SECTION FIVE
GASTROINTESTINAL DISORDERS
Robin L. Corelli
SECTION EDITOR
CHAPTER
27
Upper Gastrointestinal Disorders
John K. Siepler, Candace Smith-Scott
DYSPEPSIA 27-2
Management Strategies 27-3
Treatment Recommendations 27-3
PEPTIC ULCER DISEASE 27-3
Epidemiology 27-3
Incidence and Prevalence 27-3
Geographic Variation 27-4
Gender 27-4
Age 27-4
Morbidity and Mortality 27-4
Physiology of the Upper Gastrointestinal Tract 27-4
Pathogenesis 27-5
Helicobacter pylori 27-5
Risk Factors 27-6
Clinical Presentation 27-6
Treatment 27-6
H2-Antagonists 27-6
Mechanism of Action 27-6
Efficacy 27-6
Potency 27-7
Pharmacokinetics 27-8
Adverse Effects 27-8
Drug Interactions 27-8
Dosing 27-9
Proton Pump Inhibitors 27-9
Mechanism of Action 27-9
Efficacy 27-9
Pharmacokinetics 27-10
Adverse Effects 27-10
Drug Interactions 27-10
Sucralfate 27-10
Mechanism of Action 27-10
Efficacy 27-10
Adverse Effects 27-10
Drug Interactions 27-10
Antacids 27-10
Mechanism of Action 27-10
Efficacy 27-11
Adverse Effects 27-11
Drug Interactions 27-11
Eradication of H. pylori 27-11
Monotherapy 27-11
Combination Therapy 27-11
Recommended Combination Regimens 27-12
Detection of Helicobacter 27-13
Drug-Induced Peptic Ulcer Disease 27-15
Etiology and Clinical Presentation 27-15
Mechanism of Action 27-15
Treatment 27-16
H2-Receptor Antagonists 27-16
Proton Pump Inhibitors 27-16
ZOLLINGER-ELLISON SYNDROME 27-17
Pathogenesis 27-17
Clinical Presentation 27-17
Upper gastrointestinal (GI) disorders encompass a variety of
conditions that can cause gastric discomfort, including dyspepsia, peptic ulcer disease (PUD), and gastroesophageal reflux disease (GERD). This chapter addresses four topics in the
following order: dyspepsia, PUD (including Zollinger-Ellison
[ZE] syndrome), GERD, and prophylaxis of stress-related
mucosal lesions.
The term dyspepsia refers to symptoms thought to originate
in the upper GI tract and is used commonly to refer to persis-
Diagnosis 27-17
Treatment 27-17
Proton Pump Inhibitor Administration 27-18
GASTROESOPHAGEAL REFLUX
DISEASE 27-18
Pathogenesis 27-19
Clinical Presentation 27-19
Treatment 27-19
Goals 27-19
Lifestyle Changes 27-19
Drug Therapy 27-20
Antacids 27-20
H2-Antagonists 27-20
Proton Pump Inhibitors 27-20
Sucralfate 27-20
Metoclopramide 27-20
Maintenance Therapy 27-21
STRESS-RELATED MUCOSAL BLEEDING 27-21
Pathogenesis 27-21
Risk Factors 27-21
Treatment 27-22
H2 -Antagonists 27-22
Sucralfate 27-22
Proton Pump Inhibitors 27-22
tent or recurrent pain or discomfort centered in the upper abdomen.1 This pain includes ulcer-like, GERD-like, and
dysmotility-like discomfort. Discomfort is defined as a subjective, unpleasant feeling that the patient does not interpret as
pain but that can include symptoms such as fullness, bloating,
or nausea.1,2 It is estimated that 25% to 55% of the U.S. population will experience some form of dyspepsia in their lifetime
(Fig. 27-1). Dyspepsia of some kind accounts for approximately 60% of all upper GI complaints in the U.S. population.
27-1
27-2
•
GASTROINTESTINAL DISORDERS
U.S. Population
Dyspepsia
25–55%
(<50% H. pylori positive)
Peptic ulcer
6–15%
(85–90% H. pylori positive)
Asymptomatic
45–74%
(~25% H. pylori positive)
Nonulcer dyspepsia
or gastritis
20–40%
(~50% H. pylori positive)
FIGURE 27-1 Prevalence of dyspepsia and peptic acid disease in the
United States.
Approximately 4% to 10% of all Americans will develop a
peptic ulcer during their lifetime, and the prevalence of active
disease is approximately 3%.3 The incidence of PUD varies
with the type of ulcer (e.g., gastric or duodenal), geographic
location, gender, age, and a variety of environmental factors.
Race, socioeconomic status, and psychological stress do not
correlate with the development of PUD.4 As discussed in
more detail later, three factors stand out as being the most important to the development of PUD: bacterial GI infection
with Helicobacter pylori (H. pylori), ingestion of nonsteroidal
anti-inflammatory drugs (NSAIDs), and cigarette smoking.4
It is estimated that up to 90% of peptic ulcers, in the absence
of NSAID exposure, are associated with H. pylori infection.
However, one should avoid the false impression that the presence of H. pylori colonization is an indication that an ulcer
will develop. As illustrated in Figure 27-2, a high proportion
(approximately 40%) of the general population tests positive
for H. pylori colonization, but only 15% to 30% of those with
positive test results will develop PUD at some time in their
life.
GERD is defined as the presence of heartburn two or more
times weekly that is associated with a change in lifestyle.5 It
is associated with a backflow (i.e., reflux or regurgitation) of
GI contents into the esophagus resulting in heartburn and regurgitation symptoms. The classic symptom of reflux is
“heartburn,” which is described commonly either as a pain in
the center of the chest (which may mimic cardiac angina), or
as a sensation of “burping up” stomach contents into in the
mouth. Patients with chronic, persistent heartburn are more
likely to develop esophageal adenocarcinoma.6 Esophagitis is
associated with GERD and is the presence of inflammation in
the esophagus. The most common causes of GERD are inappropriate lower esophageal sphincter (LES) relaxation and reduced resting pressure in the sphincter: both facilitate the regurgitation of acid from the stomach into the esophagus.
Although it is normal for the esophageal and lower
esophageal sphincters to relax to allow food passage, relaxation of these sphincters at other times is abnormal. A hiatal
hernia (a defect in the diaphragm that allows the stomach to
slide into the chest cavity) does not cause GERD but may exacerbate the situation by decreasing the ability of gastric acid
from draining back through the sphincter because of differences in the pressure gradient within the abdomen. Some
drugs (e.g., verapamil, theophylline) also may cause the lower
esophageal sphincter to relax.
Terminology can sometimes be misleading; therefore,
think of GERD as a disease, heartburn as a symptom, and
esophagitis as an endoscopic finding. These disorders are not
mutually exclusive, and effective treatment of one disorder
does not guarantee that the patient will be symptom free. This
principle is most relevant to the treatment of PUD. With the
realization that peptic ulcer often has an infectious cause, it is
now possible to talk of treatment in terms of “cure” of the ulcer after antibiotic therapy, not just symptom relief or temporary healing. The presence of continued symptoms could indicate coexistence of nonulcer dyspepsia, GERD, or both.
DYSPEPSIA
Dyspepsia is usually the main complaint for patients who present with upper GI problems. As defined above, dyspepsia occurs in approximately 26% of the population in the United
States and in as many as 41% in England.1,2 As dyspepsia is a
symptom complex that may apply to several patient conditions, the exact cause can be one or several different disorders.
Once investigated, approximately 50% of patients have a specific problem (e.g., PUD or GERD). In the remainder, no
cause is often discovered.
There have been several attempts to define dyspepsia,1,7
and it can be classified into several subclassifications which
attempt to associate the type of dyspepsia with a cause. Patients who present with dyspepsia but have not undergone any
diagnostic tests are said to have “uninvestigated” dyspepsia.
In addition, patients with a heartburn-like dyspepsia are said
to have “GERD-like” dyspepsia, those with dyspepsia that is
U.S. Population
H. pylori positive: 40%
Peptic ulcer
15–30%
H. pylori negative: 60%
Nonulcer
Asymptomatic
Peptic ulcer
Nonulcer
Asymptomatic
dyspepsia or
30–65%
Rare
dyspepsia or
60–80%
gastritis
gastritis
20–40%
20–40%
FIGURE 27-2 Relationship of Helicobacter pylori to peptic ulcer and nonulcer dyspepsia.
UPPER GASTROINTESTINAL DISORDERS
described as crampy are said to have “dysmotility-like” dyspepsia, and those with abdominal pain that is burning and relieved by meals are said to have “ulcer-like” dyspepsia. Some
disagree with the inclusion of heartburn in dyspepsia classifications and would consider dyspepsia to be limited to ulcerlike or dysmotility-like. Despite these classifications, the predictive value of dyspepsia for specific pathology is poor.
Understanding these classifications is essential to understanding studies that investigate this problem. When evaluating
studies, close attention must be paid to the authors’ definitions
and inclusion criteria for study subjects when attempting to
review results.
Diagnosis for a patient with a new complaint of dyspepsia
is usually directed at the suspected cause. Thus, a patient who
complains of “GERD-like” dyspepsia will be diagnosed and
treated like a patient with GERD, and a patient who complains of “ulcer-like” dyspepsia will be diagnosed and treated
like a patient with PUD. Once a patient has undergone diagnostic procedures (usually endoscopy) without finding a specific cause for their dyspepsia, it will be classified as “nonulcer” dyspepsia.
The management strategy for patients who have dyspepsia
of unknown cause or are classified as having nonulcer dyspepsia varies and has been the subject of numerous studies.
For treatment, most of these patients will receive H. pylori
testing and eradication, antisecretory medications (either H2antagonists or proton pump inhibitors), or a combination of
both. The remainder of this section reviews the efficacy of
these strategies.
Management Strategies
Perhaps the first management option is whether empiric treatment or further diagnosis followed by a specific treatment is
the most effective course of action.8 Several trials examined
whether H. pylori testing and eradication would provide better symptom control than a strategy that based treatment on
results of endoscopy.9–11 The entry criteria for the largest of
the three trials included patients who presented to their primary care practitioners with dyspepsia. These patients had
truly uninvestigated dyspepsia. Symptoms were controlled
better in the endoscopy-directed treatment group. The remaining two trials, which enrolled patients referred for endoscopy, failed to find a difference in symptoms. It is likely
that the patients in the two unsuccessful studies were selected
by an initial empiric trial by their primary care practitioner.10,11
If the initial treatment strategy is empiric treatment, acid
suppression is often the first choice. There are numerous trials that compare the various options in this area. Three trials
comparing PPIs and H2-antagonists found patients receiving
PPIs to have significantly better symptom control.12–14 In these
studies, PPIs appear to offer superior control of heartburn-like
dyspepsia. However, the Cochrane Database review concludes that there is insufficient evidence to make the claim
that PPIs are superior to H2-antagonists.8
Whereas the role of H. pylori is widely accepted in PUD,
its role in other GI conditions such as dyspepsia is not clear.
When patients infected with H. pylori are queried, a broad
range of symptoms are reported including dyspepsia and
•
27-3
heartburn. Until recently, studies designed to determine the
role of H. pylori in nonulcer dyspepsia have not studied appropriate outcomes. Recently several studies comparing H.
pylori eradication with alternate therapy have been published
that used appropriate end points. Most of these trials find no
significant difference in symptom resolution between the H.
pylori eradication group and the control subjects. However,
McColl and colleagues reported a significant improvement in
symptoms in nonulcer dyspepsia patients who had H. pylori
eradicated (with antisecretory and antimicrobial agents) compared to those receiving 4 weeks of PPI monotherapy.15 This
study used a continuous symptom assessment tool that patients recorded for 12 months, but they also included many
patients who may have had PUD. While the overall success favored H. pylori eradication, symptom resolution was low and
observed in only 27% of patients compared with 12 % for the
PPI-treated group. In contrast, Blum and colleagues evaluated
H. pylori eradication versus 4 weeks of a PPI and evaluated
symptoms at 1 year.16 Control of symptoms was similar in the
two groups (26% to 30%). One main difference between the
McColl and Blum studies is that Blum excluded patients with
a history of peptic ulcer or GERD. This may explain some of
the different results as PPIs would be expected to be superior
in patients with GERD as their origin of their dyspepsia.
It appears that both H. pylori eradication and PPIs provide
symptom control in patients with nonulcer dyspepsia. Studies
arriving at different conclusions regarding empiric treatment
are likely dependent on patient selection. One clear conclusion is that overall symptom control is poor, with less than
one-third of patients being free of symptoms with either treatment regimen.
Treatment Recommendations
Patients with dyspepsia should receive appropriate diagnosis
to determine the cause of their symptoms. If the cause is determined to be peptic ulcer, GERD, an NSAID-associated ulcer, or another condition, appropriate treatment should be initiated. If no specific cause is found, it appears that PPIs or H.
pylori testing and (if positive) eradication should be tried. As
studies demonstrate only modest efficacy, appropriate followup is important.
PEPTIC ULCER DISEASE
Peptic ulcers are lesions in the stomach or duodenum that occur as a result of the activity of acid and pepsin. ZollingerEllison syndrome (ZES) is a rare form of PUD resulting from
hypersecretion as a result of a gastrin secreting tumor.
Epidemiology
Incidence and Prevalence
During the beginning of the 20th century, the incidence of
PUD significantly increased, reaching a peak in the early
1950s.17 Over the past two decades, both outpatient episodes
of duodenal ulcers and ulcers requiring hospitalization have
declined. Whether this decline reflects an actual decrease
in the incidence of ulcer disease or the combined influences
of more effective therapy, changes in hospital diagnostic
27-4
•
GASTROINTESTINAL DISORDERS
practices or criteria, and institution coding changes is unclear.
Although hospitalization for duodenal ulcers has declined,
hospitalization for gastric ulcers has remained stable. The lack
of decline in gastric ulcers may be attributable to aging and
the use of NSAIDs.
Geographic Variation
PUD occurs worldwide with significant geographic variation.
In Japan, the incidence of gastric ulcer is approximately 5 to
10 times more common than duodenal ulcer; however, in most
European countries and the United States, duodenal ulcers are
approximately twice as common as gastric ulcers.18
Gender
In the United States through the 1970s, more women than
men developed PUD.19,20 The incidence of gastric ulcers is approximately the same for men as for women; however, hospitalizations for women with gastric ulcers have increased significantly for patients older than 65.19
Age
Gastric ulcers rarely develop before age 40, and the peak incidence occurs from ages 55 to 65.20 In contrast, the incidence
of duodenal ulcers increases with age until the age of approximately 60 years.2 The prevalence of H. pylori associated ulcers is low in children, but the incidence also increases with
age.
Morbidity and Mortality
Mortality caused by PUD has declined over the past 20 years.
Fewer than 2% of ulcer patients receiving therapy are expected to have a serious complication including bleeding, perforation, or obstruction. Nevertheless, PUD remains one of
the most common GI diseases that results in loss of work and
high-cost medical services.20
Physiology of the Upper Gastrointestinal Tract
The stomach consists of three anatomically and functionally
distinct regions: the cardia, the body, and the antrum (Fig.
27-3). The body, which makes up approximately 80% to 90%
of the stomach, contains the parietal cells, which secrete acid
and intrinsic factor which is required for vitamin B12 absorption. The body of the stomach also contains chief cells, which
secrete pepsinogen. The antrum constitutes approximately
10% to 20% of the stomach and contains the G-cells, which
secrete the hormone gastrin.
Various stimuli can trigger the secretion of acid into the
gastric lumen. Neurologic impulses, originating in the central
nervous system (CNS) and initiated by the sight, smell, and
taste of food, travel along cholinergic pathways to provoke the
release of acetylcholine in both the parietal cell and antral Gcell areas (Fig. 27-4). Subsequently, gastric distention stimulates oxyntic and antral receptors, and food protein further
stimulates antral receptors to further trigger the release of
acetylcholine at nerve endings in parietal and G-cell areas.
The acetylcholine in turn stimulates the antral G-cells to
release the hormone gastrin. Other stimuli cause secretion
of histamine in the vicinity of the parietal cells. All three
mediators—acetylcholine, gastrin, and histamine—converge
to activate potassium-hydrogen-adenosine triphosphatase (KH-ATPase) located on the parietal cell surface. The secretion
of acid occurs against a concentration gradient and therefore
requires the K-H-ATPase proton pump.21 As the hydrogen
ion concentration increases, it inhibits further secretion of gastrin through a feedback pathway. Cholecystokinin, glucagon,
and vasoactive intestinal peptide also inhibit gastrin secretion.
Thus, gastric acid secretion is regulated through both positive
and negative feedback mechanisms. Pepsinogen, released from
the chief cells, is a proenzyme that will form pepsin under
acidic conditions (pH 3.5). Pepsin combines with acid to
form a proteolytic complex, which further aids in the digestive
and ulcerogenic processes.2
Several mechanisms protect the gastroduodenal mucosa
from the digestive effects of pepsin and acid. Prostaglandin E
and somatostatin, located on the basolateral membrane of the
parietal cell, inhibit gastric acid secretion, maintain mucosal
blood flow, and stimulate production of mucus and bicarbonate.22The secretion of mucus by superficial epithelial cells and
mucous cells throughout the stomach protects against the erosive effects of acid. Gastric mucus is a viscous gel that serves
as a mucosal lubricant, a trap for micro-organisms, and a barrier to the back diffusion of hydrogen ions from the mucosa.22
ESOPHAGUS
CARDIA
Mucus-Secreting Cells
DUODENUM
PYLORUS
BODY
Parietal Cells (Acid and Intrinsic Factor)
Chief Cells (Pepsinogen)
ANTRUM
G Cells (Gastrin)
FIGURE 27-3 Gastrointestinal anatomic regions.
UPPER GASTROINTESTINAL DISORDERS
•
27-5
Food (Sight, Smell, Taste)
CENTRAL
NERVOUS
SYSTEM
ANTRAL RECEPTOR
OXYNTIC RECEPTOR
Acetylcholine
Stomach Wall
Distention
Cholinergic
Pathways
Acetylcholine
Antral Distention
H
Protein in Meal
SECRETION
K H ATPase
Long Vagovagal
and Local Reflexes
Local Reflex
Gastrin
Histamine
PARIETAL CELL
ANTRAL G CELL
FIGURE 27-4 Neurochemical influences on gastric acid secretion.
Bicarbonate also is secreted throughout the stomach and creates a pH gradient that neutralizes the hydrogen ions.
A network of vascular capillaries beneath the surface epithelium provides yet another level of defense against gastric
acid injury. Mucosal blood flow, through arterioles and capillaries, transports oxygen and substrates to the mucosa and removes acids that can be damaging to the epithelium of the
stomach or duodenum.23 The rapid and continual renewal of
gastroduodenal epithelial cells also enhances resistance to injury from secreted acids. In the majority of cases, disruption
of the surface epithelium can be mitigated partially by the formation of a fibrin cap over the injured area (a process known
as restitution).23,24 These actions of prostaglandin E, somatostatin, bicarbonate, gastric mucus, mucosal blood flow, epithelial cell regeneration, and restitution all combine to protect the gastric epithelium against injury from secreted acid.
Pathogenesis
The integrity of the upper GI mucosa depends on a balance
between aggressive forces (primarily gastric acid and pepsin)
and mucosal defensive factors.24 Gastric acid is necessary for
the formation of ulcers, but an alteration in the protective defenses plays a significant role as well. Patients with ZE syndrome have an increased parietal cell mass, which secretes
large amounts of gastric acid. Conversely, patients with duodenal ulcers have normal acid secretion, and patients with
gastric ulcers tend to have normal or low acid production.24
These observations support the premise that other mechanisms are involved in the pathogenesis of ulcers. Studies have
focused on alteration of mucosal defenses as an etiology of ulcers. For example, prostaglandin inhibitors (e.g., NSAIDs)
may render the gastric mucosa susceptible to ulceration because endogenous prostaglandins protect the GI tract.26 H. pylori also has a role in the pathogenesis of PUD, and eradication of this organism can alter the natural history of the PUD.
As a result, many investigators have divided PUD into three
etiologic groups based on pathophysiologic abnormalities: (1)
ulcers associated with H. pylori infection, (2) those caused by
NSAID use, and (3) those with acid hypersecretion (i.e., ZE
syndrome).24
Helicobacter pylori
A Gram-negative spiral bacterium, Campylobacter pylori,
was isolated in 1983 from patients with gastritis, and the association of this organism to the pathogenesis of PUD began
to be investigated. Approximately 6 years later, the nomenclature of Campylobacter pylori was changed to H. pylori because the characteristics of this organism were more aligned
with bacteria in the Helicobacter genus than the Campylobacter genus.25,26 Approximately 40% of patients older than
60 are seropositive for H. pylori, whereas the prevalence in
patients younger than 30 years of age is only 10%.27
The mode of transmission of H. pylori is unknown; however, person-to-person transmission is likely because of findings of familial clustering.28 H. pylori can be isolated anywhere in the stomach but is found most consistently in the
gastric antrum, where it is associated with inflammation. This
organism is the most common cause of antral gastritis,29 and
elimination from the gastric antrum is associated with resolution of gastritis. The exact mechanism by which H. pylori
causes gastric injury is unknown, but possibilities include
production of a cytotoxin, breakdown of mucosal defenses,
and adherence to epithelial cells.30 H. pylori is unique in that
it produces large amounts of urease. Urease catalyzes the hydrolysis of urea to form ammonia, and the accumulation of
ammonia may play a role in disrupting the integrity of gastric
mucosa, rendering it susceptible to ulceration.31 In addition,
H. pylori infected individuals have increased basal and stimulated acid secretion when compared with those not infected.
Eradication of H. pylori can reverse this increased acid secretion to normal.32
H. pylori is found in approximately 90% of patients with
duodenal ulcers and in 70% of those with gastric ulcers.32
Eradication of H. pylori significantly decreases the recurrence
rate of peptic ulcers and accelerates the ulcer healing process;
therefore, H. pylori is implicated in the pathogenesis of
PUD.33 Nevertheless, not everyone with H. pylori has an ulcer, and it is often isolated from patients who do not have
PUD.33 H. pylori infection also is not associated with acute
perforated duodenal ulcers. This latter finding suggests that
perforated duodenal ulcers may have a different pathogenesis
from chronic duodenal ulcer disease and that perforation is
27-6
•
GASTROINTESTINAL DISORDERS
not a complication of H. pylori infection.34 It is possible that
NSAID use plays a significant role in this problem.
Risk Factors
A number of factors can predispose an individual to development of PUD:
• Disruption of mucosal resistance to injury appears to be
one mechanism involved in the pathogenesis of ulcers. The
inflammatory response associated with H. pylori is thought
to disrupt the architecture of the gastroduodenal mucosa,
which then alters its natural defense mechanism. Antral
gastritis associated with H. pylori infection has been found
in 75% to 95% of patients with gastric and duodenal ulcers,
respectively.24
• Overwhelming evidence associates NSAID use with PUD,
particularly gastric ulcers. NSAIDs and aspirin impair ulcer
healing and induce ulcer formation through prostaglandin
inhibition and directly irritate the gastric and duodenal mucosa.36
• Cigarette smoking impairs ulcer healing, promotes ulcer recurrence, and increases the likelihood of ulcer complications.24 Cigarette smoking may cause ulcers through stimulation of gastric acid secretion and bile salt reflux,31,32
alteration in mucosal blood flow, and reduction in
prostaglandin synthesis.4,32
• Historically, some foods were believed to be factors in the
development of ulcers. Although some foods and beverages
(e.g., caffeine-containing foods, milk, alcohol, spicy foods)
increase acid secretion and cause dyspepsia, no scientific
data support the belief that diet imparts an increased risk for
ulcer formation.3 Acute alcohol ingestion can damage the
gastric mucosal barrier, leading to acute gastric mucosal lesions and GI bleeding; however, alcohol has not been
proven to cause PUD.4
• Genetic predilection appears to be a risk factor for the development of ulcers. Approximately 20% to 50% of patients with duodenal ulcers have a positive family history of
PUD compared with 5% to 15% of nonulcer patients.20
• Although rigorous studies are lacking, stressful life events
are thought by some to exacerbate PUD.32
Clinical Presentation
Patients with gastric or duodenal ulcers present with similar
symptoms and cannot be differentiated on the basis of clinical
findings; therefore, a definitive diagnosis requires an upper GI
radiologic series or an endoscopy is needed to visualize the ulcer. The most common and often the only symptom of an ulcer
is epigastric pain. Overall, the pain associated with duodenal
and gastric ulcers is not well localized and usually is described
as annoying, burning, gnawing, and aching.3 Pain occurring
when the stomach is empty (e.g., during the night, between
meals) and when relieved by food and antacids is the most
widely described characteristic of duodenal ulcer pain. Duodenal ulcer pain usually is episodic with symptomatic periods
lasting for weeks followed by a period of no occurrence. The
pain associated with gastric ulcers is difficult to distinguish
from duodenal ulcers, but it may occur at any time of the day.
Epigastric pain does not always correlate with the presence
or absence of an ulcer; asymptomatic patients have been diagnosed with ulcers, and patients with dyspeptic symptoms
may not have active ulcer disease.1,2
Gastric and duodenal ulceration can occur in the absence
of dyspeptic symptoms and may be present in the elderly who
are taking analgesics or in those who have a high pain tolerance. Complications such as bleeding, obstruction, or perforation often are often associated with a change in the character of a patient’s pain.2
Treatment
The relief of symptoms, promotion of ulcer healing, prevention of ulcer recurrence and complications, and the provision
of cost-effective therapy are among the primary treatment
goals of uncomplicated PUD. It is especially important to remember that patients who present with PUD usually have a
primary complaint of dyspepsia. Thus, relief of this symptom
is the most important goal for PUD patient. Current therapy
for acute uncomplicated ulcers is directed toward eliminating
H. pylori, reducing gastric acidity, or enhancing mucosal defenses. When patients are infected with H. pylori, the eradication of this organism is the primary treatment goal because
of its clear association with duodenal and gastric ulcers.35,36
Healing of and reducing recurrence of gastroduodenal lesions
is associated with an effective eradication of H. pylori.36 In
contrast, gastric ulcers typically are associated with normal or
decreased acid secretion and are less frequently associated
with H. pylori infection. This may be due to the association of
gastric ulcers to NSAID use, a potential cause that is independent of H. pylori infection.35,36 Gastric ulcers can be associated with gastric carcinoma. This possibility must be addressed in the diagnosis.
Drug treatment of peptic ulcers (Tables 27-1 and 27-2) generally consists of diagnosis and eradication of H. pylori as well
as medications that neutralize gastric acid (e.g., antacids), inhibit acid secretion (e.g., H2-antagonists, and PPIs), and protect
the gastroduodenal mucosa (e.g., sucralfate). Table 27-1 lists
the antisecretory medications used, but it must be remembered
that eradication of H. pylori is the primary treatment for PUD
in infected individuals. Virtually all patients with a duodenal ulcer are infected. With the advent of antibiotic treatment for H.
pylori, acid suppression alone is rarely indicated except for patients with bacteriologic cure and recurrent ulcers.
H2-Antagonists
MECHANISM OF ACTION
H2-receptor antagonists inhibit the secretion of gastric
acid. Histamine, released primarily from mast cells, binds to
H2-receptors and activates adenylate cyclase, and thereby increases intracellular cyclic adenosine monophosphate
(cAMP). The increased levels of cAMP activate the proton
pump of the parietal cell to secrete hydrogen ions against a
concentration gradient in exchange for potassium ions.37 H2receptor antagonists competitively and selectively inhibit the
action of histamine on the H2-receptors of the parietal cells,
thus reducing basal and stimulated gastric acid secretion.
EFFICACY
There are four H2-receptor antagonists available in the United
States. All are effective for the treatment of duodenal and gastric
ulcers (see Table 27-1). Use of these medications is associated
with an overall healing rate of 70% to 95% after 4 to 8 weeks of
therapy. They are equally effective in the acute healing of duodenal and gastric ulcers and are equally well tolerated.38
UPPER GASTROINTESTINAL DISORDERS
Table 27-1
•
27-7
Antiulcer and GERD Indications
H2RAs
Cimetidine
Famotidine
Nizatidine
Ranitidine
Proton Pump Inhibitors
Esomeprazole
Omeprazole
Lansoprazole
Pantoprazole
Rabeprazole
Other Agents
Misoprostol
Sucralfate
PUD
Hypersecretory
GERD
Esophagitis
Xa,b
Xa,b
Xa,b
Xb,c
X
X
X
X
X
X
X
X
X
X
Xa
Xb,c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xc
NSAID-Induced Ulcer
X
Xd,e
Xe
Xb,c
a
Duodenal and gastric ulcer.
Maintenance for duodenal ulcer.
c
Duodenal ulcer.
d
NSAID-induced ulcer healing.
e
NSAID-induced ulcer prevention.
X, approved indication.
b
Table 27-2
Antiulcer and GERD Medications: Doses
Duodenal Ulcer
H2RAs
Cimetidine
Famotidine
Nizatidine
Ranitidine
Proton Pump Inhibitors
Esomeprazole
Lansoprazole
Omeprazole
Pantoprazole
Rabeprazole
Other Agents
Sucralfate
300 mg QID
400 mg BID
800 mg HS
20 mg BID
40 mg HS
150 mg BID
150 mg BID
300 mg HS
30 mg QD
60 mg QD
20 mg QD
40 mg QD
20mg QD
Duodenal
Ulcer
Maintenance
Gastric Ulcer
GERD
Esophagitis
Hypersecretory
400 mg HS
300 mg QID
800 mg BID
400 mg QID
800 mg BID
400 mg QID
300 mg QIDa
20 mg BID
40 mg HS
20 mg BID
20 mg BID
20 mg BIDa
150 mg BID
150 mg HS
150 mg BID
150 mg BID
150 mg BID
150 mg BID
150 mg QID
150 mg QID
150 mg BIDa
15 mg QD
30 mg QD
20 mg QD
30 mg QD
20 mg QD
30 mg QD
60 mg QDa
60 mg QDa
10 mg QD
20 mg QD
40 mg QD
20 mg QD
20 mg QD
60 mg QDa
40 mg QD
20 mg QD
40 mg QD
20 mg QD
40 mg QDa
60 mg QDa
20 mg QD
NSAID
30 mg QDb
1 mg QID
2 gm BID
Misoprostol
200 g QIDc
a
Titrate dose to acid secretory response.
Prevention NSAID ulcers and NSAID ulcer healing.
Prevent NSAID ulcers.
BID, twice daily; HS, at bedtime; QD, once daily; QID, four times daily.
b
c
POTENCY
Although the relative antisecretory potency on a milligram-per-milligram basis of these four agents differs (famotidine has the greatest potency, followed by nizatidine, ranitidine, and lastly, cimetidine), this issue is not clinically
relevant because the formulations of these four drugs have
been adjusted accordingly. The serum concentration that is
necessary to inhibit 50% of pentagastrin-stimulated secretion
of acid determines the dosage and frequency of administration of each H2-receptor antagonist. Famotidine is the most
potent and possess the longest duration of action.39
27-8
•
GASTROINTESTINAL DISORDERS
PHARMACOKINETICS
Although these agents have identical mechanisms of action
and similar clinical benefits, they differ in their pharmacokinetic profiles (Table 27-3).
Oral absorption of all the H2-receptor antagonists is rapid,
and peak drug concentrations usually are achieved within 1 to
3 hours after administration.39 The bioavailability is lower for
cimetidine, famotidine, and ranitidine because they are absorbed incompletely and undergo first-pass hepatic metabolism. Ranitidine undergoes the most extensive first-pass metabolism, which accounts for the large difference between the
oral and intravenous (IV) doses of this drug. Nizatidine is the
only H2-receptor antagonist that is unavailable as an IV formulation.
All four drugs are eliminated by a combination of hepatic
metabolism, glomerular filtration, and renal tubular secretion.39 Hepatic metabolism is the principal pathway for the
elimination of cimetidine and ranitidine, whereas renal excretion is the major route for the elimination of famotidine and
nizatidine.39 For each of these agents, the half-life is increased, the total body clearance is decreased, and dosage reduction is recommended for patients with moderate to severe
renal insufficiency. The pharmacokinetics of the H2-receptor
antagonists appear to be unaffected by hepatic dysfunction;
however, in patients with hepatic failure and renal insufficiency, dosage adjustment may be necessary.
ADVERSE EFFECTS
H2-receptor antagonists are remarkably safe and the frequency of severe adverse effects is low for all four drugs.40
The most common adverse effects include GI discomfort
(e.g., diarrhea, constipation), CNS effects (e.g., mental confusion, headaches, dizziness, drowsiness), and dermatologic effects (e.g., rashes).40 Cimetidine has weak antiandrogenic effects, and its use in high doses has been associated with
gynecomastia and impotence. Hepatotoxicity has occasionally been observed in patients taking H2-receptor antagonists.
The patients who are at greatest risk for developing adverse
Table 27-3
effects include the elderly, those taking higher doses, and
those with altered renal function.
DRUG INTERACTIONS
Several drugs interact with the H2-receptor antagonists
and, in particular, cimetidine (Table 27-4). Cimetidine binds
to the cytochrome (CYP) P450 mixed-function oxidase enzyme system and inhibits the biotransformation of several
drugs by the liver. It primarily affects oxidative drug metabolism while conjugation generally is not affected. The magnitude of cimetidine interaction with other drugs varies from
patient to patient; however, it generally will reduce the clearance of another drug by approximately 20% to 30%.41 This interaction is most clinically significant with drugs that have
narrow therapeutic ranges such as phenytoin, warfarin, and
theophylline.
Although ranitidine is more potent on a molar basis, it
binds less intensely to the CYP P450 system than cimetidine.41 Therefore, when used in equipotent doses, there is less
potential for ranitidine (compared with cimetidine) to interfere with the liver metabolism of other drugs.39 In contrast,
famotidine and nizatidine do not bind appreciably to the CYP
P450 system and therefore have limited ability to inhibit the
metabolism of other drugs.41 Overall, ranitidine, famotidine,
and nizatidine, when used in equipotent doses, are unlikely to
cause clinically significant drug interactions when administered concurrently with other drugs eliminated by phase I oxidative metabolism by the liver. However, the introduction of
cimetidine to a patient receiving a drug that requires the CYP
P450 system for metabolism may require a downward dosage
adjustment of the object drug to avoid increased serum concentrations. Patients receiving drugs known to interact with
H2-receptor antagonists should be monitored to prevent or
minimize the development of an adverse drug–drug interaction.
Some of the H2-receptor antagonists are eliminated via renal tubular secretion and therefore have the potential to compete with cationic compounds for tubular secretion.42 Cimeti-
Pharmacokinetic Comparison of H2-Receptor Antagonists
Variable
Cimetidine
Ranitidine
Nizatidine
Famotidine
Relative potency
Absorption
Bioavailability (%)b
Time to peak serum concentration (hr)
Volume of distribution (L/kg of body weight)
Elimination
Total systemic clearance (mL/min)
Half-life in serum (hr)
Hepatic clearance (%)
Oral
IV
Renal clearance (%)
Oral
IV
1
4–10
4–10
20–50
30–80 (60)
1–2
0.8–1.2
30–88 (50)
1–3
1.2–1.9
75–100 (98)
1–3
1.2–1.6
37–45 (43)
1–3.5
1.1–1.4
450–650
1.5–2.3
568–709
1.6–2.4
667–850
1.1–1.6
417–483
2.5–4
60
25–40
73
30
22
25
50–80
25–30
40
50–80
27
50
57–65
75
25–30
65–80
a
Adapted with permission from references 37–39.
Average values are in parentheses.
IV, intravenous.
b
UPPER GASTROINTESTINAL DISORDERS
Table 27-4
•
27-9
Clinically Significant Drug Interactions With Cimetidinea
Effect on Serum
Drug Concentration
Drug
Phenytoin
Nifedipine
Procainamideb
Theophyllineb
Warfarin
Benzodiazepines (diazepam, chlordiazepoxide)
Carbamazepine
Propranolol
Quinidine
↑
↑
↑
↑
↑
↑
↑
↑
↑
TCAs (imipramine, desipramine, amitriptyline)
Verapamil
↑
↑
b
Mechanism
Inhibits metabolism; 140% ↑ serum levels
↑ AUC by 60–90%
Competition for renal tubular secretion; 44% ↑ AUC
Inhibits metabolism; 20–40% ↑ in serum levels
Inhibits metabolism of R isomer; 20% ↑ PT
Inhibition of metabolism; 30–60%
Inhibition of metabolism; variable
Inhibition of metabolism; 1.5- to 3-fold ↑ in plasma level
Inhibition of metabolism and may
↓ renal clearance; 14.5% ↑ AUC
Inhibition of metabolism; variable
↑ clearance by up to 35%
a
Adapted from references 40–45.
There also are fewer interactions with ranitidine.
AUC, area under the curve; PT, prothrombin time; TCAs, tricyclic antidepressants.
b
dine and ranitidine inhibit the renal tubular secretion of procainamide and its metabolite by this mechanism.43 Patients
taking any one of these H2-receptor antagonists have a decreased area under the concentration-time curves (AUCs) of
procainamide and N-acetyl procainamide and their renal
clearance is decreased. The interaction with ranitidine appears
to be concentration and dose dependent; therapeutic doses of
ranitidine (i.e., 300 mg/day) did not cause an interaction,
whereas large doses (i.e., 750 mg/day) alter the pharmacokinetics of procainamide.43 Although famotidine is a cationic
drug that is excreted via active tubular secretion, it does not
inhibit the renal elimination of procainamide or its metabolite.44 A possible reason for this discrepancy is that the serum
concentrations attained by the usual therapeutic dose (i.e., 20
mg twice a day) of famotidine may be too low to compete
with other drugs at the site of renal tubular secretion.39
All four H2-receptor antagonists can potentially affect the
absorption and reduce the bioavailability of some drugs by altering the gastric pH.45 By increasing the pH of the GI tract,
cimetidine slows the dissolution of ketoconazole, ultimately
reducing its absorption. Most H2-receptor antagonists are
weak inhibitors of gastric alcohol dehydrogenase. Thus, therapeutic doses of cimetidine, ranitidine, and nizatidine, enhance the absorption of ethanol following ingestion of moderate amounts of alcohol (approximately one or two glasses of
wine or cans of beer).45 This interaction is thought to be a result of gastric alcohol dehydrogenase inhibition. According to
these findings, systemic effects of alcohol may be exacerbated
and the safety of patients compromised. Famotidine has little
effect on this enzyme, but in a more recent study, H2-receptor
antagonists did not alter serum ethanol levels following moderate to large alcohol consumption.46 Until more data are
available confirming the results of the latter study, possible
adverse effects associated with ethanol use should be considered when selecting an H2-receptor antagonist for patients
who routinely consume alcohol.
DOSING
When cimetidine was first introduced, it was administered
four times a day. However, based on clinical studies, recommendations now range anywhere from once daily to four
times a day (see Table 27-2). The hypothesis that control of
nighttime acid secretion is more effective in healing duodenal
ulcers led to studies that compared night-time dosing with
multiple-daily-dosing regimens finding similar healing
rates.47
Proton Pump Inhibitors
MECHANISM OF ACTION
The proton pump inhibitors (PPIs) are highly specific inhibitors of gastric acid secretion. They act by irreversibly
binding to K-H-ATPase (an enzyme that transports acid
across the parietal cell), these drugs inhibit basal and stimulated gastric acid secretion in a dose-dependent and sustained
fashion.48–50 PPIs cause almost total elimination of acid release because they inhibit the terminal step in the acid production cycle.
EFFICACY
The PPIs (i.e., omeprazole [Prilosec], lansoprazole [Prevacid], rabeprazole [Aciphex], pantoprazole [Protonix], and
esomeprazole [Nexium]) relieve symptoms and heal duodenal
and gastric ulcers more quickly than the H2-receptor antagonists (in 2 to 4 weeks compared with 4 to 8 weeks). However,
the absolute healing rates for drugs in both groups are
comparable (i.e., 90%) after completion of the requisite
course of therapy.51 All the PPIs inhibit 90% of gastric
acid secreted in 24 hours.52 While PPIs are indicated for
the short-term treatment of active duodenal ulcers, eradication of H. pylori is the first-line treatment. PPIs are also effective in healing benign gastric ulcers, erosive reflux
esophagitis, and controlling the hypersecretion associated
with ZE syndrome.
27-10
•
GASTROINTESTINAL DISORDERS
PHARMACOKINETICS
The PPIs are formulated as enteric-coated granules within
capsules or enteric-coated tablets because they are unstable in
acid media.53–55 Both omeprazole and pantoprazole are available in an IV formulation. Only IV pantoprazole is available
in the United States. An IV formulation of lansoprazole is
currently being investigated. All PPIs are rapidly absorbed after oral administration, with peak concentrations occurring 2
to 4 hours after administration of enteric-coated preparations.55 The bioavailability of these agents ranges from 50% to
80%. Currently available PPIs serve as prodrugs for the formation of active metabolites. The parent drugs are absorbed in
the small intestine and brought to parietal cells via the systemic circulation. The active metabolite of omeprazole
(omeprazole sulfonamide) and the active metabolites of lansoprazole (lansoprazole sulfone and hydroxy lansoprazole)
are protonated in the acidic region of the gastric parietal cell
secretory canaliculi. These active metabolites then bind covalently to sulfhydryl groups on the H-K-ATPase (proton
pump) to noncompetitively and irreversibly inhibit this enzyme and block release of acid. The PPIs are eliminated almost entirely by hepatic metabolism, and the elimination
plasma half-lives are approximately 1 to 2 hours.51–57 Despite
the short plasma half-lives, antisecretory effect still is present
36 to 72 hours after a dose because the drugs bind covalently
to the HK-ATPase in the parietal cell.55 Dosages need not
be adjusted for patients with renal impairment, but adjustment
may be prudent in those with severe liver disease.51–57 Esomeprazole, the S-enantiomer of omeprazole, has a similar
pharmacokinetic profile to omeprazole.
ADVERSE EFFECTS
The adverse effects of these agents are relatively infrequent
and comparable to those of H2-receptor antagonists. Some adverse effects include GI discomfort (e.g., nausea, diarrhea, abdominal pain), CNS effects (e.g., dizziness, headache), and
isolated reactions (e.g., skin rash, gynecomastia, increase in
liver transaminases).52 Theoretically, the PPIs can cause hypergastrinemia through their profound ability to inhibit gastric secretion because antral G-cells release gastrin when gastric pH
increases.53 Chronic hypergastrinemia in humans is thought to
lead to hyperplasia of enterochromaffin-like cells and carcinoid tumors of the stomach; however, there is no evidence of
tumors actually occurring even after several years of continued
treatment with high doses in patients with esophagitis.56
DRUG INTERACTIONS
All PPIs bind to P450 oxidative enzymes and therefore potentially interfere with hepatic drug metabolism. Data indicate
that omeprazole has a differential affinity for specific CYP P450
isoenzymes, especially CYP2C19, and can affect drugs primarily metabolized by that enzynme.58 Omeprazole decreases the
metabolism of diazepam, phenytoin, warfarin, and tolbutamide
and may increase the serum concentrations of these drugs. Patients taking these drugs with omeprazole should be monitored
for any potential toxic effects. Although lansoprazole has not
been shown to interact with drugs that are metabolized by the
CYP P450 system, there are reports of slight decreases in the
AUC for theophylline; this interaction may not be clinically insignificant.58 The bioavailability of omeprazole, lansoprazole,
and probably the other PPIs may be reduced by sucralfate. Be-
cause pantoprazole also is metabolized by a cytosolic sulfotransferase, it appears to interact less with drugs that compete
with the P450 enzyme system. This may explain why pantoprazole may have a lower potential for drug interactions.58 Rabeprazole can modestly increase digoxin serum concentrations; however, no interactions have been observed with phenytoin,
warfarin, or theophylline.5 Esomeprazole may inhibit the P450
enzyme system less than omeprazole.59
Sucralfate
MECHANISM OF ACTION
Sucralfate (Carafate) protects ulcerated tissue from aggressive factors such as pepsin, acid, and bile salts.60 At a pH
of 2.0 to 2.5, sucralfate binds to damaged and ulcerated tissue,
forming a physical barrier to injury from aggressive forces.
The drug is not absorbed systemically and does not possess an
antisecretory activity. However, sucralfate may have other
protective actions on the mucosa that are possibly mediated
by prostaglandin and gastric bicarbonate secretion.
EFFICACY
In doses of 1 g four times a day, sucralfate is more effective than placebo in healing duodenal ulcers61; it also appears
to be as safe and effective as H2-receptor antagonists in the
treatment of acute duodenal and gastric ulcers.62 The fourtimes-a-day dosing regimen for sucralfate is problematic for
most patients, but studies indicate that a 2-g twice-daily regimen is as effective as 1 g four times daily in the short-term
treatment of active duodenal ulcers.63 Sucralfate is effective,
but not approved by the U.S. Food and Drug Administration
(FDA), for acute or maintenance therapy of gastric ulcers. Although sucralfate is generally not used in H. pylori eradication regimens, one recent study demonstrated an eradication
rate of 75% when used with amoxicillin and clarithromycin.64
ADVERSE EFFECTS
Sucralfate is not appreciably absorbed systemically and
therefore adverse effects are uncommon. The most common
adverse side effect of sucralfate is constipation, possibly due
to the aluminum content of the compound. Other side effects
include dry mouth, nausea, and rashes. Sucralfate tablets are
large, and some patients, particularly the elderly, may have
difficulty swallowing them. Because sucralfate is available as
both a tablet and a suspension, the liquid formulation can be
used when patients encounter swallowing difficulties.
DRUG INTERACTIONS
The bioavailability of digoxin, fluoroquinolone antimicrobials, ketoconazole, levothyroxine, phenytoin, quinidine,
tetracycline, theophylline, and warfarin may be reduced when
concomitantly administered with sucralfate. The mechanism
of the interaction is thought to be caused by binding of the
agent with sucralfate in the GI tract. Because sucralfate may
reduce the absorption of other drugs, it should be administered separately (e.g., 2 hours after other agents).
Antacids
MECHANISM OF ACTION
Antacid products contain either sodium bicarbonate, aluminum hydroxide, magnesium hydroxide, calcium carbonate,
aluminum phosphate, or a combination of these agents.
UPPER GASTROINTESTINAL DISORDERS
Antacids relieve epigastric pain and promote healing of peptic ulcers by providing a cytoprotective effect, neutralizing
gastric acid, and stimulating restitution of the gastric mucosa.65 The cytoprotective effect of antacids may be related to
the stimulation of prostaglandins involved in gastric mucosal
defense.
EFFICACY
In clinical studies, antacids in various dosing regimens
promoted the healing of duodenal ulcers in 46% to 88% of patients after 4 weeks of therapy compared with 24% to 45% of
patients treated with placebo.65
Antacids need to be taken multiple times a day to neutralize gastric acid, and patient adherence to multiple-times-a-day
regimens (e.g., 1 and 3 hours after meals and at bedtime) is
difficult. As a result, antacids primarily are used to provide relief of ulcer pain and dyspepsia and are taken on an “asneeded” basis as often as the patient requires them. Antacids
are thought to work within 5 to 15 minutes; however, the duration of relief is estimated to be only approximately 2
hours.65 Although antacids are available in both liquid and
tablet formulations, the liquid formulation has a more rapid
acid-neutralizing action than the tablets. Tablet formulations
should be chewed well to maximize their action.65 Because of
the inconvenient dosage regimen, the high incidence of adverse reactions (primarily diarrhea), and lack of coverage by
most prescription plans, antacids are best used as a supplement to other PUD treatments for occasional dyspepsia.
ADVERSE EFFECTS
Sodium bicarbonate is a potent, rapidly acting antacid with
a short duration of dyspeptic relief.65 It should not be used for
prolonged periods because systemic alkalosis can result from
the accumulation of bicarbonate. Aluminum hydroxide commonly is combined with magnesium hydroxide or another
magnesium salt because, by itself, it has low acid-neutralizing
capacity compared with magnesium hydroxide or calcium
carbonate. Magnesium hydroxide usually produces diarrhea,
but when combined with aluminum, it offsets aluminum’s
constipating effects. Diarrhea usually predominates when
large doses of aluminum- or magnesium-containing antacids
are used. Small amounts of aluminum and magnesium are absorbed after antacid administration, and aluminum or magnesium levels can accumulate in patients with renal insufficiency. This is not a problem in patients with normal renal
function because both are excreted effectively. Magnesium
should be avoided in patients with significant renal impairment (creatinine clearance [ClCr] 20 mL/min) because accumulation can lead to CNS effects (e.g., sedation, nausea, vomiting). Calcium carbonate is a rapidly acting, very effective
neutralizer of gastric acidity; however, high dosages of 4 to 8
g/day also have the potential to stimulate gastric acid production and to induce the milk-alkali syndrome (i.e., hypercalcemic nephropathy with alkalosis).62
DRUG INTERACTIONS
Antacids, by alteration of gastric pH, can interfere with the
absorption of drugs (e.g., digoxin, phenytoin, isoniazid) that
require an acidic environment for dissolution and absorption.65 Ketoconazole, a dibasic compound, requires sufficient
gastric acid for dissolution and absorption, and concurrent ad-
•
27-11
ministration of ketoconazole with antacids can decrease the
plasma concentration of this antifungal drug. When antacids
increase gastric pH, they also have the potential to dissolve
the enteric coating of concurrently administered medications,
which are designed to dissolve in an environment more alkaline than the stomach, resulting in premature dissolution of
enteric-coated drugs.
By binding to concomitantly administered drugs, the calcium, aluminum, or magnesium component in antacids can
interfere with the absorption of drugs that are susceptible to
complexation with these salts. The bioavailability of
ciprofloxacin is decreased by 50% by antacids because aluminum and magnesium ions chelate with the quinolone antibiotic to form and insoluble, inactive complex potentially
leading to treatment failure. The administration of ciprofloxacin 2 hours before the antacid increases ciprofloxacin
bioavailability more than when administered 2 hours after the
antacid.66 Tetracycline is another antibiotic well known to interact with antacids. Antacids containing multivalent cations
(Mg2, Ca2, Al3) have a strong affinity for tetracycline, and
absorption of the antibiotic can vary according to the extent
of complexation.66 Patients taking any form of tetracycline
should be counseled not to take antacids for at least 2 to 3
hours after tetracycline administration. Overall, separating the
administration times of each drug by 2 hours generally can
minimize drug–drug interactions with antacids.
Eradication of H. pylori
We now know that most patients with a duodenal ulcer and
many with gastric ulcers are colonized with H. pylori.36,67 Bismuth with acid suppression was initially used in the treatment
of H. pylori–infected patients with peptic ulcers because it is
active against H. pylori at a minimum inhibitory concentration of 16 mg/mL,67–69 and its use was associated with a reduction in ulcer recurrence.67,68 Patients who remain positive
for H. pylori have a higher recurrence rate within the first year
after healing compared with patients in whom eradication of
H. pylori is achieved. A variety of regimens have been used to
eradicate H. pylori, and most currently accepted regimens use
several antibiotics plus acid suppression.
MONOTHERAPY
Although FDA-approved (omeprazole or lansoprazole plus
clarithromycin) regimens are available, their eradication rates
are in the 70% range. This is currently considered less than
acceptable by experts.67
COMBINATION THERAPY
Because monotherapy with antibiotics and monotherapy
with acid suppressants has not been optimal, combination
therapy consisting of antibiotics in conjunction with acid suppressants (PPIs or H2-receptor antagonists) have become the
primary mainstays in the management of H. pylori–positive
ulcer patients.71 In two prospective studies, H2-receptor antagonists were compared with combination antimicrobial therapy
to evaluate the differential contributions of decreased acid secretion to H. pylori eradication and on the recurrence rate of
ulcers.70,72,73 In these studies, recurrence rates for both gastric
and duodenal ulcers after 1 year were significantly lower (approximately 10%) with combination therapy than with ranitidine therapy alone (approximately 85%).71,74
27-12
•
GASTROINTESTINAL DISORDERS
A variety of regimens have been used to eradicate H. pylori, each with different dosing schedules, durations of therapy, adverse effects, and costs. Several studies have evaluated
antibiotic regimens for H. pylori eradication. Three were
noted to be cost-effective and associated with good outcomes:
(1) triple therapy of bismuth, metronidazole, and tetracycline
for 14 days; (2) clarithromycin, PPI, and metronidazole or
amoxicillin for 7 to 14 days; and (3) triple therapy of bismuth,
metronidazole, and tetracycline, plus a PPI for 7 days.70–75 For
patients who cannot receive metronidazole or when resistance
to metronidazole is either established or suspected, the regimen of choice is 7 to 14 days of clarithromycin, amoxicillin,
and a PPI. Another therapeutic regimen (i.e., bismuth 2 tablets
four times a day with meals and at bedtime, metronidazole
500 mg four times a day, and amoxicillin or tetracycline 500
mg four times a day for 14 days) results in an eradication rate
of 80% to 85%.74
RECOMMENDED COMBINATION REGIMENS
Regardless of the regimen chosen, effective eradication of
H. pylori requires combination therapy, and the ideal regimen
contains two antibiotics combined with either a PPI or bismuth.67,75 Recommended H. pylori eradication regimens can be
found in Table 27-5 and are discussed in further detail below.
1. PPIAC: The combination of a PPI, amoxicillin, and clarithromycin is approximately 90% to 95% effective and of
moderate to high expense. Patient adherence to this regimen may be good because the regimen uses twice-daily
dosing and can be for a 7- to 14-day duration. This regimen (using lansoprazole) is available commercially as
Prevpac in a 14-day “bingo card.” When using this regimen, the PPI should be taken twice daily before meals for
14 days; the amoxicillin 1,000 mg twice daily should be
taken with meals for 14 days; and the clarithromycin (Bi-
Table 27-5
axin) 500 mg twice daily should be taken with meals for 14
days. More recently, 10-day PPI regimens with amoxicillin and clarithromycin have been approved by the FDA.
Seven-day regimens are currently not FDA approved and
are generally less effective than the 10- to 14-day regimens. All PPIs are equally effective and the choice can be
determined based on cost and third-party prescription coverage. H2-antagonists should not be added to regimens that
contain a PPI.
2. PPIMC: Metronidazole at a dose of 500 mg BID can be
substituted for amoxicillin with similar rates of eradication.71,72
3. BMT-H2: The combination of bismuth, metronidazole, and
tetracycline plus an H2-antagonist may be given generically as separate medications or in a carton with 14 daily
blister cards and instructions (Helidac kit). This regimen is
relatively inexpensive but is complicated, requiring four
drugs administered four times daily for 2 weeks followed
by an additional 16 days of H2-antagonist therapy. The bismuth is given as bismuth subsalicylate 262 mg (PeptoBismol) and the tablets (two) are to be chewed four times
a day for 14 days with meals and at bedtime. Bismuth
given on a four-times-a-day dosing schedule before meals
appears to be more effective than twice-daily dosing.74 The
metronidazole is taken as 250 mg four times a day for 14
days with meals and at bedtime. The tetracycline in this
regimen is given as 500 mg four times a day for 14 days
with meals and at bedtime. The effect of meals in decreasing the absorption of the tetracycline is not of concern because a local, rather than systemic, action is the objective.
An H2-antagonist is needed for 30 days to enhance symptom relief and possibly enhance healing rate. A PPI taken
twice daily can be substituted for the H2-antagonist.
4. RBC-C: The combination of ranitidine, bismuth citrate,
and clarithromycin is available commercially as Tritec
Helicobacter pylori Eradication Regimens
Duration
(days)
Efficacy
(%)
PPIa BID
Clarithromycin 500 mg BID
Amoxicillin 1,000 mg BID
7, 10, 14
88–95
FDA approved (most PPIs); efficacy improves with
increased duration of therapy; relatively simple
regimen; available as “bingo card” (Prevpac)
PPIMC
PPIa BID
Clarithromycin 500 mg BID
Metronidazole 500 mg BID
7, 10, 14
88–95
Relatively simple regimen; efficacy improves with
increased duration of therapy; caution with
alcohol use
BMT-H2
H2RAb
Bismuth two tablets QID
Tetracycline
Metronidazole
14–28
75–85
Complicated regimen; FDA approved (“bingo card”);
efficacy less than PPIAC or PPIMC
RBC-C
Ranitidine Bismuth subcitratec
Clarithromycin 500 mg BID
Ranitidine 150 mg BID
14
75–80
FDA approved
Regimen
Agents/Dose/Frequency
PPIAC
a
PPI doses: omeprazole 20 mg BID; lansoprazole 30 mg BID; rabeprazole 20 mg BID; pantoprazole 40 mg BID; esomeprazole 20 mg BID.
H2RA doses: cimetidine 400 mg BID; ranitidine 150 mg BID; famotidine 20 mg BID; nizatidine 150 mg BID.
Ranitidine administered for 2 weeks after completing bismuth and antibiotics.
b
c
Comment
UPPER GASTROINTESTINAL DISORDERS
(ranitidine 150 mg plus bismuth citrate 240 mg twice a day
for 4 weeks combined with clarithromycin 500 mg three
times a day for the first 2 weeks). This regimen is less effective (80% to 85% cure rates) and more costly. Moreover, the dosing schedule is complicated, the duration of
therapy is longer (i.e., 4 weeks), and the regimen includes
only one antibiotic. RBC may be an option in a penicillin
allergic patient in whom it is desirable to avoid metronidazole due to ethanol use.
1. M.B., a 27-year-old female executive, presents with a 1week history of midepigastric upper abdominal pain, partially
relieved both by eating and by calcium carbonate tablets (Tums),
which she takes in the morning for calcium supplementation.
She describes the pain as being moderately severe and different
from gas pains which are associated with a bowel movement. She
has not noticed darkening of the stool or the presence of blood in
her stools. She has no other medical problems. In particular, she
does not recall any chronic abdominal complaints such as gas,
bloating, or heartburn and she has not been diagnosed previously with ulcer disease. She takes no other medications and is a
nonsmoker. Her use of NSAIDs is limited to 200 to 400 mg of
nonprescription ibuprofen tablets (Advil), but she does not take
ibuprofen more than three times per week. What is the likelihood this patient has a peptic ulcer?
Most patients with PUD initially present with nonlocalized
epigastric pain as the only symptom, much like this patient.
The relief of pain in this patient by both food and calcium
carbonate makes one suspicious of a duodenal ulcer, but this
in itself is not diagnostic. NSAIDs can increase the risk for
the development of ulcer disease and she has been taking
ibuprofen. However, her dose of ibuprofen is low, and she has
used these drugs in the past without difficulty. Although a diagnosis of ulcer disease in this patient is uncertain based on
her current history, she should discontinue the use of ibuprofen for now.
2. M.B. is counseled to use acetaminophen in place of ibuprofen and is given a prescription for famotidine (Pepcid) 40 mg HS
to be taken for 6 weeks. What are reasonable courses of action
for the management of this patient, and is famotidine treatment
appropriate before a diagnosis of PUD has been established?
If PUD is suspected, M.B. should be tested (serology or
breath test) for H. pylori and if positive, receive an H. pylori
eradication regimen. Endoscopic diagnosis before starting
treatment is usually not indicated in cases of PUD for patients
who are not suspected of having a complication.
Endoscopy may be indicated if the patient is older than 55,
if complications such as bleeding are present or suspected, if
weight loss is present, or if epigastric symptoms have recurred
after previous conservative treatment. It must be remembered
that H. pylori testing alone does not diagnose the presence of
an ulcer with certainty, because almost 50% of the population
is colonized with this organism. A definitive workup (e.g., endoscopy, upper GI series) may be necessary if M.B. does not
respond to the initial therapy, or if symptoms recur after initial therapy.
Detection of Helicobacter
3. What available tests for the detection of H. pylori are appropriate for M.B.?
•
27-13
H. pylori can be identified by direct testing of bacterial
colonies from a culture medium or indirectly by biochemical
assays and serologic tests. Because the organism is distributed
unevenly throughout the gastric mucosa, at least two specimens from the antrum should be obtained.67,74,75 Histologic
identification of H. pylori correlates well with culture results,
with a sensitivity and specificity of 85% to 100% and 50% to
100%, respectively.67,74,75 Factors implicated in the failure to
culture the organism include ingestion of simethicone, contamination of biopsy forceps with an antibacterial agent, recent treatment with antibiotics or PPIs, and biopsy in areas
with low organism counts.67 The rapid urease test can detect
the large amounts of urease produced by H. pylori within 2 to
3 hours with an endoscopically obtained biopsy specimen.67
In clinical practice, direct biopsy and culture are reserved for
patients in whom other tests are nondiagnostic.
Noninvasive tests for H. pylori are preferred when screening for this organism.67 The noninvasive breath test detects
urease in the stomach subsequent to the oral administration of
13
C- or 14C-labeled urea. If urease is present in the stomach
(presumably from H. pylori), the carbon dioxide exhaled in the
breath will contain the 13C isotope (detected by mass spectrometer) and the 14C isotope (detected by a scintillation
counter).67 The Meretek UBT (urea breath test) appears to be
highly specific, but is costly and associated with 5% to 10%
false-negative results.67 Another noninvasive test, the enzymelinked immunosorbent assay (ELISA) detects IgG and IgA antibodies to H. pylori in the serum. Sensitivity and specificity of
these antibody tests are approximately 95%; however, a positive test can represent either past or present exposure to H. pylori. Serologic antibody tests may be helpful for the initial diagnosis of H. pylori but are more problematic for documenting
eradication of this organism.67 However, long-term serologic
surveillance investigations indicate that IgG and IgA anti–H.
pylori antibody concentrations decrease rapidly and progressively after the eradication of the infection and increase with
recurrence of H. pylori infection. As a result, these noninvasive
serologic tests are used commonly to determine the presence
of H. pylori because of their simplicity and relative low costs.68
Serology testing is now commonly used because of its simplicity and relative low cost. Breath testing is more sensitive,
but cost prohibitive in many situations. Direct biopsy, culture,
and the rapid urease tests require endoscopy and are reserved
for situations in which endoscopy is warranted. In patients
with recurrent or refractory ulcers, further testing should be
considered because false-negative results are sometimes encountered.77,78 In this latter situation, other etiologies of PUD
also should be evaluated. Although any of the aforementioned
tests are acceptable for M.B., the most rational approach is
testing with serology and eradication of H. pylori using one of
the methods listed above. Treatment without testing for H. pylori has been advocated in some patients with a duodenal ulcer due to the high prevalence of H. pylori in patients with
duodenal ulcers. However, since most duodenal ulcers are diagnosed by endoscopy, it is simple to biopsy the gastric mucosa and test for H. pylori.
4.
Should M.B. discontinue using Tums tablets?
Although there is no logic for taking full-dose scheduled
antacids in conjunction with PUD treatment, patients generally
are instructed to continue to take antacids on an as-needed
27-14
•
GASTROINTESTINAL DISORDERS
basis for breakthrough symptoms, especially for the first few
days after starting treatment. In this particular situation, M.B.
has been taking the Tums as a calcium supplement for osteoporosis prevention. Although she is still at low risk for osteoporosis because of her young age, there is no need to discontinue the Tums. She should be instructed to take extra doses as
needed and to contact her physician or pharmacist if symptoms
have not resolved within 2 weeks.
5. PPIs are superior acid suppressants compared with H2-antagonists. Would it be better to initiate therapy in this patient
with a PPI?
The PPIs are superior to the H2-antagonists in acid suppression and provide more rapid symptom relief. Despite this,
acute treatment of patients with PUD by either H2-antagonists
or PPIs without H. pylori eradication is not indicated. There is
probably little, if any, role for PPIs or H2-antagonists for acute
treatment of peptic ulcers except as part of an H. pylori regimen. This is due to the rapid recurrence of the ulcer after completing an acute regimen.
6. J.L., a 37-year-old woman, is in the clinic today for a routine follow-up after treatment for a second episode of suspected
peptic ulcer. She relates a 14-year history of multiple GI complaints including postprandial bloating, “fullness,” belching, occasional nausea, reflux, and heartburn. There is no predictable
pattern to these complaints; they may be present daily for weeks
at a time, while at other times they may occur just a few times
per week. The heartburn and reflux may occur in the absence of
the bloating, belching, fullness, and nausea and vice versa. She
has taken a variety of antacids over the years including Maalox,
Mylanta, generic equivalents of both, Gaviscon, and Tums, all of
which give partial or complete, but temporary, relief.
Four years ago, J.L. had one episode of increased mid-upper
epigastric pain that lasted for several days. The discomfort was
relieved by food and was present during the night. Bowel movements had no discernible effect on the pain. Her physician informed her that she probably had an ulcer and prescribed a 10week regimen of cimetidine 400 mg twice a day. The abdominal
pain abated, but since then she has continued to take either cimetidine or nonprescription H2-antagonists as needed almost daily
for her chronic symptoms.
Six weeks ago, a similar abdominal pain developed and she
was treated empirically with clarithromycin 500 mg three times
daily for 2 weeks and omeprazole 20 mg twice a day for the first
2 weeks and then 20 mg of omeprazole daily for an additional 2
weeks. Once again, the acute pain subsided, but her underlying
complaints remain. She states that she was compliant most of the
time, but sometimes had difficulty remembering all three doses
of the clarithromycin each day. However, she continued to take
them until they were all gone. She lost track of how long it took
for all of the medicine to be gone.
The only other medication she has taken in the past year is an
oral contraceptive, Triphasil (ethinylestradiol/levonorgestrel),
which she has been taking for many years. She takes acetaminophen for headaches and avoids NSAIDs. She also relates
multiple episodes of bladder/urethral and vaginal infections over
the past 16 years, treated variously with trimethoprim-sulfamethoxazole, clotrimazole, and metronidazole. The last time
she had any of these infections was 5 years ago.
She has no other medical problems despite a 15-year history
of cigarette smoking. She has never undergone endoscopy. H. py-
lori testing was never performed before any of her treatments,
but an H. pylori serology taken 5 days ago is positive. No other
laboratory test results are available.
Based on the data provided, is this patient’s history consistent
with PUD? If endoscopy were to be performed today, is it likely
that an active ulcer would be found?
In the absence of endoscopy, it is impossible to know if this
patient has ever had an ulcer. However, the following scenario
could be hypothesized. For 14 years, she either experienced
nonulcer dyspepsia, GERD, and/or PUD. The postprandial
bloating, fullness, and nausea are all consistent with nonulcer
dyspepsia. The reflux and heartburn could be either true
GERD or a variant of nonulcer dyspepsia. In addition, PUD
can also present with these symptoms. Thus, the acute change
of symptoms 4 years ago, with the resolution after a course of
H2-antagonists, is consistent with an acute ulcer followed by
healing. However, her symptoms continued. Six weeks ago, it
appeared as though she once again developed a peptic ulcer.
This is not surprising considering her failure to receive H. pylori eradication treatments. During this second presumed ulcer
episode, her primary care provider decided to try H. pylori
eradication with a combination of a single antibiotic and a PPI.
Once again the acute symptoms resolved. Thus, one might
conclude that this patient does indeed have a history of PUD,
but endoscopy is needed for further diagnosis.
7. Does the presence of a positive H. pylori serology 5 days
ago indicate treatment failure of the antibiotic–PPI regimen?
One should not conclude that the positive H. pylori serology in this patient indicates treatment failure. It should be recalled that H. pylori serology is the simplest and least expensive way to test for H. pylori infection. However, this test is
limited because it only indicates the presence of antibodies to
H. pylori, not the actual organism itself. Thus, it remains positive both in persons with an active infection and in those after successful eradication of the organism. Serology testing is
most useful as a screening tool in an individual who has never
received antibiotics that are active against H. pylori. In that
situation, a positive test presumably is a marker of an active
infection, although false-positive results may still occur. Although some data indicate that antibody titer levels decline after successful eradication, this is a less sensitive measurement
tool than an enzymatic breath test that indirectly indicates the
presence of living organisms, or results from a rapid urease
test of endoscopically derived tissue. Furthermore, none of
the confirmatory test procedures should be done within 4 to 6
weeks of the last dose of a PPI because these drugs suppress
H. pylori growth without actually killing the organisms. In
this patient, we have no prior antibody titers for comparison.
The only conclusion that can be drawn from her positive
serology is that she has been infected with H. pylori at some
time in her life. She may or may not be infected now. If she
had tested negative for H. pylori antibodies, the clinician
would have suspected either a false-negative result from her
recent omeprazole treatment, an ulcer not associated with
H. pylori (which is relatively uncommon), or the absence of
PUD entirely.
8. Because of the lack of specificity of the H. pylori serology
test, a carbon isotope urea breath test is ordered. This test indicates a continued infection. What factors may have contributed
to the lack of eradication of H. pylori in this patient?
UPPER GASTROINTESTINAL DISORDERS
Although the failure of medications to eradicate the H. pylori in this patient can be attributed to several variables, the issue of J.L.’s adherence to her prescribed regimen should be
considered. However, she has stated that she did complete the
regimen despite having missed some doses. One other explanation could perhaps be focused on a poor choice of antibiotic
regimen (i.e., only one antibiotic with a PPI).
•
27-15
doscopy is undertaken and if the endoscopic sample is positive for H. pylori, treatment is indicated because of the association between H. pylori infection and gastric cancer. The
treatment options for GERD are presented in later cases.
Drug-Induced Peptic Ulcer Disease
Etiology and Clinical Presentation
9. Should patient J.L. be re-treated at this time? If so, what
antibiotic regimen would presumably be the most appropriate?
Although J.L. no longer has acute epigastric pain right
now, she is at high risk for a recurrence of peptic ulcers if she
still is infected with H. pylori. The most successful regimens
for eradication of H. pylori contain either a PPI or a bismuthcontaining compound (generally bismuth subsalicylate in the
United States) plus two of the following antibiotics as described above. It is known that this patient had difficulty complying with her previous regimen, which was relatively simple. Thus, she may not do well with the BMT regimen of
bismuth (Pepto-Bismol), metronidazole, and tetracycline,
which requires a total of 16 tablets and capsules four times
daily for 14 days plus an H2-antagonist or PPI for 2 to 4
weeks. In reality, the risk of resistance may be remote because
it has been several years since she took the metronidazole. Using the Helidac kit, in which the medications are supplied in
a carton with 14 daily blister cards and instructions for use,
could enhance compliance. A better regimen might be a PPI
plus amoxicillin (or metronidazole) and clarithromycin for
10–14 days. The shorter course may enhance compliance. The
most important principle is to develop a regimen with a high
likelihood of success. Although cost of the medications is often foremost in the minds of third-party payers, this should
not be a primary consideration because successful treatment
will save much more in future costs than re-treatment, physician’s visits, and hospitalization for complications. The most
expensive regimen is the one that the patient does not take or
that does not work.
10. What is the likelihood that the urea breath test could have
been reported back as a false-negative result? How would a negative test result alter the treatment plan for this patient?
The single antibiotic regimen, which was chosen for this
patient, is not optimal. The combination of A PPI plus amoxicillin will result in bacteriologic cure in 40% to 50% of cases.
If the H. pylori in this patient has been eradicated, no further
antibiotic treatment is necessary. A false-negative urea breath
test is also possible, especially if the patient is tested too soon
after the initial treatment. Nevertheless, further workup (e.g.,
retesting or endoscopy) is not required unless symptoms recur. As many as 40% of patients who have had successful H.
pylori eradication will continue to require acid suppression
medications to control persistent dyspeptic symptoms. Thus,
clinicians should remember that bacteriologic cure might not
provide complete relief of epigastric symptoms because patients also may have concurrent nonulcer dyspepsia or GERD.
In this particular case, it should be recalled that this patient
still has symptoms and that these may be suggestive of nonulcer dyspepsia or GERD. Dietary adjustments, simethicone,
and/or H2-antagonists may or may not help provide symptom
relief for J.L.’s nonulcer dyspepsia. If GERD is suspected, endoscopy may be necessary to rule out esophagitis. If en-
11. A.C., a 65-year-old woman, experienced orthostasis and
diarrhea after attending a lecture. She has been in good health
without any previous complaints. She has not been taking any
medications other than ibuprofen 400 mg Q 4 to 6 hr PRN for
headaches and arthritic knees for the past 4 weeks. Laboratory
tests are unremarkable except for a hemoglobin (Hgb) of 8 g/dL,
a hematocrit (Hct) of 26%, and a guaiac-positive stool. A.C. was
admitted to the hospital for an endoscopy to rule out bleeding
from the GI tract. Endoscopy revealed two antral ulcers (0.2 cm
and 0.4 cm). What is the cause of A.C.’s GI bleeding?
[SI units: Hgb, 4.96 mmol/L; Hct, 0.26]
A.C.’s GI bleeding probably is most likely secondary to
chronic ingestion of ibuprofen, which is an NSAID. The
prevalence of endoscopically confirmed GI ulcers in NSAID
users is 15% to 30%.80 Although most NSAID-induced ulcers
are gastric ulcers (12% to 30%), duodenal ulcers (2% to 19%)
are observed as well.81,82 Some investigators hypothesize that
duodenal ulcers associated with NSAID use may represent an
exacerbation, reactivation, or complication of PUD, because
there is a higher incidence of duodenal ulcers unrelated to
NSAID use.80
12. Why did A.C. not experience epigastric pain symptoms associated with NSAID-induced ulcers?
Symptomatic ulcers (ulcers associated with pain, bleeding,
or perforation) occur in only approximately 1% of patients after 3 to 6 months of NSAID use and in 2% to 4% of patients
after 1 year of therapy.69 NSAID-associated ulcers do not correlate well with pain possibly because the analgesic action of
NSAIDs may mask the ulcer pain.80 As illustrated by A.C., patients often take NSAIDs for chronic pain conditions such as
arthritis; therefore, their perception of pain may be changed
and they may tend to ignore modest epigastric pain. The reason is not clear, but NSAID ulcers in many patients are
asymptomatic. Thus, complications (e.g., GI bleeding, syncope) may develop in the absence of typical symptoms. It is
not unusual to find perforations, bleeding, or gastroduodenal
ulcerations in asymptomatic individuals.69 The orthostasis experienced by A.C. probably is merely reflective of volume loss
secondary to GI bleeding, and epigastric pain simply was not
present or was masked.
Mechanism of Action
13. How do NSAIDs cause ulcers?
The most common site for NSAID-associated ulcers is the
antral portion of the stomach, although some occur in the gastric body and fundus.69 NSAIDs appear to produce gastric
damage by two mechanisms: a direct irritant effect and a systemic effect mediated by cyclo-oxygenase (COX) inhibition
leading to a reduction in prostaglandin synthesis.76,81,82 Therefore, both rectal and IV administration of NSAIDs can cause
27-16
•
GASTROINTESTINAL DISORDERS
GI damage despite the apparent absence of direct mucosal
contact.81 Agents that are more water soluble (e.g., aspirin)
cause more topical injury.82 Aspirin, in a dose-related fashion,
disrupts the gastric mucosal barrier. When the consumption of
aspirin exceeds 22 tablets a week, the occurrence of ulcers
is increased.76 Although enteric-coated tablets are designed
to minimize gastric irritation, the potential for ulceration
still exists but to a lesser degree.80 Inhibition of mucosal
prostaglandin synthesis is thought to be an important factor in
the pathogenesis of aspirin- and NSAID-induced ulcers.80,83
COX-1 is responsible for producing prostaglandins that protect the GI mucosa by maintaining blood flow and stimulating
bicarbonate and mucus production.76 Therefore, low levels of
prostaglandin would be expected to impair the ability of the
gastric mucosa to defend itself against aggressive factors. An
isoform of COX-1, COX-2, is involved in the inflammatory
response. Both isoforms have the same affinity to convert
arachidonic acid to prostaglandin; however, the prostaglandins produced by COX-2 are associated with pain and inflammation. COX-2 inhibition is believed to be responsible
for the anti-inflammatory and analgesic effects of NSAIDs,
whereas inhibition of COX-1 may be associated with NSAID
adverse effects including GI and renal effects.80,83 Therefore,
NSAIDs such as celecoxib (Celebrex), rofecoxib (Vioxx), and
valdecoxib, which have the greatest inhibitory effects on
COX-2 while maintaining minimal or no inhibition on COX1, will have the maximum effect on inflammation and minimal (but not totally eliminated) mucosal-damaging adverse
effects.69
Treatment
14. What therapeutic steps should be taken in the treatment of
A.C.’s gastric ulcer?
When peptic ulcers develop in patients taking NSAIDs, the
preferred approach is to stop the NSAID when possible. Ulcers heal slowly during treatment with H2-antagonists when
NSAIDs are continued and more quickly when they are
stopped.69
Therefore, A.C. should discontinue or decrease the dose of
the ibuprofen and she should be evaluated for H. pylori infection. For mild to moderate pain, acetaminophen or another
analgesic option can be used. If an anti-inflammatory action
is required for her arthritic knee, a COX-2 NSAID can be
used.69
Variables that may influence the healing of NSAIDassociated ulcers include continued NSAID therapy, ulcer
site, ulcer size, history of PUD, and the presence of H. pylori
gastritis.69,84–88 Discontinuation of the NSAID may allow for
mucosal restitution and more rapid ulcer healing. The continued use of NSAIDs does not appear to prevent healing of
small ulcers; however, the healing process may be delayed.
H2-antagonists are generally not effective in preventing or
healing NSAID-associated gastric ulcers when the NSAID is
continued. An exception is famotidine given at a dose of 40
mg twice daily.69,87 Double doses of other H2-antagonists have
not been studied.
Another option is to test for and treat for H. pylori (if positive). If H. pylori testing is negative, a PPI may provide a
more rapid resolution of symptoms and quicker healing of the
ulcer. If the COX-2 is not an effective alternative for A.C. and
if she must continue with her NSAID for management of her
arthritis, a PPI would be preferred over an H2-antagonist. The
H2-antagonists are not very effective for healing or preventing
NSAID-associated gastric ulcers during continued therapy
with NSAIDs.69
15. A.C.’s ulcer has healed after 8 weeks of omeprazole 20
mg/day and the discontinuation of her NSAID. However, her
arthritic knees continue to be a problem, and NSAID therapy
needs to be reinstated. What concurrent medications should A.C.
receive to minimize future ulcer formation?
Prophylactic therapy or a COX-2 NSAID should be considered for patients who are unable to discontinue NSAID
therapy and who have risk factors for NSAID-associated ulcers. Patients particularly at risk include those who are taking
concurrent anticoagulants or corticosteroids; those with a history of ulcer complications or ulcer disease; those who are elderly; and high-surgical risk, debilitated patients who cannot
tolerate complications.69 If a COX-2 NSAID is chosen, the
clinician must remember that these agents do not provide
complete freedom from ulceration and other GI-associated
complications of NSAIDs.
H2-RECEPTOR ANTAGONISTS
A few studies have examined prophylactic regimens for
NSAID-associated ulcers. The H2-receptor antagonist, ranitidine, has been associated with a decrease in the incidence of
NSAID/aspirin-associated duodenal ulceration, but this association was not apparent in patients with gastric ulcers.69,81,86
Double dose famotidine (40 mg twice daily) in another study
was noted to have reduced the incidence of both gastric and
duodenal ulcers compared with placebo in patients receiving
long-term NSAID therapy.87 In this study, famotidine at either
20 mg or 40 mg twice a day was more effective in preventing
duodenal than gastric ulcers. Some investigators postulate
that NSAID-associated duodenal ulcers represent an exacerbation of pre-existing duodenal ulcer disease.69,87 The H2antagonists seem to be more effective in the prevention of
NSAID-induced duodenal ulcer disease than in the prevention
of NSAID-induced gastric ulcers.
Misoprostol (Cytotec), a synthetic prostaglandin E1 analog,
has both antisecretory and cytoprotective properties and can
prevent both duodenal and gastric ulcers in the NSAID/
aspirin user.88–90 Despite the effectiveness of misoprostol in
the prevention of duodenal and gastric NSAID-associated ulcers, it paradoxically causes GI symptoms such as diarrhea
and abdominal pain.69 Diarrhea is dose dependent and is due
to stimulation of intestinal smooth muscle and fluid and electrolyte secretion. Lowering the dose to 100 g four times a
day or giving the dose less frequently (i.e., 200 g twice
daily) decreases the incidence of diarrhea, but this dose also
is less effective in preventing ulcers.69,89 Misoprostol is contraindicated in women of child-bearing age unless adequate
contraceptive measures are taken, because prostaglandins are
uterotonic and capable of increasing the frequency of uterine
contractions, bleeding, and abortions.90
PROTON PUMP INHIBITORS
In one study, the efficacy of omeprazole was compared
with misoprostol in 935 patients who required continuous
NSAID therapy and who had gastric and/or duodenal ulcers.
UPPER GASTROINTESTINAL DISORDERS
At 8 weeks, treatment was successful in 76% of the patients
given omeprazole 20 mg daily, in 75% of those given omeprazole 40 mg daily, and in 71% of those given misoprostol 200
g four times a day.91 The rates of gastric ulcer healing were
significantly higher with omeprazole 20 mg daily (87%) than
with misoprostol (73%). Healing rates among patients with
duodenal ulcers were higher (85%) with omeprazole 20 mg
daily than with misoprostol (74%), whereas healing rates
among patients with erosions alone were higher with misoprostol (84% versus 77%). More patients remained in remission during maintenance treatment with omeprazole (61%)
than with misoprostol (48%) and with either drug than with
placebo. More adverse events were noted during the healing
phase in the misoprostol group than in the groups given
omeprazole.91 The success of ranitidine, misoprostol, and
omeprazole in preventing NSAID-associated duodenal ulcers
suggests that acid suppression is important in the prevention
of duodenal ulcers. A.C. is a candidate for prophylactic therapy because she is elderly, requires continued NSAID therapy,
and has an ulcer history. The PPIs appear to be more effective
in the healing of gastric ulcers than misoprostol and more effective than the H2-antagonists in healing and preventing ulcers.69 Therefore, it would be reasonable for A.C. to receive
omeprazole 20 mg daily to minimize the risk of ulcer recurrence that is associated with NSAIDs. A COX-2 NSAID may
also be an option.
ZOLLINGER-ELLISON SYNDROME
Pathogenesis
ZE syndrome is a rare (occurring in fewer than 1 in 10,000 patients with DU) condition characterized by a triad of clinical
findings, which include severe recurrent PUD, significant hypersecretion of gastric acid, and non–-islet tumors (gastrinomas) of the pancreas.92 Normally, G-cells in the antral mucosa
secrete gastrin, which stimulates the parietal cells to secrete
gastric acid. In ZE syndrome, an ectopic source (gastrinoma)
also secretes gastrin with a subsequent hyperstimulation of
gastric acid secretion.92 Although gastrinomas are located primarily in the pancreas, they also have been found in other regions, particularly the duodenum.
Clinical Presentation
16. M.J., a 62-year-old man, was referred from his private
physician for evaluation of his continuing ulcers. He has been
treated for 2 to 3 years for PUD and has not experienced relief despite H. pylori suppression and escalating doses of various H2receptor antagonists. M.J. was evaluated twice to rule out a possible myocardial infarction because of severe chest pain. He also
complains of frequent diarrhea and abdominal pain. All routine
laboratory tests were found to be within normal limits except a
serum gastrin level, which was 5,243 pg/mL (normal, 0 to 100
pg/mL). Radiographic and endoscopic studies demonstrate a distal esophageal ulceration, dilation of the duodenum and jejunum
with thickened folds, and a 0.1-cm ulceration in the distal duodenum. After a secretin test, his serum gastrin level was 400 pg/mL
greater than the basal level. M.J. was diagnosed with ZE syndrome. Why is M.J.’s presentation consistent with ZE syndrome?
[SI unit: gastrin, 5,243 ng/L]
•
27-17
Diagnosis
The diagnosis of ZE syndrome is based on gastric acid hypersecretion (basal acid output 15 mmol/hr in a patient without
prior gastric surgery or 5 mmol/hr in a patient with prior
acid-reducing surgery) in conjunction with a fasting serum
gastrin level 1,000 pg/mL.93,94 Some healthy individuals and
patients with duodenal ulcers may have marginally increased
serum concentrations of gastrin.93 Therefore, a provocative
test is often used to identify patients with ZE syndrome. The
secretin provocative test is the most sensitive, reliable, and
simplest test for diagnosing and predicting the probability of
a patient to remain disease free.93 If a patient has ZE syndrome, IV secretin will cause a significant increase in serum
gastrin.93 A positive test, consistent with the diagnosis of gastrinoma, is defined as an absolute increase in serum gastrin of
200 pg/mL from the basal concentration.94 M.J.’s baseline
and stimulated serum gastric levels are well above normal.
Symptoms of ZE syndrome are similar to severe PUD but
may be more persistent and less responsive to standard antiulcer therapy.93–95 This is consistent with M.J.’s 2- to 3-year
history of unrelenting pain despite H. pylori eradication and
high doses of H2-receptor antagonists. Many patients have no
endoscopically or radiographically detectable GI ulcers at the
time of diagnosis (18% to 25%), whereas others present with
solitary or multiple ulcers (as in M.J.’s case).95 Most patients
with ZE syndrome have an ulcer, usually in the duodenum or
jejunum. Because the disease often presents as a routine peptic ulcer, the diagnosis of ZE syndrome may be delayed for a
prolonged time.95 M.J.’s history is consistent with this description because he was evaluated in the past for complaints
resembling a severe peptic ulcer, but ZE syndrome was not
considered until radiographic evidence was present.
Abdominal pain and diarrhea (both present in M.J.) are the
most common symptoms at presentation and may occur in the
absence of a mucosal ulcer.95 Diarrhea occurs in approximately 30% to 50% of patients and is caused by increased
amounts of gastric acid. High gastric acid levels inhibit
sodium and water absorption in the jejunum and damage the
GI mucosa. Abdominal pain remains the most common symptom of ZE syndrome and is localized or diffuse in nature. The
pain is similar to that found in a duodenal ulcer in that food
and antacids often relieve it.
Treatment
17. A PPI has been prescribed for M.J. Why would PPIs be
more likely to be successful in the management of ZE compared
with H2-antagonists?
Because of the excessive amounts of gastric acid produced
by patients with ZE syndrome, patients have an increased
chance of severe GI discomfort, bleeding, and gastroduodenal
perforation. Before the routine use of acid secretory suppressant medications (H2RAs and PPIs), total gastrectomy was the
treatment of choice. Now, most patients can be effectively
treated using PPIs. Despite this, some patients will require a
surgical excision of the gastrinoma to control symptoms associated with excessive gastric acid production that persist despite large doses of PPIs.95 Most patients will be adequately
managed with medical treatment which usually provides
symptomatic pain relief and control of gastric acid secretion.
27-18
•
GASTROINTESTINAL DISORDERS
An acceptable criterion for long-term control of gastric secretion is a postdrug gastric acid secretion of 10 mEq/hr for the
last hour before the next dose of medication.95 Successful
medical management requires individualized titration of the
drug dose with periodic reassessment.
Histamine2-antagonists were the first drugs successfully
used to control gastric hypersecretion, but they are not totally
effective in the medical management of ZE syndrome. Large
doses and more frequent dosing than typically used to treat
PUD are generally required (see Table 27-2).95 This is due to
the very high doses needed are usually inadequate to control
the high gastric acid secretion.79 It is likely that total acid suppression can never be achieved by H2-antagonists alone because these drugs do not directly suppress either gastrin or
acetylcholine. As a result, PPIs have become the treatment of
choice for ZE.
PPIs have an advantage over H2-antagonists because by selectively and irreversibly binding to H-K-ATPase, they can
inhibit nearly all gastric acid production irrespective of the
cause. In addition, PPIs have a long duration of action and
thus require less frequent dosing than the H2-antagonists. All
PPIs are effective for ZE syndrome, large doses generally are
necessary, and doses should be adjusted as needed.77
Although surgical correction of the gastrinoma is likely,
M.J. should begin at least 60 mg/day of omeprazole and
titrated to response. Patients frequently are seriously ill when
the initial diagnosis of ZE syndrome is confirmed, and it is
important that the high gastric acid secretion be controlled.95
The total daily dose should be given in two to three divided
doses initially.78,95 Octreotide, is a potent inhibitor of gastrin
and an option in the management of ZE; however, because it
is only available as a parenteral product, its use is limited.78
Proton Pump Inhibitor Administration
18. M.J. is scheduled for surgery, and omeprazole is to be administered through an nasogastric (NG) tube. What difficulties
are likely to be encountered by this order, and what are reasonable solutions?
In patients with NG tubes who are unable to take medications by mouth, drugs are often placed either directly into the
NG tube or crushed and mixed with water to make a slurry/
suspension. Omeprazole, lansoprazole, and esomeprazole are
formulated as enteric-coated granules within gelatin capsules
because they are unstable in acid media and must be absorbed
to become converted to their active metabolites. Analogous to
sustained-release products, the enteric-coated beads should
not be chewed or crushed because they are designed to dissolve in the GI tract when the pH of the medium is 6.95
However, when the capsules are opened, added to a bicarbonate solution, and the enteric-coated beads are not crushed, the
AUC and the effectiveness of gastric acid suppression of enteric-coated omeprazole granules delivered via an NG tube
can be comparable to that of encapsulated enteric-coated
granules taken orally.98 Esomeprazole has been studied by
opening the capsule and suspending in water.99 Suspensions
of omeprazole and lansoprazole compounded from capsules
and sodium bicarbonate solution are stable for up to 14 days
at 24°C.100,101
When the lansoprazole gelatin capsule is opened, the intact
granules can be mixed in 40 mL of apple juice and adminis-
tered in a suspension of granules via the NG tube according
to the manufacturer’s instructions. While FDA approved, this
method is difficult to administer properly, as the granules sink
to the bottom of the syringe used to inject into the NG tube.
This apple juice and lansoprazole granule suspension must be
agitated in the syringe as it is injected into the NG tube. Failure to do this, will administer a “bolus” of granules into the
NG tube and will likely clog the tube. Crushing pantoprazole
tablets and preparing a suspension in sodium bicarbonate has
also been studied and found to produce blood levels similar to
intact tablet administration.102
Continuous IV H2-receptor antagonists can be used to control gastric acid hypersecretion adequately in patients with ZE
syndrome during surgery.103 Frequent dosage adjustments are
required may be required in the perioperative period to control gastric acid output. IV omeprazole has been available in
Europe for many years. As PPIs also are more effective in
controlling gastric hypersecretion, IV pantoprazole may be
the most effective option for M.J. Other IV formulations of
PPIs are being developed
GASTROESOPHAGEAL REFLUX DISEASE
Gastroesophageal reflux is a disorder in which reflux of gastric or intestinal contents occurs into the esophagus and results in patient complaints of heartburn and/or other symptoms (e.g., as a sensation of “burping up” stomach contents or
as the taste of bitter contents in the mouth). The classic symptom of reflux is “heartburn,” which commonly is described as
a pain in the center of the chest that, at times, might mimic
cardiac angina. An estimated 44% of adults in the United
States experience heartburn at least once per month and 7%
of people have daily GERD symptoms. Acid reflux is also associated with asthma and when this occurs, is called “atypical
GERD.” These symptoms, when accompanied by dysphagia
(swallowing difficulty or a sensation of food sticking in the
throat), odynophagia (severe pain on swallowing), or persistent nocturnal symptoms, usually are sufficient to make the
patient aware of the need for medical attention. GERD symptoms are not necessarily associated with inflammation and tissue damage to the esophagus (esophagitis). An endoscopic
examination is necessary to diagnose esophagitis. Esophagitis
commonly is graded using the Savary-Miller system. This
system grades esophagitis from grade 1 (mild) to grade 4 (severe, erosive changes). Although it is possible for esophagitis
to be present in the absence of symptoms (and vice versa), it
is important to understand that symptoms are poorly correlated with the grade of esophagitis.104–107 Complications associated with the reflux of gastric material into the esophagus
include strictures, hemorrhage, perforation, aspiration, and
the development of Barrett’s esophagus (see following discussion).
Infants (up to 18 months of age) can experience a form of
GERD that is characterized by postmeal regurgitation or small
volume vomiting, which can occur several times per day due
to a poorly functioning sphincter. Esophagitis is usually absent
in these children, but a small percentage may develop chronic
GERD. This form of GERD may respond very well to liquid
formulations of gastric motility–stimulating agents. True
motility dysfunction resulting in slowed or absent esophageal
food transit times are uncommon in adults with GERD.
UPPER GASTROINTESTINAL DISORDERS
Pathogenesis
The esophagus functions to transport food from the mouth to
the stomach and to prevent the retrograde flow (i.e., “backflow”) of GI contents. As food enters the esophagus, the LES
opens and remains open until the peristaltic contractions of
esophageal muscles have swept the food into the stomach.
Contraction of the lower esophageal sphincter after the passage of food into the stomach serves to prevent the reflux of
gastric contents back into the esophagus.
The development of GERD is associated with a disruption
of the balance between defensive mechanisms (e.g., LES closure, esophageal peristalsis) and aggressive factors (e.g., acid,
pepsin, bile salts).108 Three pathophysiologic mechanisms predispose a patient to reflux: (1) a spontaneous transient or sustained relaxation of the lower esophageal sphincter, (2) a low
resting LES pressure, and (3) increased gastric pressure (e.g.,
bending over, pregnancy, obesity).109 All these pathophysiologic mechanisms can occur in normal healthy individuals,
but additional variables may contribute to the development of
esophageal damage. For example, the amount of acid and
pepsin that refluxes within a 24-hour period, the length of
time that acid and pepsin remain in the esophagus, and the
natural sensitivity of the esophageal mucosa to damage by aggressive forces all determine the susceptibility of an individual to GERD.104
Clinical Presentation
19. R.L., a 37-year-old, 100-kg, 68-inch tall man, has been experiencing heartburn for approximately 4 to 6 weeks. The pain
usually occurs after dinner while he is lying on the couch watching television and often is accompanied by regurgitation of a
warm, foul-tasting fluid into his mouth. He also has experienced
these symptoms, after his night-time snack of chocolate ice
cream, soon after he goes to bed. He smokes 1 to 2 packs/day of
cigarettes and drinks 2 beers every evening while watching television. His symptoms are relieved by Mylanta, which he drinks
directly from the bottle. What symptoms does R.L. have that are
consistent with GERD?
Retrosternal burning, commonly referred to as heartburn,
is the characteristic symptom of GERD and is caused by the
contact of refluxed GI material with an inflamed esophageal
mucosa.104 The epigastric pain can be angina-like and is described as a burning, substernal pain that travels up the esophagus toward the throat.104 In some patients, especially the elderly, no heartburn or chest pain is experienced and coughing
or wheezing may be the only symptoms noted. However, the
absence of symptoms does not necessarily imply the absence
of esophageal damage. Symptoms of GERD often are
episodic because GI contents are not refluxed continuously.104
The frequency of heartburn symptoms and the presence of
esophagitis are correlated with the duration and intensity of
acid exposure (often defined in terms of percentage of time
per 24 hours that the pH is 4.0).
Symptoms of GERD may be aggravated by certain foods,
specific body positioning, or drugs. Foods with high-fat content (e.g., ice cream) can lead to GERD symptoms because
these foods decrease the LES pressure. Other food products
such as spices, onions, citric juices, and coffee can contribute
to the development of GERD by direct mucosal irritation.109
•
27-19
Although symptoms of esophageal reflux can occur in any
body position at any time, many patients experience symptoms primarily when they are supine or when bending over.
The swallowing of saliva, water, or antacids (e.g., the Mylanta
ingested by R.L.) frequently relieves the pain. R.L.’s symptoms of heartburn, the regurgitation of gastric contents soon
after eating, and the association of these symptoms when he
lies on the couch after dinner and when he goes to bed at night
are all consistent with GERD. R.L.’s ingestion of two beers after dinner and of chocolate ice cream before bedtime and the
apparent temporal relationship of these activities to the appearance of epigastric pain also are consistent with GERD.
Concurrent drug therapy (e.g., alcohol, -adrenergic agonists,
-adrenergic agonists, verapamil, diazepam, dopamine,
meperidine, progesterone, prostaglandins, theophylline) also
can exacerbate GERD.110
Treatment
Goals
20. What are the therapeutic goals for the treatment of R.L.’s
GERD?
The therapeutic goals for GERD are: alleviate pain and
symptoms, diminish the frequency and duration of esophageal reflux, promote healing of esophagitis (if present), avoid
complications, prevent recurrence, and provide cost-effective
therapy.110,111 One concern of uninvestigated GERD is Barrett’s esophagus (histologic change whereby the lower
esophageal tissue begins to resemble the columnar epithelium
similar to the lining of the stomach). Barrett’s esophagus predisposes the patient to the development of esophageal cancer:
the more frequent, more severe, and longer-lasting the
symptoms of reflux, the greater the risk. Persons with longstanding (>20 years’ duration) and severe symptoms of reflux
(reflux-symptom score of 4.5) were 43.5 times more likely
(95% confidence interval) for development of esophageal
adenocarcinoma.110
Lifestyle Changes
21. What nondrug measures can improve R.L.’s symptoms?
Initially, all patients should change their lifestyle to eliminate factors that can exacerbate reflux.110,112 Weight loss and
loose-fitting clothes are recommended because obesity and
tight clothes may exacerbate reflux by continuously increasing the gastroesophageal pressure gradient.112 Cigarette smoking directly provokes acid reflux and decreases lower
esophageal sphincter pressure; efforts should be initiated to
discontinue cigarette smoking.113 Foods that lower esophageal
sphincter pressure (e.g., chocolate, alcohol, peppermint, fatty
meals), irritate the gastric mucosa (e.g., spicy food, citric
juices), or stimulate acid secretion (e.g., cola, beer) should be
avoided. Most experts believe lifestyle modifications provide
improved symptoms control in only approximately 20% of
patients.104,110 These measures are widely promoted in the lay
press and on web sites that discuss GERD. It is likely that
many patients have already tried lifestyle modification before
seeking medical help, thus many clinicians fail to find significant improvements in symptoms when they ask patients to
use these measures. Despite these doubts about effectiveness,
27-20
•
GASTROINTESTINAL DISORDERS
all recommended lifestyle measures should be used by patients with GERD. Lifestyle modification as a sole treatment
has never been demonstrated to heal esophagitis and should
not be used as the sole treatment in these patients.104
R.L. should be instructed to lose weight, cease smoking,
avoid lying on the couch in a position that increases gastric
pressure, and avoid foods (chocolate ice cream, beer) that precipitate symptoms or decrease the LES pressure. He also
should avoid meals 2 hours before lying down. R.L.’s symptoms appear to be the most troublesome while lying on the
couch when he is watching television and at night. For patients like R.L., elevating the head of the bed with 6- to 8-inch
blocks or sitting in an upright position might be helpful in enhancing the gravitational flow of gastric contents away from
the esophagus.112,113
Drug Therapy
Because patients with GERD have frequent reflux episodes of
acid, effective inhibition of gastric acid secretion is necessary
to facilitate healing and relieve symptoms.102,110,116 Antisecretory drugs, such as H2-receptor antagonists and PPIs, are generally used and the choice of drug is based on the severity of
the disease.104,110
ANTACIDS
Antacids can provide relief of mild symptoms associated
with GERD. Antacids have short durations of action and do
not promote healing of esophagitis.104,110 Consequently,
antacids are used primarily as adjunctive agents to provide
daytime symptomatic relief of GERD.
H2-ANTAGONISTS
H2-antagonists can be effective for management of mild
GERD when used in full-sized doses. Healing rates with H2antagonists for patients with mild esophagitis are significantly
better than placebo.111,117 The severity of the disease, the dose
of the drug, and the duration of therapy affect the response to
H2-antagonists. For example, endoscopic healing was observed in 65% of patients with moderate esophagitis (grade
II), in contrast to only 15% of patients with severe esophagitis (grade III) after 8 weeks of ranitidine therapy.96,110
Gastric acid suppression throughout the day is important in
the treatment of reflux disease. As a result, H2-antagonists administered in daily divided doses provide superior symptom
relief and healing than does once-daily dosing.110 Duration of
H2-antagonist treatment is another major determinant of
esophagitis healing rates.116 In one multicenter trial, 57% of
patients with esophagitis were healed after 6 weeks of therapy,
and 70% healed after 12 weeks of therapy. In another study,
45% of patients taking nizatidine experienced esophagitis
healing after 6 weeks of therapy and 80% were healed after 12
weeks.118 In both studies, symptom relief occurred earlier than
esophagitis healing, confirming the poor correlation between
symptom relief and presence of esophagitis. In addition, it is
clear that esophagitis in some patients does not heal in response to H2-antagonists. Some investigators attribute this
lack of response to H2-antagonist drug tolerance.110
PROTON PUMP INHIBITORS
PPIs such as omeprazole (Prilosec), lansoprazole (Prevacid), rabeprazole (Aciphex), pantoprazole (Protonix), or es-
omeprazole (Nexium), which can inhibit gastric acid secretion for a sustained period, are highly effective in the treatment of GERD. Normal, once-daily doses of PPIs for 4 weeks
will heal approximately 85% to 90% of patients with the mild
esophagitis and approximately 60% to 80% of patients with
severe esophagitis (grade IV).104,110,111 Higher doses (usually
twice the “normal” dose sometimes given in divided doses
twice daily) are sometimes required to heal esophagitis in patients with more severe erosive disease.
In clinical trials, PPIs heal esophagitis quicker and more
effectively than H2-antagonists. In one randomized, blinded,
controlled study, healing occurred in 67% of patients after
4 weeks of omeprazole (20 mg daily) compared with 31%
of patients with ranitidine (150 mg twice a day).119 After
8 weeks, the healing rates increased further to 85% and 50%
with omeprazole and ranitidine therapy, respectively. The
higher healing rate for omeprazole also was accompanied by
a more rapid improvement of symptoms. Omeprazole was notably more effective than ranitidine in patients with severe
esophagitis.119
PPIs are also effective in healing esophagitis refractory to
H2-antagonists. After 12 weeks of therapy, 80% of patients
with severe esophagitis experienced healing with 20 to 40
mg/day of omeprazole despite previous failures to prolonged
therapy with H2-receptor antagonists.119,120 In another multicenter, randomized, blinded study, lansoprazole (30 mg/day)
was more effective in healing erosive esophagitis in patients
who were resistant to standard doses of H2-receptor antagonists than continuation of ranitidine (150 mg twice a day).121
The healing rate for lansoprazole was 89% at 8 weeks compared with 38% for ranitidine (P 0.001). In comparative trials, PPIs have been shown to heal all grades of esophagitis in
at least 65% to 90% of patients in 4 to 8 weeks.
When one compares esophagitis healing, PPIs are generally equally effective in healing mild to moderate reflux
esophagitis. In one multicenter trial that evaluated healing of
erosive esophagitis, lansoprazole 30mg daily and omeprazole
20 mg had similar healing rates at 8 weeks. Patients taking
lansoprazole (30 mg/day) had significantly better pain relief
(by 11%) than the omeprazole group in the first week.122 Similar results have been seen with rabeprazole and esomeprazole
(40mg/day) when compared with omeprazole (20 mg/day).
SUCRALFATE
Sucralfate (Carafate) appears to be effective in resolving
mild cases of esophagitis but is less effective in management
of severe disease.117,123 As a result, sucralfate is not as widely
used as the acid suppressants to manage GERD.
METOCLOPRAMIDE
Metoclopramide (Reglan) stimulates the motility of the
upper GI tract without affecting gastric acid secretion. When
administered as 10 mg, four times a day, 30 to 60 minutes before meals and at bedtime, it increases gastric peristalsis,
which leads to accelerated gastric emptying.5 Duodenal peristalsis is increased and intestinal transit time is decreased in
patients with GERD.124 Metoclopramide also increases the
LES resting tone within 1 to 3 minutes following IV administration and in 30 to 60 minutes after oral administration.116
Metoclopramide’s adverse effect profile (e.g., drowsiness, diarrhea, abdominal cramps, extrapyramidal reactions) and the
UPPER GASTROINTESTINAL DISORDERS
general lack of GI motility dysfunction in adult patients with
GERD significantly limit the usefulness of this medication for
the treatment of GERD. Cisapride (Propulsid) is no longer
commercially available. The manufacturer (Janssen) has a
special investigational limited access program for cisapride
distribution which is primarily intended for patients with diabetic gastroparesis. Tegaserod, a 5-HT4 receptor agonist, improves LES tone and will reduce the esophageal exposure to
gastric acid when compared to placebo, but its effective use in
GERD has not yet been demonstrated.125
22. R.L. has lost approximately 5 kg of body weight over the
past 6 weeks and has discontinued drinking two beers each night
and eating all spicy foods. However, he continues to smoke cigarettes despite efforts at cessation. His symptoms of reflux have
continued despite his regular use of nonprescription cimetidine
tablets, which were purchased at his local pharmacy. What drug
therapy is appropriate for the treatment of his GERD at this time?
The traditional treatment of GERD has been based on the
premise of incremental increases in the intensity of treatment
options (i.e., begin first with lifestyle management and nonprescription doses of an H2-antagonist, which can be replaced,
if needed, by nonprescription omeprazole or prescription
strength H2-antagonists, and ultimately by increasing doses of
a PPI in lieu of the H2-antagonist). Even though R.L. has
modified his lifestyle, with the exception of cigarette cessation, his condition has not responded to nonprescription cimetidine. In addition he lost weight. He should be referred for
endoscopy to determine if he has an esophageal stricture or
esophageal adenocarcinoma which can obstruct his esophagus resulting in dysphagia and weight loss.
If esophagitis is seen on endoscopy, he will likely be
placed on a PPI. This is because PPIs are more effective than
standard and high (double)-dose H2-antagonists in symptom
relief, healing, and maintenance of remission of esophagitis.
The superiority of PPIs presumably are related to the inability
of even high-dose H2-antagonists to control acid secretion and
possibly also due to the development of tolerance to H2antagonists.The PPIs provide quicker relief of symptoms than
H2-antagonists and, as a result, are possibly more of an incentive for patients to adhere to therapy.126
Maintenance Therapy
23. Esophagitis was noted in R.L.’s endoscopy, and he was
prescribed omeprazole 20 mg twice daily. Eight weeks later, a repeat endoscopy revealed the esophagitis had healed, and the
omeprazole was stopped. Since that time, he has begun to reexperience some mild symptoms occasionally. Is maintenance
therapy recommended for R.L.’s occasional symptoms?
Unfortunately, even after complete healing, a large percentage of patients experience a recurrence of symptoms within 6
to 12 months after therapy is discontinued.5,110,116,122,123,127
Therefore, maintenance therapy is often required. One recent
study demonstrated that continuous maintenance treatment
with a daily PPI is the most effective treatment strategy. This
study compared the recurrence rates of reflux esophagitis over
a 12-month period with either omeprazole 20 mg/day,
omeprazole 20 mg three times a week, or ranitidine 150 mg
twice daily. At 12 months, endoscopy showed sustained remission of disease in 89% of patients receiving omeprazole
•
27-21
daily, in 32% receiving omeprazole three times a week, and in
25% receiving ranitidine.128 Trials using other PPIs have
found similar results. Maintenance therapy with a PPI should
be initiated in R.L. after further medical workup because the
risk of morbidity can be high and GERD often is a chronic
condition.126
STRESS-RELATED MUCOSAL BLEEDING
Acute stress-related mucosal lesions (SRML) are distinctly different from chronic PUD.129 They occur in critically ill patients,
are usually unrelated to a previous history of ulcer disease, and
are seen within 24 to 48 hours of admission to hospital.130 Multiple superficial ulcerative lesions can develop in the proximal
stomach along the boundaries of the acid-secreting mucosa and
the duodenum.129,130 Approximately 50% of these lesions bleed,
but because they are superficial, significant bleeding will occur
in only 5% to 20% of untreated patients in intensive care
units.114 Patients in whom GI bleeding develops have a higher
mortality rate than those critically ill patients who do not have
GI bleeding.130 During the early 1970s, stress ulcers and their
complications had reached near epidemic proportions.114 However, the occurrence of stress ulcer bleeding has decreased to
2% of the intensive care patient population due to widespread
use of agents that prophylactically neutralize gastric acids and
advanced medical care.131
Pathogenesis
Stress ulcers primarily occur because impaired protective
mechanisms cause an imbalance between aggressive and defensive forces resulting in mucosal damage. Although hydrogen ions are necessary for the development of stress ulcers,
large quantities of acid secretion are not necessary.114 In fact,
critically ill patients usually secrete normal amounts of gastric
acid.130 For example, trauma patients secrete normal or decreased amounts, whereas hypersecretion is found in patients
with sepsis, CNS injuries, or small bowel resections.131,132 Despite the critical role of gastric acid and other aggressive factors in the pathogenesis of stress ulceration, mucosal defenses
also are important and these are often compromised in the
critically ill patient. Gastric mucosal blood flow is diminished
in patients with hemorrhagic, cardiogenic, and septic
shock,114 resulting in a number of unfavorable events: (1) decreased nutrient and oxygen delivery, (2) inability of the mucosa to remove or neutralize gastric acids, and (3) a decrease
in bicarbonate efflux into the gastric epithelium.130 During
stressful situations, there also is a decreased rate of proliferation and cellular turnover of the gastric mucosa.114 Furthermore, in many critically ill patients, diffusion of bile salts
backward from the duodenum into the stomach and high concentrations of urea in the blood (e.g., renal failure) can disrupt
the gastric barrier and contribute to stress injury. The lack of
prostaglandin and mucous formation in the critically ill also
may contribute to the development of stress-related damage.
Risk Factors
24. M.L., a 64-year-old woman who was admitted with diverticular disease, is transferred to the intensive care unit (ICU) because of her deteriorating respiratory condition and septic
27-22
•
GASTROINTESTINAL DISORDERS
shock. She has no significant past medical history and was a
healthy individual. She is in respiratory distress with a respiratory rate of 36 breaths/min, temperature of 104°F, heart rate of
120 beats/min, and a blood pressure (BP) of 60/40 mm Hg. Relevant laboratory tests include the following: sodium (Na), 147
mEq/L; potassium (K), 5.6 mEq/L; chloride (Cl), 119 mEq/L; bicarbonate, 12 mEq/L; blood urea nitrogen (BUN), 57 mg/dL;
serum creatinine (SrCr), 2.7 mg/dL; and white blood cell (WBC)
count, 36,000 cells/mm3. Her respiratory status deteriorates to a
point that endotracheal intubation is necessary. In addition to
empiric antibiotics and fluids, treatment for stress ulcers is being
contemplated. M.L has no history of PUD. What are the risk factors for stress ulcers that are present in M.L?
[SI units: Na, 147 mmol/L; K, 5.6 mmol/L; Cl, 119 mmol/L; bicarbonate, 12
mmol/L; BUN, 20.3 mmol/L; WBC count, 36,000 106 cells/L]
Numerous risk factors have been identified for stress ulcers
and these include shock, burns (>30% of the body), multiple
organ failure, trauma (intra-abdominal or thoracoabdominal
injuries), sepsis (intraperitoneal or pulmonary infections), coagulopathy, and CNS injury. However, in a prospective multicenter study that evaluated potential risk factors for stress ulceration in 2,252 critically ill medical ICU patients, the only
independent risk factors for GI bleeding were respiratory failure and coagulopathy. They concluded that prophylaxis against
stress ulcers may be required only in critically ill patients who
have a coagulopathy or require mechanical ventilation for 48
hours.114 In another study, respiratory failure (mechanical ventilatory support 24 hours) and high-dose corticosteroid administration (250 mg/day of hydrocortisone) was associated
with an increased risk of stress ulcer bleeding.131
M.L. currently is in septic shock and will require mechanical ventilation; therefore, she should receive stress ulcer prophylaxis.
Treatment
25. What can be done to prevent the complications associated
with SRML in patients like M.L.?
Despite the low occurrence of serious bleeding in critically
ill patients, when it occurs, the accompanying mortality is
very high. Aggressive prophylactic therapy may prevent significant complications and reduce both morbidity and mortality rates. Because alteration in defense mechanisms predisposes a patient to stress ulceration and bleeding, the most
important approach is to treat the underlying disease state and
physiologic conditions. The keystones are early fluid resuscitation, immediate oxygenation, early hemodynamic stabilization, prevention of infections, and effective analgesia and sedation.114 For example, improving blood flow by correcting
shock should be a priority in the management of M.L.114,131
Other important measures are maintaining adequate nutrition
and respiratory support. Some studies suggest that enteral nutrition may aid in the prevention of GI bleeding.132 Acid-base
imbalances and uremia should be corrected because of their
propensity for injury to the gastric mucosa. M.L. has evidence
of both a metabolic acidosis (HCO3, 12 mEq/L) and renal insufficiency (SrCr, 2.7 mg/dL).
Adequate neutralization of gastric acid is of paramount importance because stress-associated ulceration does not occur
in the absence of acid, and if the intragastric pH is maintained
between 3.5 and 4, the frequency of bleeding is lowered in
stressed patients. At a pH of 4.5, pepsin is inactivated,
whereas 99.9% of acid is neutralized at a pH of 5. In vitro observations demonstrate that when the gastric pH is 5 to 7,
coagulation function and platelet aggregation are impaired.130
Therefore, therapy should be directed at maintaining the gastric pH between 3.5 and 4 to prevent SRML.
26. What pharmacologic therapy can be used to prevent
SRML in M.L.?
Aggressive antacid therapy (e.g., Mylanta 30 to 60 mL
every hour) very effectively maintains the gastric pH above
3.5.131 Numerous studies have compared H2-antagonists with
antacids for prevention of stress-related bleeding. Most have
found pH control to be superior with antacids (when antacids
are given hourly), but the rate of significant bleeding was not
found to be different between these two treatment regimens.133
Although antacids are effective in preventing stress ulcers,
they are inconvenient to administer and are associated with
accumulation of magnesium, aluminum, or calcium. Diarrhea
can also occur.
H2-Antagonists
H2-antagonists effectively prevent stress ulcers. In an analysis
of data from 16 prospective, randomized trials, cimetidine
was as effective as antacids in preventing significant stress
ulcer bleeding.133 Another prospective, randomized trial compared the efficacy of several H2-receptor antagonists (cimetidine, famotidine, and ranitidine) and antacids in the prevention of stress ulceration.133 In a double blinded trial comparing
cimetidine constant infusion (50 to 100 mg/hr) with placebo
designed to prevent GI bleeding from SRML in critically ill
patients, the cimetidine group had significantly fewer bleeding episodes.134
Proton Pump Inhibitors (PPIs)
PPIs are potent acid suppressant drugs, and in contrast to H2receptor antagonists, PPIs inhibit both histamine and vagally
induced gastric acid secretion. Because of this, these agents
should be expected to be useful in the management of stress
ulcer patients. Data regarding use of PPIs to prevent bleeding
associated with SRML is summarized below.
27. M.L. is to be started on ranitidine. How should it be administered?
Because the goal is to maintain the gastric pH 4.0 for the
prevention of SRML and 7.0 for the treatment of bleeding
ulcers, the proper administration of these agents is critical
(see Table 27-6 for recommended dosing). Intermittent bolus
injection has been used; however, this method of administration is labor intensive, and a continuous IV infusion of the H2receptor antagonists is more effective in maintaining the gastric pH above 4.135–137 Dosages should be adjusted according
to the severity of the patient’s illness, renal function, and the
intragastric pH. The intragastric pH can be determined with
an indwelling probe or by measuring the pH of an NG aspirate. Signs of bleeding (e.g., significant bleeding out the nasogastric tube, low blood pressure, dropping Hct and Hgb)
also should be assessed constantly.
UPPER GASTROINTESTINAL DISORDERS
Table 27-6
•
27-23
Stress-Related Mucosal Bleeding Prevention: Regimens and Doses
Agent
Dose and Frequency of Administration
Antacid
30 mL PO/NG Q 1–2 hr
No
Cimetidine
300 mg IV Q 6–8 hr
300 mg IV loading dose then 50 mg/hr continuous IV infusion
No
Yes
Famotidine
20 mg IV Q 12 hr
1.7 mg/hr continuous IV infusion
No
No
Ranitidine
50 mg IV Q 6–8 hr
6.25 mg/hr continuos IV infusion
No
No
Sucralfate
1 g PO/NG Q 4–6 hr
No
Omeprazole
FDA Approved
b
No
b
20–40 mg PO/NG Q 24 hr
Lansoprazole
30–60 mg PO/NG Q 24 hr
No
Pantoprazole
40 mg IV Q 12–24 hr
No
a
For prevention of SRMB.
By suspension in bicarbonate.
IV, intravenous; NG, by nasogastric tube; PO, by mouth.
b
Sucralfate
28. Is there any role for sucralfate in treating M.L.?
In the critically ill patient receiving stress ulcer prophylaxis
with acid-suppressing medications or neutralizing agents,
growth of Gram-negative bacteria is common.115 Because an
elevated gastric pH promotes proliferation of bacteria in the
stomach, aspiration of these organisms may be important in
the pathogenesis of nosocomial pneumonia. Sucralfate does
not alter gastric pH significantly but has generally been found
to be effective in preventing SRML associated bleeding.138,139
Several investigators have evaluated the association between
SRML prophylaxis nosocomial pneumonia in the critically ill
patient.115,138,139 Most studies have failed to demonstrate a significant difference in development of nosocomial pneumonia
between sucralfate and H2-antagonists.115,138,139 A more recent
study found that in critically ill patients requiring mechanical
ventilation there was no significant difference in the occurrence of pneumonia, and ranitidine was more effective than sucralfate in reducing the rate of GI bleeding.140
Sucralfate is available as a suspension and administration
through M.L.’s NG tube would be simple; however, M.L. has
decreased renal function and sucralfate can cause aluminum
toxicity in renally impaired patients. Therefore, sucralfate
may not be a good therapeutic option for M.L. A continuous
IV infusion of an H2-antagonist may be appropriate in this situation. The dose of the H2-receptor should be adjusted ac-
cording to M.L.’s calculated creatinine clearance (i.e., ClCr
10 mL/ min, use 0.8 mg/hr famotidine).
29. Is there a role for PPIs in the prevention of SRML for
M.L.?
PPIs administered by NG tube have been shown to provide
sufficient acid suppression to prevent SRML.98–102 In one
study comparing an omeprazole suspension (in bicarbonate)
administered in the NG tube with ranitidine, the NG omeprazole group had fewer GI significant bleeding episodes.135
These authors had a very broad definition of GI bleeding
(Hgb drop of 2), and the GI bleeding episodes noted may have
been from non-GI sources; thus, many believe the difference
noted may not be reproducible in actual practice. It is likely
that NG PPIs are effective, but superiority over other regimens needs to be confirmed in further studies.
Intravenous PPIs have been used in numerous studies, but
blinded, randomized trials in SRML prophylaxis have not yet
been published. Thus, comparative efficacy with other options
is not yet possible. Intravenous omeprazole and pantoprazole
are available in Canada and most of Europe, but only pantoprazole is available for intravenous use in the US. Several
trials are currently ongoing comparing IV PPIs with H2antagonists, but results are not available yet. It is likely they
are effective at preventing SRML associated GI bleeding, but
further work is necessary to determine comparative efficacy
of any PPIs with the other available options.
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