labeled H2RA for the prevention of SRMB. Despite
evidence suggesting that continuous infusions of the H2RAs are
superior to intermittent dosing at maintaining an intragastric pH
>4, there is no evidence to suggest better outcomes with respect to
prevention of SRMB.106 Thus, intermittent bolus doses of H2RAs
are used more commonly than continuous infusions.107,109 Drug
interactions are more common with cimetidine, and for this
reason the other H2RAs (famotidine, ranitidine) are used more
frequently.106 Adverse events associated with the use of H2RAs for
the critically ill patient include thrombocytopenia, mental status
changes (more common in older patients or individuals with renal
or hepatic compromise), and tachyphylaxis (especially with par-
enteral or high dose therapy).106 Given that the H2RAs are renally
eliminates, dosage reductions are recommended for patients with
renal dysfunction.
582
TABLE 40-14 Pharmacotherapy Options for Prophylaxis
of Stress-Related Mucosal Bleeding
SECTION 4
Drug and Route Dosage
Parenteral H2RAs
Cimetidine 300 mg IV loading dose followed by a 50 mg/h as a
continuous infusiona or 300 mg IV every 6 to 8 hours
Ranitidine 6.25 mg/h as a continuous infusion or 50 mg IV every
6 to 8 hours
Famotidine 1.7 mg/h as a continuous infusion or 20 mg IV every
12 hours
Gastrointestinal Disorders
Oral/NG PPIs
Omeprazole 2040 mg orally/NGb every 12 to 24 hours
Omeprazole/ 40 mg orally/NG to start, then followed by an additional
bicarbonate powder 40 mg in 6 to 8 hours as a loading dose, and then
for oral suspension 40mg every 24 hours
Lansoprazole 30 mg orally/NGb,c every 12 to 24 hours
Pantoprazole 40 mg orally/NGb every 12 to 24 hours
Parenteral PPIs
Pantoprazole 40-80 mg IV every 12 to 24 hours
Esomprazole 40 mg IV every 12 to 24 hours
H2RA, histamine-2 receptor antagonist; PPI, proton pump inhibitor; IV, intravenous; NG, nasogastric tube.
a
Product is FDA approved for the prevention of stress-related mucosal bleeding.
b
Administered as an extemporaneously compounded suspension made with sodium bicarbonate.
c
Administered as a rapidly disintegrating tablet given orally or by NG dissolved in 10 mL of water.
The PPIs are more potent than H2RAs in inhibiting acid secretion
and, unlike H2RAs, tolerance does not develop.106,107,109,122 Although
there are limited data assessing the efficacy of PPIs for the prevention
of SRMB, recent reports suggest that PPIs may be used as alternatives
to H2RAs or sucralfate.122,125,126 Initial open-label studies of PPIs for
SRMB prophylaxis were performed with omeprazole compounded
suspensions given as 40 mg for two doses on the first day, followed
by 20 mg/day thereafter in critically ill or trauma patients requiring
mechanical ventilation and the presence of at least one additional
risk factor.127,128 The results of these studies demonstrated significant
pH control above 4 and no GI bleeding in either trial. Because of the
small number of subjects, no firm clinical outcomes can be derived
from these studies. Since then, numerous extemporaneously com-
pounded sodium bicarbonate suspensions of PPIs (see Table 4011)
have been used as cost-effective regimens for stress ulcer prophylaxis
in patients with NG tubes.106,109,122,129 In one study, immediate-release
omeprazolesodium bicarbonate suspension (40 mg 2 doses, then
40 mg/day) was more effective than continuous infusion cimetidine
in maintaining intragastric pH >4 in critically ill patients, but there
was no difference in the incidence of clinically important SRMD
between the two groups.125 Based on meeting the prespecified
criteria for noninferiority, immediate-release omeprazole gained
FDA labeling for the prevention of SRMB.125 In another trial of ICU
patients requiring mechanical ventilation, patients were randomized
to receive either lansoprazole 30 mg given as a rapidly disintegrating
tablet mixed in 10 mL of water and administered via an NG tube
or lansoprazole 30 mg given as an intravenous infusion (no longer
available in the United Satates) once daily for 72 hours.130 Enterally
administered lansoprazole, despite having a lower bioavailability,
resulted in superior intragastric pH control when compared with the
intravenously administered lansoprazole.
One of the most compelling dose-finding pilot studies to evaluate
the use of intravenous PPIs for SRMB prophylaxis was performed
in over 200 ICU patients examining five different dosing strategies
of pantoprazole (40 mg given every 8 hours, every 12 hours, and
every 24 hours or 80 mg given every 12 hours or every 24 hours)
versus cimitidine given as a 300 mg intravenous bolus followed by a
50 mg/h continuous infusion.126 Each regimen was given for at least
48 hours and for up to 7 days. The time the intragastric pH was 4
increased from day 1 to day 2 in all the pantoprazole groups, whereas
it actually decreased in the cimetidine group suggesting tachyphy-
laxis. No bleeding was identified in any of the treatment groups. The
results suggest appropriate pH control can be obtained with doses
of 80 mg given on day 1 and 40 mg given every 12 hours thereafter.
The use of intravenous esomeprazole has also demonstrated efficacy
in a small number of clinical studies.106 Given the relatively limited
data, the overall efficacy, optimal dosage, frequency, and route of
administration for PPIs in the prevention of SRMB remains to be
fully elucidated.106,107 Based on the available evidence, several PPI
dosing regimens for SRMB prophylaxis exist (see Table 4014).
Adverse events that have been described when the PPIs are used for
this indication include an increased risk of enteric infections, includ-
ing C. difficile associated diarrhea and noscomial pneumonia.106
 When deciding on the most appropriate pharmacotherapy
plan for the prevention of SRMB for a specific patient, the clinical
presentation of the patient and medication costs should be used
as a guide. Patients who can take oral medication or have a work-
ing NG tube in place may be placed on an oral or compounded
PPI suspension as a cost-effective measure. For most patients who
are not able to utilize one of these routes, an intravenous H2RA is
appropriate. However, if the patient has renal dysfunction, develops
thrombocytopenia, or mental status changes while on an H2RA,
then an intravenous PPI may be the most appropriate prophylaxis
option. Consideration should be given to both the patients clinical
condition as well as the most cost effective option when developing
protocols for preventing SRMB.
Improvement in the patients overall medical condition (resolu-
tion of risk factors, discharge from the ICU, extubation, and oral
intake) suggests that prophylactic therapy can be discontinued.106
Too often the patient is continued on SRMB prophylaxis upon
transition to the general medical/surgical unit and is often dis-
charged on oral PPI therapy without an appropriate indication.131
This results in unnecessary costs for the patient and the healthcare
system.131 Pharmacists should identify patients in which SRMB
prophylaxis is no longer indicated.106 If a patient develops clinically
important bleeding, endoscopic evaluation of the GI tract is indi-
cated along with aggressive antisecretory therapy (see the section
Peptic Ulcer-Related Bleeding).
ABBREVIATIONS
BAO: basal acid output
COX-1: cyclooxygenase-1
COX-2: cyclooxygenase-2
CYP450: cytochrome P450
ECL: enterochromaffin-like
ELISA: enzyme-linked immunosorbent assay
GERD: gastroesophageal reflux disease
H. pylori: Helicobacter pylori
H2RA: histamine-2 receptor antagonist
ICU: intensive care unit
MALT: mucosa-associated lymphoid tissue
MAO: maximal acid output
MEN: multiple endocrine neoplasia
NSAID: nonsteroidal antiinflammatory drug
NG: nasogastric
NUD: nonulcer dyspepsia
PG: prostaglandin
PPI: proton pump inhibitor

PUD: peptic ulcer disease
SRMB: stress-related mucosal bleeding
SRMD: stress-related mucosal damage
UBT: urea breath test
ZES: Zollinger-Ellison syndrome
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