49
Chapter
PHYSIOLOGY OF GASTRIC SECRETION
■■ Parietal Cell H+,K+-ATPase
Pharmacotherapy for Gastric Acidity,
Peptic Ulcers, and Gastroesophageal
Reflux Disease
Keith A. Sharkey and Wallace K. MacNaughton
■■ Gastric Defenses Against Acid
PROTON PUMP INHIBITORS
■■ Mechanism of Action and Pharmacology
■■ ADME
■■ Therapeutic Uses and Adverse Effects
H2 RECEPTOR ANTAGONISTS
■■ Mechanism of Action and Pharmacology
■■ ADME
■■ Therapeutic Uses and Adverse Effects
TOLERANCE AND REBOUND WITH ACID-SUPPRESSING
MEDICATIONS
Gastric acid and pepsin in the stomach normally do not produce damage
or symptoms of acid-peptic diseases because of intrinsic defense mech-
anisms. The stomach is protected by a number of factors, collectively
referred to as “mucosal defense,” many of which are stimulated by the
local generation of PGs and NO. If these defenses are disrupted, a gastric
or duodenal ulcer may form. The treatment and prevention of acid-related
disorders are accomplished by decreasing gastric acidity and enhancing
mucosal defense. The appreciation that an infectious agent, Helicobacter
pylori, plays a key role in the pathogenesis of acid-peptic diseases rev-
olutionized approaches to prevention and therapy of these common
disorders.
Barriers to the reflux of gastric contents into the esophagus comprise
the primary esophageal defense. If these protective barriers fail and reflux
occurs, dyspepsia or erosive esophagitis may result. Therapies are directed
at decreasing gastric acidity, enhancing the tone of the lower esophageal
sphincter, and stimulating esophageal motility (see Chapter 50).
Physiology of Gastric Secretion
Gastric acid secretion is a complex and continuous process: Neuronal
(ACh, GRP); paracrine (histamine); and endocrine (gastrin) factors reg-
ulate the secretion of H+ by parietal cells (acid-secreting cells) (Figure
49–1). Their specific receptors (M3, BB2, H2, and CCK2, respectively)
are on the basolateral membrane of parietal cells in the body and fun-
dus of the stomach. Some of these receptors are also present on ECL
cells, where they regulate the release of histamine. The H2 receptor is a
GPCR that activates the Gs–adenylyl cyclase–cyclic AMP–PKA pathway
(see Chapters 3 and 39). ACh and gastrin signal through GPCRs that
couple to the Gq-PLC-IP3-Ca2+ pathway in parietal cells; GRP uses the
same signaling pathway to activate gastrin secretion from G cells. In
parietal cells, the cyclic AMP and the Ca2+-dependent pathways activate
H+,K+-ATPase (the proton pump), which exchanges H+ and K+ across
the parietal cell membrane. This pump generates the largest ion gradient
Brunton_Ch49_p0907-p0920.indd 909
AGENTS THAT ENHANCE MUCOSAL DEFENSE
■■ Misoprostol
■■ Sucralfate
■■ Antacids
■■ Other Acid Suppressants and Cytoprotectants
THERAPEUTIC STRATEGIES FOR SPECIFIC ACID-PEPTIC
DISORDERS
■■ Gastroesophageal Reflux Disease
■■ Peptic Ulcer Disease
■■ Treatment of Helicobacter pylori Infection
■■ NSAID-Related Ulcers
■■ Stress-Related Ulcers
■■ Zollinger-Ellison Syndrome
■■ Functional Dyspepsia
■■ Functional Esophageal Disorders
known in vertebrates, with an intracellular pH of about 7.3 and an intra-
canalicular pH of about 0.8.
The important structures for CNS stimulation of gastric acid secretion
are the dorsal motor nucleus of the vagal nerve, the hypothalamus, and
the solitary tract nucleus. Efferent fibers originating in the dorsal motor
nuclei descend to the stomach via the vagus nerve and synapse with gan-
glion cells of the enteric nervous system. ACh release from postganglionic
vagal fibers directly stimulates gastric acid secretion through muscarinic
M3 receptors on the basolateral membrane of parietal cells. The CNS pre-
dominantly modulates the activity of the enteric nervous system via ACh,
stimulating gastric acid secretion in response to the sight, smell, taste, or
anticipation of food (the “cephalic” phase of acid secretion). ACh also
indirectly affects parietal cells by increasing the release of histamine from
the ECL cells in the fundus of the stomach and of gastrin from G cells in
the gastric antrum.
The ECL cells, the source of gastric histamine, are usually in close prox-
imity to parietal cells. Histamine acts as a paracrine mediator, diffusing
from its site of release to nearby parietal cells, where it activates H2 receptors
to stimulate gastric acid secretion.
Gastrin, produced by antral G cells, is the most potent inducer of acid
secretion. Multiple pathways stimulate gastrin release, including CNS acti-
vation, local distention, and chemical components of the gastric contents.
In addition to releasing ACh, some vagal fibers to the stomach also release
GRP (a peptide of 27 amino acids); GRP activates the BB2 bombesin recep-
tor on G cells, activating the Gq-PLC-IP3-Ca2+ pathway and causing secre-
tion of gastrin. Gastrin stimulates acid secretion indirectly by inducing
the release of histamine by ECL cells; a direct effect on parietal cells also
plays a lesser role.
Somatostatin, produced by antral D cells, inhibits gastric acid secretion.
Acidification of the gastric luminal pH to less than 3 stimulates soma-
tostatin release, which in turn suppresses gastrin release in a negative-
feedback loop. Somatostatin-producing cells are decreased in patients
with H. pylori infection, and the consequent reduction of somatostatin’s
inhibitory effect may contribute to excess gastrin production.
08/09/17 12:02 PM
 910
Abbreviations
ACh: acetylcholine
cAMP: cyclic adenosine monophosphate
CCK: cholecystokinin
CNS: central nervous system
CYP: cytochrome P450
DU: duodenal ulcer
ECG: electrocardiogram
ECL: enterochromaffin-like cell
ENS: enteric nervous system
GERD: gastroesophageal reflux disease
GI: gastrointestinal
GPCR: G protein–coupled receptor
GRP: gastrin-releasing peptide
GU: gastric ulcer
HIST: histamine
IP3: inositol 1,4,5-trisphosphate
CHAPTER 49 PHARMACOTHERAPY FOR GASTRIC ACIDITY, PEPTIC ULCERS, AND GERD
NO: nitric oxide
NSAID: nonsteroidal anti-inflammatory drug
OTC: over the counter
PG: prostaglandin
PK: protein kinase
PLC: phospholipase C
PPI: proton pump inhibitor
SST: somatostatin
Parietal Cell H+,K+-ATPase
H+,K+-ATPase is the enzyme responsible for secreting protons into the
lumen of the gastric gland (Shin et al., 2009). It is a heterodimeric protein
composed of two subunits that are the products of two genes. The ATP4A
gene encodes the α subunit that contains the catalytic sites of the enzyme
and forms the membrane pore, and the ATP4B encodes the β subunit of
the H+,K+-ATPase, which contains an N-terminal cytoplasmic domain, a
transmembrane domain, and a highly glycosylated extracellular domain.
Hydronium ions bind to three active sites present in the α subunit, and
secretion involves conformational change that allows the movement of
protons. This movement is balanced by the transport of K+. The stoichi-
ometry of transport is pH dependent, varying between two H+ and two
K+ per molecule of ATP to one of each under more acidic conditions.
Inhibiting the H+,K+-ATPase (or proton pump) is the mainstay of modern
pharmacotherapy for acid-related disorders.
Gastric Defenses Against Acid
The extremely high concentration of H+ in the gastric lumen requires
robust defense mechanisms to protect the esophagus, stomach, and prox-
imal small intestine (Wallace, 2008). The primary esophageal defense is
the gastroesophageal junction—the lower esophageal sphincter in associa-
tion with the diaphragm and angle of His—which prevents reflux of acidic
gastric contents into the esophagus. The stomach protects itself from
acid damage by a number of mechanisms that require adequate mucosal
blood flow. One key defense is the secretion of a mucous layer that helps
to protect gastric epithelial cells by trapping secreted bicarbonate at the
cell surface. Gastric mucus is soluble when secreted but quickly forms
an insoluble gel that coats the mucosal surface of the stomach, slows ion
diffusion, and prevents mucosal damage by macromolecules such as pep-
sin. Mucus production is stimulated by PGs E2 and I2, which also directly
inhibit gastric acid secretion by parietal cells. Thus, drugs that inhibit PG
formation (e.g., NSAIDs, ethanol) decrease mucus secretion and predis-
pose to the development of acid-peptic disease. The proximal part of the
duodenum is protected from gastric acid through the production of bicar-
bonate, primarily from mucosal Brunner glands.
Brunton_Ch49_p0907-p0920.indd 910
Figure 49–1 outlines the rationale and pharmacological basis for the
therapy of acid-peptic disease. The PPIs are used most commonly, fol-
lowed by the histamine H2 receptor antagonists.
Proton Pump Inhibitors
The most potent suppressors of gastric acid secretion are inhibitors of the
gastric H+,K+-ATPase or proton pump (Figure 49–2). These drugs dimin-
ish the daily production of acid (basal and stimulated) by 80%–95% (Shin
and Sachs, 2008).
Mechanism of Action and Pharmacology
Six PPIs are available for clinical use: omeprazole and its S-isomer, esome-
prazole, lansoprazole and its R-enantiomer, dexlansoprazole, rabeprazole,
and pantoprazole. All PPIs have equivalent efficacy at comparable doses.
Proton pump inhibitors are prodrugs that require activation in an acid
environment. After absorption into the systemic circulation, the prodrug
diffuses into the parietal cells of the stomach and accumulates in the acidic
secretory canaliculi. Here, it is activated by proton-catalyzed formation of a
tetracyclic sulfenamide (see Figure 49–2), trapping the drug so that it can-
not diffuse back across the canalicular membrane. The activated form then
binds covalently with sulfhydryl groups of cysteines in the H+,K+-ATPase,
irreversibly inactivating the pump molecule. Acid secretion resumes only
after new pump molecules are synthesized and inserted into the luminal
membrane, providing a prolonged (up to 24- to 48-h) suppression of acid
secretion, despite the much shorter plasma t1/2 of about 0.5–3 h of the
parent compounds. Because they block the final step in acid production,
the PPIs effectively suppress stimulated acid production, regardless of the
physiological stimulus, as well as basal acid production.
The amount of H+,K+-ATPase increases after fasting; therefore, PPIs
should be given before the first meal of the day. In most individuals, once-
daily dosing is sufficient to achieve an effective level of acid inhibition,
and a second dose, which is occasionally necessary, can be administered
before an evening meal. Rebound acid hypersecretion occurs following
prolonged treatment with PPIs, and clinical studies suggest that rebound
after ceasing treatment can provoke symptoms such as dyspepsia.
To prevent degradation of PPIs by acid in the gastric lumen and
improve oral bioavailability, oral dosage forms are supplied in different
formulations:
• Enteric-coated pellets within gelatin capsules (omeprazole, dexlanso-
prazole, esomeprazole, lansoprazole, rabeprazole)
• Delayed-release tablets (omeprazole formulations)
• Delayed-release capsules (dexlansoprazole, esomeprazole formulations)
• Delayed-release oral suspension packets (esomeprazole, omeprazole,
pantoprazole)
• Enteric-coated microgranules in orally disintegrating tablets
(lansoprazole)
• Enteric-coated tablets (pantoprazole, rabeprazole, and omeprazole)
• Powdered omeprazole combined with sodium bicarbonate (capsules
and oral suspension)
The delayed-release and enteric-coated tablets dissolve only at alkaline
pH, whereas admixture of omeprazole with sodium bicarbonate simply
neutralizes stomach acid; both strategies substantially improve the oral
bioavailability of these acid-labile drugs. Patients for whom the oral route
of administration is not available can be treated parenterally with esome-
prazole sodium or pantoprazole.
ADME
Because an acidic pH in the parietal cell acid canaliculi is required for
drug activation and food stimulates acid production, these drugs ideally
should be given about 30 min before meals. Concurrent administration of
food may reduce somewhat the rate of absorption of PPIs, but this effect is
not thought to be clinically significant. Once in the small bowel, PPIs are
rapidly absorbed, highly protein bound, and extensively metabolized by
hepatic CYPs, particularly CYP2C19 and CYP3A4. Asians are more likely
08/09/17 12:02 PM
 911
Muscarinic
Gastrin Gastrin antagonists
G cell
1 M3
K+ K+
BB2 ACh
Cl– Cl–
CCK2 H2
GRP antagonists
CCK2 Ca2+-dependent
pathway
K+
HIST HIST H2 H+, K+
cAMP-dependent Proton pump
ATPase inhibitors
M1 ECL cell pathway
NSAIDs
H+ Antacids
ACh EP3
Parietal cell
Bismuth
C20 fatty PGE2
Metronidazole
acids PGI2
Misoprostol H. pylori Tetracycline
ENS Clarithromycin
N neuron Amoxicillin
Muscarinic
antagonists

SECTION VI GASTROINTESTINAL PHARMACOLOGY

M1 EP3 Mucus

ACh Sucralfate
Cyto-
protection Carben-
oxolone
M1
2 Pirenzepine 3 ACh HCO3–
Superficial epithelial cell

Mucous layer Gastric lumen

pH 7 pH 2

Figure 49–1  Pharmacologist’s view of gastric secretion and its regulation: the basis for therapy of acid-peptic disorders. Shown are the interactions among neural
input and a variety of enteroendocrine cells: an ECL cell that secretes histamine, a ganglion cell of the ENS, a G cell that secretes gastrin, a parietal cell that secretes
acid, and a superficial epithelial cell that secretes mucus and bicarbonate. Physiological pathways, shown in solid black, may be stimulatory (+) or inhibitory (−). 1
and 3 indicate possible inputs from postganglionic cholinergic fibers; 2 shows neural input from the vagus nerve. Physiological agonists and their respective mem-
brane receptors include ACh and its muscarinic (M) and nicotinic (N) receptors; GRP and its receptor, the BB2 bombesin receptor; gastrin and its receptor, the
CCK2; HIST and the H2 receptor; and PGE2 and the EP3 receptor. A red line with a T bar indicates sites of pharmacological antagonism. A light blue dashed arrow
indicates a drug action that mimics or enhances a physiological pathway. Shown in red are drugs used to treat acid-peptic disorders. NSAIDs can induce ulcers via
inhibition of cyclooxygenase. Not shown is a physiological pathway that reduces acid secretion: a D cell that secretes SST, which inhibits G-cell release of gastrin.

OCH3
H3C CH3

N
N S
O
NH

OCH3
OMEPRAZOLE

H+

OCH3 CYCLIC SULFENAMIDE SULFENIC ACID

H3C CH3 OCH3 OCH3

H3C CH3 H 3C CH3
+ Enzyme SH
N + +
S Enzyme N N
S
N NH S S
N N H2O N NH OH

OCH3
OCH3 OCH3
ENZYME-INHIBITOR COMPLEX

Figure 49–2  Activation of a PPI from its prodrug form. Omeprazole is converted to a sulfenamide in the acidic secretory canaliculi of the parietal cell. The sulfen-
amide interacts covalently with sulfhydryl groups in the proton pump, thereby irreversibly inhibiting its activity. Lansoprazole, rabeprazole, and pantoprazole
undergo analogous conversions.

Brunton_Ch49_p0907-p0920.indd 911 08/09/17 12:02 PM

 912 than Caucasians or African Americans to have the CYP2C19 genotype
that correlates with slow metabolism of PPIs (23% vs. 3%, respectively),
which may contribute to heightened efficacy or toxicity in this ethnic
group (Camilleri, 2012).
Because not all pumps and all parietal cells are active simultaneously,
maximal suppression of acid secretion requires several doses of the PPIs.
For example, it may take 2–5 days of therapy with once-daily dosing to
achieve the about 70% inhibition of proton pumps that is seen at steady
state. More frequent initial dosing (e.g., twice daily) will reduce the time
to achieve full inhibition but has not been shown to improve patient out-
come. The resulting proton pump inhibition is irreversible; thus, acid
secretion is suppressed for 24–48 h, or more, until new proton pumps are
synthesized and incorporated into the luminal membrane of parietal cells.
Chronic renal failure does not lead to drug accumulation with once-a-day
dosing of the PPIs. Hepatic disease substantially reduces the clearance of
esomeprazole and lansoprazole. Thus, in patients with severe hepatic dis-
ease, dose reduction is recommended for esomeprazole and lansoprazole.
Therapeutic Uses and Adverse Effects
CHAPTER 49 PHARMACOTHERAPY FOR GASTRIC ACIDITY, PEPTIC ULCERS, AND GERD
Prescription PPIs are primarily used to promote healing of gastric and
duodenal ulcers and to treat GERD, including erosive esophagitis, which
is either complicated or unresponsive to treatment with H2 receptor antag-
onists. They are also used in conjunction with antibiotics for the eradica-
tion of Helicobacter pylori. PPIs also are the mainstay in the treatment of
pathological hypersecretory conditions, including the Zollinger-Ellison
syndrome. Lansoprazole, pantoprazole, and esomeprazole are approved
for treatment and prevention of recurrence of NSAID-associated gas-
tric ulcers in patients who continue NSAID use. It is not clear if PPIs
affect the susceptibility to NSAID-induced damage and bleeding in the
small and large intestine. All PPIs are approved for reducing the risk of
duodenal ulcer recurrence associated with H. pylori infections. Over-the-
counter omeprazole, esomeprazole, and lansoprazole are approved for
the self-treatment of acid reflux. Therapeutic applications of the PPIs are
discussed further in the section Therapeutic Strategies for Specific Acid-
Peptic Disorders.
The PPIs generally cause remarkably few adverse effects and have an
excellent safety record (Chen et al., 2012; Reimer, 2013). The most com-
mon side effects are nausea, abdominal pain, constipation, flatulence, and
diarrhea. Subacute myopathy, arthralgias, headaches, interstitial nephritis,
and skin rashes also have been reported. PPIs are metabolized by hepatic
CYPs and therefore may interfere with the elimination of other drugs
cleared by this route. PPIs have been observed to interact with warfa-
rin (esomeprazole, lansoprazole, omeprazole, and rabeprazole); diazepam
(esomeprazole and omeprazole); and cyclosporine (omeprazole and rabe-
prazole). Among the PPIs, only omeprazole inhibits CYP2C19 (thereby
decreasing the clearance of disulfiram, phenytoin, and other drugs) and
induces the expression of CYP1A2 (thereby increasing the clearance of
imipramine, several antipsychotic drugs, tacrine, and theophylline). There
is some evidence that PPIs can inhibit conversion of clopidogrel (at the
level of CYP2C19) to the active anticoagulating form, but this is contro-
versial (Huang et al., 2012). Pantoprazole is less likely to result in this
interaction; concurrent use of clopidogrel and PPIs (mainly pantopra-
zole) significantly reduces GI bleeding without increasing adverse cardiac
events (see Chapter 32). Another drug interaction is between methotrex-
ate and PPI therapy because PPIs can competitively inhibit methotrexate
elimination and thereby increase methotrexate levels.
Chronic treatment with omeprazole decreases the absorption of vitamin
B12, but the clinical relevance of this effect is not clear. Loss of gastric acidity
also may affect the bioavailability of such drugs as ketoconazole, ampicillin
esters, and iron salts. Chronic use of PPIs has been reported to be associated
with an increased risk of bone fracture and with increased susceptibility to
certain infections (e.g., hospital-acquired pneumonia, community-acquired
Clostridium difficile, spontaneous bacterial peritonitis in patients with
ascites). Hypergastrinemia is more frequent and more severe with PPIs than
with H2 receptor antagonists and associated with this is ECL hyperplasia,
fundic gland polyposis, and atrophic gastritis. This hypergastrinemia may
Brunton_Ch49_p0907-p0920.indd 912
predispose to rebound hypersecretion of gastric acid on discontinuation
of therapy and also may promote the growth of GI tumors, although the
risk appears very low (Song et al., 2014). Recently, there have been asso-
ciations made between long-term PPI use and increased risk of chronic
kidney disease and dementia. These studies are not yet supported by well-
controlled prospective trials and the evidence for these significant adverse
effects remains very limited (Freedberg et al, 2017).
H2 Receptor Antagonists
The arrival of selective histamine H2 receptor antagonists was a landmark
in the treatment of acid-peptic disease. Before the availability of the H2
receptor antagonists, the standard of care was simply acid neutralization in
the stomach lumen, generally with inadequate results. The long history of
safety and efficacy with the H2 receptor antagonists led to their availability
without a prescription. Increasingly, however, PPIs are replacing the H2
receptor antagonists in clinical practice.
CH2CH2NH2
NH N
HISTAMINE
H3C CH2SCH2CH2N CNHCH3
HN HN C N
CIMETIDINE
Mechanism of Action and Pharmacology
The H2 receptor antagonists inhibit acid production by reversibly com-
peting with histamine for binding to H2 receptors on the basolateral
membrane of parietal cells (Black, 1993). Four different H2 receptor antag-
onists, which differ mainly in their pharmacokinetics and propensity to
cause drug interactions, are available in the U.S.: cimetidine, ranitidine,
famotidine, and nizatidine. These drugs are less potent than PPIs but still
suppress 24-hour gastric acid secretion by about 70%. Suppression of
basal and nocturnal acid secretion is about 70%; because suppression of
nocturnal acid secretion is important in the healing of duodenal ulcers,
evening dosing of an H2 receptor antagonist is adequate therapy in most
cases. There is little evidence for the use of H2 receptor antagonists for the
treatment of bleeding ulcers, and they are no longer recommended for this
purpose. All four H2 receptor antagonists are available as prescription and
over-the-counter formulations for oral administration. Intravenous and
intramuscular preparations of cimetidine, ranitidine, and famotidine also
are available for use in critically ill patients (Table 49–1)
ADME
The H2 receptor antagonists are rapidly absorbed after oral administra-
tion, with peak serum concentrations within 1–3 h. Absorption may be
enhanced by food or decreased by antacids, but these effects probably
are unimportant clinically. Therapeutic levels are achieved rapidly after
intravenous dosing and are maintained for 4–5 h (cimetidine), 6–8 h
TABLE 49–1 ■ INTRAVENOUS DOSES OF H2 RECEPTOR
ANTAGONISTS
CIMETIDINE RANITIDINE FAMOTIDINE
Intermittent 300 mg every 50 mg every 20 mg every
bolus 6–8 h 6–8 h 12 h
Continuous 37.5–100 mg/h 6.25–12.5 mg/h 1.7–2.1 mg/h
infusion
08/09/17 12:02 PM
 (ranitidine), or 10–12 h (famotidine). The t1/2 values of these agents after
oral administration in adults range from 1 to 3.5 h; cimetidine clearance
is faster in children, reducing its t1/2 by about 30%. Only a small fraction
of these drugs is protein bound. The kidneys excrete these drugs and their
metabolites by filtration and renal tubular secretion, and it is important to
reduce drug doses in patients with decreased creatinine clearance. Neither
hemodialysis nor peritoneal dialysis clears significant amounts of these
drugs. Hepatic metabolism accounts for a small fraction of clearance
(from < 10% to about 35%), but liver disease per se is generally not an
indication for dose adjustment.
Therapeutic Uses and Adverse Effects
The major therapeutic indications for H2 receptor antagonists are to
promote healing of gastric and duodenal ulcers, to treat uncomplicated
GERD, and to prevent the occurrence of stress ulcers. For more infor-
mation about the therapeutic applications of H2 receptor antagonists, see
Therapeutic Strategies for Specific Acid-Peptic Disorders.
The H2 receptor antagonists generally are well tolerated, with a low
(<3%) incidence of adverse effects (Sabesin, 1993). Side effects are minor
and include diarrhea, headache, drowsiness, fatigue, muscular pain, and
constipation. Less-common side effects include those affecting the CNS
(confusion, delirium, hallucinations, slurred speech, and headaches),
which occur primarily with intravenous administration of the drugs or in
elderly subjects. Several reports have associated H2 receptor antagonists
with various blood disorders, including thrombocytopenia. H2 receptor
antagonists cross the placenta and are excreted in breast milk. Although
no major teratogenic risk has been associated with these agents, caution
is warranted when they are used in pregnancy.
All agents that inhibit gastric acid secretion may alter the rate of absorp-
tion and subsequent bioavailability of the H2 receptor antagonists (see
Antacids section). Drug interactions with H2 receptor antagonists occur
mainly with cimetidine, and its use has decreased markedly. Cimeti-
dine inhibits CYPs (e.g., CYP1A2, CYP2C9, and CYP2D6) and thereby
can increase the levels of a variety of drugs that are substrates for these
enzymes. Ranitidine also interacts with hepatic CYPs, but with an affinity
of only 10% of that of cimetidine. Famotidine and nizatidine are even safer
in this regard. Slight increases in blood alcohol concentration may result
from concomitant use of H2 receptor antagonists and alcohol.
Tolerance and Rebound With Acid-Suppressing
Medications
Tolerance to the acid-suppressing effects of H2 receptor antagonists
may develop within 3 days of starting treatment and may be resistant to
increased doses of the medications (Sandevik et al., 1997). Diminished
sensitivity to these drugs may result from the effect of the secondary
hypergastrinemia to stimulate histamine release from ECL cells.
Agents That Enhance Mucosal Defense
Misoprostol
Misoprostol (15-deoxy-16-hydroxy-16-methyl-PGE1) is a synthetic ana-
logue of PGE1 that is FDA approved to prevent NSAID-induced mucosal
injury.
Mechanism of Action and Pharmacology
Prostaglandin E2 and prostacyclin (PGI2) are the major PGs synthesized
by the gastric mucosa. Contrary to their cyclic AMP–elevating effects on
many cells via EP2 and EP4 receptors, these prostanoids bind to the EP3
receptor on parietal cells and stimulate the Gi pathway, thereby decreasing
intracellular cyclic AMP and gastric acid secretion. PGE2 also can prevent
gastric injury by cytoprotective effects that include stimulation of mucin
and bicarbonate secretion and increased mucosal blood flow. Acid sup-
pression appears to be the most important effect clinically (Wolfe and
Sachs, 2000).
Brunton_Ch49_p0907-p0920.indd 913
Because NSAIDs diminish PG formation by inhibiting cyclooxygenase, 913
synthetic PG analogues offer a logical approach to counteract NSAID-
induced damage.
ADME
Misoprostol is rapidly absorbed after oral administration and is rapidly
and extensively deesterified to form misoprostol acid, the principal and
active metabolite of the drug. A single dose inhibits acid production
within 30 min; the therapeutic effect peaks at 60–90 min and lasts for
up to 3 h. Food and antacids decrease the rate of misoprostol absorption.
The free acid is excreted mainly in the urine, with an elimination t1/2 of
20–40 min.
Therapeutic Uses and Adverse Effects
Misoprostol is rarely used because of its side effects (Rostom et al., 2009).
The degree of inhibition of gastric acid secretion by misoprostol is directly
related to dose; oral doses of 100–200 μg significantly inhibit basal acid
secretion (up to 85%–95% inhibition) or food-stimulated acid secretion
(up to 75%–85% inhibition). The usual recommended dose for ulcer pro-
phylaxis is 200 μg four times a day.
Diarrhea, with or without abdominal pain and cramps, occurs in up to
SECTION VI GASTROINTESTINAL PHARMACOLOGY
30% of patients who take misoprostol. Apparently dose related, it typically
begins within the first 2 weeks after therapy is initiated and often resolves
spontaneously within a week; more severe cases may necessitate drug dis-
continuation. Misoprostol can cause clinical exacerbations of inflammatory
bowel disease (see Chapter 51). Misoprostol is contraindicated for reducing
the risk of NSAID-induced ulcer in women of childbearing potential unless
the patient is at high risk of complications from gastric ulcers associated with
use of the NSAID. It is also completely contraindicated during pregnancy
because it can increase uterine contractility.
Sucralfate
Mechanism of Action and Pharmacology
In the presence of acid-induced damage, pepsin-mediated hydrolysis of
mucosal proteins contributes to mucosal erosion and ulcerations. This
process can be inhibited by sulfated polysaccharides. Sucralfate consists
of the octasulfate of sucrose to which Al(OH)3 has been added. In an acid
environment (pH < 4), sucralfate undergoes extensive cross-linking to
produce a viscous, sticky polymer that adheres to epithelial cells and ulcer
craters for up to 6 h after a single dose. In addition to inhibiting hydrolysis
of mucosal proteins by pepsin, sucralfate may have other cytoprotective
effects, including stimulation of local production of PGs and epidermal
growth factor (Szabo, 2014). Sucralfate also binds bile salts; thus, some
clinicians use sucralfate to treat individuals with the syndromes of biliary
esophagitis or gastritis (the existence of which is controversial).
Therapeutic Uses and Adverse Effects
The use of sucralfate to treat peptic acid disease has diminished in recent
years. Nevertheless, because increased gastric pH may be a factor in the
development of nosocomial pneumonia in critically ill patients, sucral-
fate may offer an advantage over PPIs and H2 receptor antagonists for the
prophylaxis of stress ulcers. Sucralfate also has been used in conditions
associated with mucosal inflammation/ulceration that may not respond to
acid suppression, including oral mucositis (radiation and aphthous ulcers)
and bile reflux gastropathy. Administered by rectal enema, sucralfate also
has been used for radiation proctitis and solitary rectal ulcers. Because it
is activated by acid, sucralfate should be taken on an empty stomach 1 h
before meals. Use of antacids within 30 min of a dose of sucralfate should
be avoided. The dose of sucralfate is 1 g four times daily (for active duode-
nal ulcer) or 1 g twice daily (for maintenance therapy). For children, it is
given 40–80 mg/kg/d in divided doses every 6 h.
The most common side effect of sucralfate is constipation (about 2%).
Sucralfate should be avoided in patients with renal failure who are at risk
for aluminum overload (Marks, 1991). Likewise, aluminum-containing
antacids should not be combined with sucralfate in these patients.
Sucralfate forms a viscous layer in the stomach that may inhibit absorp-
tion of other drugs, including phenytoin, digoxin, cimetidine, ketoco-
nazole, and fluoroquinolone antibiotics. Sucralfate therefore should be
08/09/17 12:02 PM
 914 taken at least 2 h after the administration of other drugs. The “sticky”
nature of the viscous gel produced by sucralfate in the stomach also may
be responsible for the development of bezoars in some patients.
Antacids
Mechanism of Action and Pharmacology
There are far more effective and persistent agents than antacids, but their
price, accessibility, and rapid action make them popular with consumers as
OTC medications, and they can be used for the acute treatment of acid reflux
(“heartburn”) and esophagitis (see discussion that follows). Many factors,
including palatability, determine the effectiveness and choice of antacid.
Although sodium bicarbonate effectively neutralizes acid, it is very water
soluble and rapidly absorbed from the stomach, and the alkali and sodium
loads may pose a risk for patients with cardiac or renal failure. CaCO3
rapidly and effectively neutralizes gastric H+, but the release of CO2 from
bicarbonate- and carbonate-containing antacids can cause belching, nausea,
abdominal distention, and flatulence. Calcium also may induce rebound
acid secretion, necessitating more frequent administration. Combinations
of Mg2+ (rapidly reacting) and Al3+ (slowly reacting) hydroxides provide a
CHAPTER 49 PHARMACOTHERAPY FOR GASTRIC ACIDITY, PEPTIC ULCERS, AND GERD
relatively balanced and sustained neutralizing capacity and are preferred
by most experts. Magaldrate, a hydroxymagnesium aluminate complex,
is converted rapidly in gastric acid to Mg(OH)2 and Al(OH)3, which are
absorbed poorly and thus provide a sustained antacid effect. Although fixed
combinations of Mg2+ and Al3+ theoretically counteract the adverse effects of
each other on the bowel (Al3+ can relax gastric smooth muscle, producing
delayed gastric emptying and constipation; Mg2+ exerts the opposite effects),
such balance is not always achieved in practice. Simethicone, a surfactant
that may decrease foaming and hence esophageal reflux, is included in many
antacid preparations. However, other fixed combinations, particularly those
with aspirin, that are marketed for “acid indigestion” are potentially unsafe
in patients predisposed to gastroduodenal ulcers and should not be used.
Therapeutic Uses and Adverse Effects
Antacids are given orally 1 and 3 h after meals and at bedtime. For severe
symptoms or uncontrolled reflux, antacids can be given as often as every
30–60 min. In general, antacids should be administered in suspension
form because this probably has greater neutralizing capacity than powder
or tablet dosage forms. Antacids are cleared from the empty stomach in
about 30 min. However, the presence of food is sufficient to elevate gas-
tric pH to about 5 for about 1 h and to prolong the neutralizing effects of
antacids for about 2–3 h.
Antacids vary in the extent to which they are absorbed and hence in
their systemic effects. In general, most antacids can elevate urinary pH by
about 1 pH unit. Antacids that contain Al3+, Ca2+, or Mg2+ are absorbed
less completely than are those that contain NaHCO3. With renal insuffi-
ciency, absorbed Al3+ can contribute to osteoporosis, encephalopathy, and
proximal myopathy. About 15% of orally administered Ca2+ is absorbed,
causing transient hypercalcemia. The hypercalcemia from as little as 3–4 g
of CaCO3 per day can be problematic in patients with uremia. In the past,
when large doses of NaHCO3 and CaCO3 were administered commonly
with milk or cream for the management of peptic ulcer, the milk-alkali
syndrome (alkalosis, hypercalcemia, and renal insufficiency) occurred
frequently. Today, this syndrome is rare and generally results from the
chronic ingestion of large quantities of Ca2+ (five to forty 500-mg tablets
per day of calcium carbonate) taken with milk.
By altering gastric and urinary pH, antacids may affect a number of
drugs (e.g., thyroid hormones, allopurinol, and imidazole antifungals,
by altering rates of dissolution and absorption, bioavailability, and renal
elimination). Al3+ and Mg2+ antacids also are notable for their propensity
to chelate other drugs present in the GI tract and thereby decrease their
absorption. Most interactions can be avoided by taking antacids 2 h before
or after ingestion of other drugs.
Other Acid Suppressants and Cytoprotectants
The M1 muscarinic receptor antagonists pirenzepine and telenzepine (see
Chapter 9) can reduce basal acid production by 40%–50%. The ACh
receptor on the parietal cell itself is of the M3 subtype, and these drugs are
Brunton_Ch49_p0907-p0920.indd 914
believed to suppress neural stimulation of acid production via actions on
M1 receptors of intramural ganglia (see Figure 49–1). Because of their rela-
tively poor efficacy, significant and undesirable anticholinergic side effects,
and risk of blood disorders (pirenzepine), they rarely are used today.
Rebamipide is used for ulcer therapy in parts of India and Asia. Its cytopro-
tective effects are exerted by increasing PG generation in gastric mucosa and
by scavenging reactive oxygen species. Ecabet, which appears to increase the
formation of PGE2 and PGI2, also is used for ulcer therapy, mostly in Japan.
Carbenoxolone, a derivative of glycyrrhizic acid found in licorice root, has
been used with modest success for ulcer therapy in Europe. Unfortunately,
carbenoxolone inhibits the type I isozyme of 11β-hydroxysteroid dehydroge-
nase, which protects the mineralocorticoid receptor from activation by corti-
sol in the distal nephron; it therefore causes hypokalemia and hypertension
due to excessive mineralocorticoid receptor activation (see Chapter 46). Bis-
muth compounds (see Chapter 50) are frequently prescribed in combination
with antibiotics to eradicate H. pylori and prevent ulcer recurrence. Bismuth
compounds bind to the base of the ulcer, promote mucin and bicarbonate
production, and have significant antibacterial effects.
Therapeutic Strategies for Specific Acid-Peptic
Disorders
Gastroesophageal Reflux Disease
Although most cases of acid reflux or gastroesophageal regurgitation fol-
low a relatively benign course, these symptoms, often referred to as non-
erosive reflux disease, can still be troubling (Boeckxstaens et al., 2014).
More severe GERD is erosive esophagitis, characterized by endoscopically
visible mucosal damage. This can lead to stricture formation and Barrett
metaplasia (replacement of squamous by intestinal columnar epithelium),
which is associated with a small but significant risk of adenocarcinoma.
The goals of GERD therapy are complete resolution of symptoms and
healing of esophagitis (Altan et al., 2012). PPIs clearly are more effective
than H2 receptor antagonists in achieving these goals (see Figure 49–3).
In general, the optimal dose for each patient is determined based on
symptom control. Strictures associated with GERD also respond better to
PPIs than to H2 receptor antagonists. One of the complications of GERD,
Barrett esophagus, appears to be more refractory to therapy because nei-
ther acid suppression nor antireflux surgery has been shown convincingly
to produce regression of metaplasia.
Regimens for the treatment of GERD with PPIs and histamine H2
receptor antagonists are listed in Table 49–2. Although some patients with
Untreated
H2 receptor antagonist
Proton pump inhibitor
24 h
No Further Improvement
Hours per day at desired pH
16 h Duodenal GERD H. pylori
ulcer eradication
8h
pH > 3 pH > 4 pH > 5
Intragastric pH
Figure 49–3  Comparative success of therapy with PPIs and H2 antagonists.
Data show the effects of a PPI (given once daily) and an H2 receptor antag-
onist (given twice daily) in elevating gastric pH to the target ranges (i.e.,
pH 3 for duodenal ulcer, pH 4 for GERD, and pH 5 for antibiotic eradication
of H. pylori).
08/09/17 12:02 PM
 915
TABLE 49–2 ■ ANTISECRETORY DRUG REGIMENS FOR TREATMENT OF GERD
DRUG ADULT DOSAGE PEDIATRIC DOSAGE
H2 receptor antagonists a

Cimetidine 400 mg 4 times daily or 800 mg twice daily 20–40 mg/kg/d divided every 6 h for 8–12 weeks
for 12 weeks
Famotidine 20 mg twice daily for up to 12 weeks 0.5 mg/kg/d at bedtime or divided every 12 h
(infants < 3 months)b
Nizatidine 150 mg twice daily <12 years: 10 mg/kg/dc divided every 12 h
>12 years: 150 mg twice daily

Ranitidine 150 mg twice daily 5–10 mg/kg/d divided, every 8–12 h

Proton pump inhibitors
Esomeprazole magnesium
Esomeprazole sodium
Esomeprazole strontium
20–40 mg daily for 4–8 weeks 2.5 – 20 mg dailyd up to 8 weeks
20–40 mg daily (IV)e IVd,e: 0.5 mg/kg daily (infants > 1 month). Children: 10 mg
daily (<55 kg); 20 mg daily (>55 kg)
24.65 or 49.3 mg daily for 4–8 weeks

SECTION VI GASTROINTESTINAL PHARMACOLOGY

Dexlansoprazole 30 mg daily for 4 weeks (nonerosive GERD); erosive Safety/efficacy not established
GERD: 60 mg daily up to 6 months, then 30 mg daily
up to 6 months (maintenance therapy)
Lansoprazole 15 mg (nonerosive GERD) or 30 mg (erosive GERD) 15–30 mg dailyd for up to 12 weeks
daily up to 8 weeks
Omeprazole 20 mg daily 5–20 mg dailyd
Pantoprazole 40 mg daily (erosive GERD) 20–40 mg dailyd for up to 8 weeks
Rabeprazole 20 mg daily (erosive GERD) Children 1–11 years old: 5–10 mg daily up to 12 weeks
Adolescents: 20 mg daily up to 8 weeks
a
Not for erosive disease.
b
For children and adolescents, individualize treatment duration and dose based on clinical response or pH determination (gastric or esophageal) and endoscopy. For infants,
employ conservative measures (e.g., thickened feedings) and limit therapy to 8 weeks.
c
Indicates off-label use.
d
Varies by weight.
e
Used when oral PPI cannot be given; short-term use only.

mild GERD symptoms may be managed by nocturnal doses of H2 receptor
antagonists, twice-daily dosing usually is required. Antacids are insuffi-
cient and are recommended only for the patient with mild, infrequent
episodes of acute acid reflux. In general, prokinetic agents (see Chapter 50)
are not particularly useful for GERD, either alone or in combination with
acid-suppressant medications. There is reasonable evidence that PPIs, and,
to a lesser extent, H2 receptor antagonists, are safe and effective for the
treatment of GERD in children (Tighe et al., 2014).
Severe Symptoms and Nocturnal Acid Breakthrough
In patients with severe symptoms or extraintestinal manifestations of
GERD, twice-daily dosing with a PPI may be needed. However, it is dif-
ficult, if not impossible, to render patients achlorhydric, and two-thirds
or more of subjects will continue to make acid, particularly at night. This
phenomenon, called nocturnal acid breakthrough, has been invoked as
a cause of refractory symptoms in some patients with GERD. However,
decreases in gastric pH at night while on therapy generally are not asso-
ciated with acid reflux into the esophagus, and the rationale for suppress-
ing nocturnal acid secretion remains to be established. Patients with
continuing symptoms on twice-daily PPIs are often treated by adding an
H2 receptor antagonist at night. Although this can further suppress acid
production, the effect is short lived, probably due to the development of
tolerance (Fackler et al., 2002).
Therapy for Extraintestinal Manifestations of GERD
Acid reflux has been implicated in a variety of atypical symptoms, includ-
ing noncardiac chest pain, asthma, laryngitis, chronic cough, and other
ear, nose, and throat conditions. PPIs (at higher doses) have been used
with some success in certain patients with these disorders.
GERD and Pregnancy
Acid reflux is estimated to occur in 30%–50% of pregnancies, with an
incidence approaching 80% in some populations (Richter, 2003). In the
vast majority of cases, GERD ends soon after delivery and thus does not
represent an exacerbation of a preexisting condition. Because of its high
prevalence and the fact that it can contribute to the nausea of pregnancy,
treatment often is required. Treatment choice in this setting is complicated
by the paucity of safety data about use during pregnancy for the most
commonly used drugs. In general, most drugs used to treat GERD fall in
FDA category B, with the exception of omeprazole (FDA category C; see
Appendix I for information on these categories). Mild cases of GERD dur-
ing pregnancy should be treated conservatively; antacids or sucralfate are
considered the first-line drugs. If symptoms persist, H2 receptor antago-
nists can be used, with ranitidine having the most established track record
in this setting. PPIs are reserved for women with intractable symptoms or
complicated reflux disease. In these situations, omeprazole, lansoprazole,
and pantoprazole are considered the safest choices (Ali and Egan, 2007).
Pediatric GERD
Reflux disease in infants and children is increasing at an alarming rate
(Vandenplas, 2014). Children over 10 years can be diagnosed and treated
similarly to adults, but infants and very young children require care-
ful diagnosis to rule out cow’s milk allergy or eosinophilic esophagitis.
Many nonpharmacologic approaches can be used to alleviate some of
the very troubling symptoms of this condition, which may not be due to
acid reflux. If acid reduction is indicated, PPIs are more effective than H2
receptor antagonists; however, the therapeutic efficacy of PPIs in new-
borns and infants is low, and there is an increased risk of adverse effects,

Brunton_Ch49_p0907-p0920.indd 915 08/09/17 12:02 PM

 916 including respiratory tract infections and gastroenteritis, which should
be carefully considered. It is likely PPIs are overused in the treatment of
pediatric GERD.
Peptic Ulcer Disease
Peptic ulcer disease is best viewed as an imbalance between mucosal
defense factors (bicarbonate, mucin, PG, NO, and other peptides and
growth factors) and injurious factors (acid and pepsin) (Hunt et al., 2015;
Wallace, 2008). On average, patients with duodenal ulcers produce more
acid than do control subjects, particularly at night (basal secretion).
Although patients with gastric ulcers have normal or even diminished
acid production, ulcers rarely, if ever, occur in the complete absence of
acid. Presumably, weakened mucosal defense and reduced bicarbonate
production contribute to the injury from the relatively lower levels of
acid in these patients. Helicobacter pylori and exogenous agents such as
NSAIDs interact in complex ways to cause an ulcer. Up to 60% of peptic
ulcers are associated with H. pylori infection of the stomach. This infection
may lead to impaired production of somatostatin by D cells and, in time,
cause decreased inhibition of gastrin production, resulting in increased
CHAPTER 49 PHARMACOTHERAPY FOR GASTRIC ACIDITY, PEPTIC ULCERS, AND GERD
The NSAIDs also are frequently associated with peptic ulcers and bleed-
ing. The effects of these drugs are mediated systemically; in the stomach,
NSAIDS suppress mucosal PG synthesis (particularly PGE2 and PGI2) and
thereby reduce mucus production and cytoprotection (see Figure 49–1).
Thus, minimizing NSAID use is an important adjunct to gastroduodenal
ulcer therapy.
Treatment of Helicobacter pylori Infection
Helicobacter pylori, a gram-negative rod, has been associated with gas-
tritis and the subsequent development of gastric and duodenal ulcers,
gastric adenocarcinoma, and gastric B-cell lymphoma (Suerbaum and
Michetti, 2002). Because of the critical role of H. pylori in the pathogen-
esis of peptic ulcers, eradicating this infection is standard care in patients
with gastric or duodenal ulcers (Malfertheiner et al., 2013). Provided
that patients are not taking NSAIDs, this strategy almost completely
eliminates the risk of ulcer recurrence. Eradication of H. pylori also is
indicated in the treatment of mucosa-associated lymphoid tissue lympho-
mas of the stomach, which can regress significantly after such treatment.
Helicobacter pylori eradication is also indicated for treatment of chronic

acid production and reduced duodenal bicarbonate production. Table
49–3 summarizes current recommendations for drug therapy of gastro-
duodenal ulcers.
The PPIs relieve symptoms of duodenal ulcers and promote healing
more rapidly than do H2 receptor antagonists, although both classes of
drugs are effective in this setting (see Figure 49–3). A peptic ulcer rep-
resents a chronic disease, and recurrence within 1 year is expected in
the majority of patients who do not receive prophylactic acid suppres-
sion. With the appreciation that H. pylori plays a major etiopathogenic
role in the majority of peptic ulcers, prevention of relapse is focused on
eliminating this organism from the stomach. Intravenous esomeprazole
(80 mg IV over 30 min, followed by 8 mg/h continuous infusion for a
total of 72 h, then 40 mg orally or another single daily dose oral PPI, for
an appropriate duration; off-label use) and pantoprazole (off-label use) are
the preferred therapy in patients with acute bleeding ulcers (Laine and
Jensen, 2012; Wong and Sung, 2013). The theoretical benefit of maximal
acid suppression in this setting is to accelerate healing of the underlying
ulcer. In addition, a higher gastric pH enhances clot formation and retards
clot dissolution.
atrophic gastritis and presence of intestinal metaplasia/dysplasia (with
positive H. pylori biopsies).
Five important considerations influence the selection of an eradication
regimen (Table 49–4) (Chey and Wong, 2007; Malfertheiner et al., 2012):
• Single-antibiotic regimens are ineffective in eradicating H. pylori infec-
tion and lead to microbial resistance. Combination therapy with two or
three antibiotics (plus acid-suppressive therapy) is associated with the
highest rate of H. pylori eradication.
• A PPI significantly enhances the effectiveness of H. pylori antibiotic
regimens containing amoxicillin and clarithromycin (see Figure 49–3).
• A regimen of 10–14 days of treatment appears to be better than shorter
treatment regimens.
• Poor patient compliance is linked to the medication-related side
effects experienced by as many as half of patients taking triple-agent
regimens and to the inconvenience of three- or four-drug regimens
administered several times per day. Packaging that combines the daily
doses into one convenient unit is available and may improve patient
compliance.

TABLE 49–3 ■ REGIMENS FOR TREATING GASTRODUODENAL ULCERS IN ADULTSa

DRUG ACTIVE ULCER MAINTENANCE THERAPY
Proton pump inhibitors b

Esomeprazole magnesium NSAID risk reduction: 20 or 40 mg daily for up to 6 months  

Esomeprazole strontium NSAID risk reduction: 24.65 or 49.3 mg daily for up to 6 months
Lansoprazole 15 mg (DU) daily for 4 weeks 15 mg daily
15 mg (NSAID risk reduction) daily for up to 12 weeks
30 mg (GU including NSAID associated) daily for up to 8 weeks 30 mg dailyc
Omeprazole 20 mg (DU) daily for 4–8 weeks 20 mg dailyc
40 mg (GU) daily for 4–8 weeks
Pantoprazole 20 mg (NSAID risk reduction) dailyc 20 mg dailyc
40 mg (GU) daily c

Rabeprazole 20 mg (DU for up to 4 weeks; GUc) daily

Prostaglandin analogue
Misoprostol 200 μg four times daily (NSAID-associated ulcer prevention)d
a
There is little evidence for the use of H2 receptor antagonists for the treatment of bleeding ulcers.
b
Deslansoprazole is not labeled for the treatment of active ulcers.
c
Off-label use.
d
Only misoprostol 800 μg/d has been directly shown to reduce the risk of ulcer complications such as perforation, hemorrhage, or obstruction. (Rostom A, Moayyedi P, Hunt
R. Canadian Association of Gastroenterology Consensus Group. Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug therapy and the need for
gastroprotection: benefits versus risks. Aliment Pharmacol Ther, 2009, 29:481–496.)

Brunton_Ch49_p0907-p0920.indd 916 08/09/17 12:02 PM


TABLE 49–4 ■ THERAPY OF HELICOBACTER PYLORI
INFECTION
Triple therapy × 10–14 days: PPI + clarithromycin 500 mg +
amoxicillin 1 g twice a day (metronidazole 500 mg twice a day can be
substituted for amoxicillin)
Quadruple therapy × 10–14 days: PPI + metronidazole 250 mg +
bismuth subsalicylate 525 mg + tetracycline 500 mg four times daily
or
Sequential therapy: PPI + amoxicillin 1 g twice a day for
5 days followed by PPI + clarithromycin 500 mg and tinidazole/
metronidazole 500 mg twice a day for 5 days;
or
PPI + amoxicillin 1 g twice a day + levofloxacin 250 or 500 mg twice a
day for 10 days
PPI daily dosages:
Omeprazole: 20 mg twice a day (triple therapy); 40 mg daily
(dual therapy)
Lansoprazole: 30 mg twice a day (triple therapy); 30 mg three times
daily for 14 days (dual therapy with amoxicillin)
Rabeprazole: 20 mg twice a day for 7 days
Pantoprazole: 40 mg twice a daya
Esomeprazole magnesium: 40 mg daily (triple therapy)
Esomeprazole strontium: 49.3 mg daily (triple therapy)
Off-label use.
a evidence of structural disease. It may be associated with gastritis (with
Data from Chey and Wong, 2007.
• The emergence of resistance to clarithromycin and metronidazole
increasingly is recognized as an important factor in the failure to erad-
icate H. pylori. In the presence of in vitro evidence of resistance to met-
ronidazole, amoxicillin should be used instead. In areas with a high
frequency of resistance to clarithromycin and metronidazole, a 14-day
quadruple-drug regimen (three antibiotics combined with a PPI) gen-
erally is effective therapy.
NSAID-Related Ulcers
Chronic NSAID users have a 2%–4% risk of developing a symptomatic
ulcer, GI bleeding, or perforation. Ideally, NSAIDs should be discontinued
in patients with an ulcer if at all possible. Healing of ulcers despite contin-
ued NSAID use is possible with the use of acid-suppressant agents, usu-
ally at higher doses and for a considerably longer duration than standard
regimens (e.g., ≥ 8 weeks). PPIs are superior to H2 receptor antagonists
and misoprostol in promoting the healing of active ulcers and in prevent-
ing recurrence of gastric and duodenal ulcers in the setting of continued
NSAID administration (Lanas and Hunt, 2006; Rostom et al., 2009). The
FDA has approved fixed-dose combinations of NSAIDS with a PPI or H2
antagonist; these combinations are intended to lower the risk of ulcers in
patients who regularly use NSAIDs for arthritic pain.
Stress-Related Ulcers
Stress ulcers are ulcers of the stomach or duodenum that occur in the
context of a profound illness or trauma requiring intensive care (Bardou
et al., 2015). The etiology of stress-related ulcers differs somewhat from
that of other peptic ulcers, involving acid and mucosal ischemia. Because
of limitations on the oral administration of drugs in many patients with
stress-related ulcers, intravenous H2 receptor antagonists have been used
extensively to reduce the incidence of GI hemorrhage due to stress ulcers.
Now that intravenous preparations of PPIs are available, they are appropri-
ate to consider. However, there is some concern over the risk of pneumonia
Brunton_Ch49_p0907-p0920.indd 917
secondary to gastric colonization by bacteria in an alkaline milieu. In this 917
setting, sucralfate appears to provide reasonable prophylaxis against
bleeding without increasing the risk of aspiration pneumonia.
Zollinger-Ellison Syndrome
Patients with Zollinger-Ellison syndrome develop pancreatic or duodenal
gastrinomas that stimulate the secretion of very large amounts of acid,
sometimes in the setting of multiple endocrine neoplasia, type I (Krampitz
and Norton, 2013). This can lead to severe gastroduodenal ulceration
and other consequences of uncontrolled hyperchlorhydria. PPIs are the
drugs of choice, usually given at about twice the routine dosage for peptic
ulcers (omeprazole 60 mg daily, esomeprazole 80 mg daily, lansoprazole
60 mg daily, rabeprazole 60 mg daily, or pantoprazole 120 mg daily); some
patients need two to three times these doses to control acid secretion.
However, once control of acid secretion has been achieved, dose reduction
is usually possible. PPIs are well tolerated and safe even at very high doses.
If PPIs are unable to control gastric acid secretion, the long-acting soma-
tostatin analogue octreotide (off-label indication) can be given to inhibit
secretion of gastrin. This is not a first-line agent due to unpredictable
SECTION VI GASTROINTESTINAL PHARMACOLOGY
response rates and the side effects of the treatment.
Functional Dyspepsia
The term functional dyspepsia refers to ulcer-like symptoms in patients
who lack overt gastroduodenal ulceration (Tack and Talley, 2013). Func-
tional dyspepsia can be subdivided into postprandial distress syndrome
and epigastric pain syndrome, based on the presence of symptoms related
to meals. It is defined as the presence of one or more of the following:
postprandial fullness, early satiation, epigastric pain or burning, and no
or without H. pylori) or with NSAID use, but the pathogenesis of this
syndrome remains controversial.
The PPIs appear to be moderately effective in the treatment of patients
with functional dyspepsia (Vanheel and Tack, 2014). In general, twice-
daily PPIs are no better than once-daily PPIs. The dosing is as for GERD
(Table 49–2). H2 receptor antagonists are only marginally effective for the
treatment of functional dyspepsia. Because central mechanisms may con-
tribute to functional dyspepsia either through visceral hypersensitivity
or other mechanisms, tricyclic antidepressants such as amitriptyline or
desipramine (10 to 25 mg at night) (see Chapter 15) can be considered
in patients with functional dyspepsia whose symptoms persist despite
PPI therapy for 8 weeks. Prokinetic agents such as metoclopramide (see
Chapter 50) are not considered for functional dyspepsia because of their
side-effect profile. The novel gastroprokinetic agent acotiamide is being
investigated for use in postprandial distress syndrome, and 5HT1A sero-
tonin receptor agonists that relax the fundus (see Chapter 13) are being
tested in patients with postprandial distress syndrome with early sati-
ation. Antacids are not generally helpful for the treatment of functional
dyspepsia.
Functional Esophageal Disorders
Functional esophageal disorders are disorders that cause esophageal
symptoms and that are diagnosed on the basis of negative results on
standard esophageal tests, thereby excluding structural disorders, motil-
ity disorders like achalasia, and GERD (Amarasinghe and Sifrim, 2014).
There are four of these fairly common disorders: (1) functional heartburn,
(2) functional chest pain, (3) functional dysphagia, and (4) globus. PPI
therapy (off-label use) as outlined previously is routinely used for the ini-
tial treatment of functional heartburn, functional chest pain, and globus.
As in functional dyspepsia, central mechanisms contribute to these disor-
ders and similar approaches follow for the treatment of functional heart-
burn and functional chest pain if PPI therapy is ineffective, including the
use of tricyclic antidepressants or selective serotonin reuptake inhibitors.
For the treatment of globus, gabapentin or pregabalin is used.
Acknowledgment: Laurence L. Brunton, Willemijntje A. Hoogerwerf, Pankaj
Jay Pasricha, and John L. Wallace contributed to this chapter in earlier edi-
tions of this book. We have retained some of their text in the current edition.
08/09/17 12:02 PM
 918
Drug Facts for Your Personal Formulary: Antisecretory Agents and
Gastroprotectives
Drugs Therapeutic Uses Clinical Pharmacology and Tips
Proton Pump Inhibitors
Dexlansoprazole • Gastroesophageal reflux disease • Generally well tolerated
• Erosive esophagitis • Possible interaction with clopidogrel (controversial)
• Increased incidence of osteoporosis-related fractures of hip, wrist, or spine
• Diarrhea
• Interstitial nephritis
• May cause cyanocobalamin (vitamin B12) deficiency with daily long-term use (>3 years)
Esomeprazole • Gastric ulcers • OTC forms for acid reflux
Lansoprazole • Duodenal ulcers • Generally well tolerated
Omeprazole • Erosive esophagitis • Possible interaction with clopidogrel (controversial)
Pantoprazole • Gastroesophageal reflux disease • Increased incidence of osteoporosis-associated fractures of hip, wrist, or spine
• Helicobacter pylori eradication • Diarrhea
• Zollinger-Ellison syndrome • Interstitial nephritis
• May cause cyanocobalamin (vitamin B12) deficiency with daily long-term use (>3 years)
CHAPTER 49 PHARMACOTHERAPY FOR GASTRIC ACIDITY, PEPTIC ULCERS, AND GERD

• Interactions with diagnostic investigations for neuroendocrine tumors

Rabeprazole • Gastroesophageal reflux disease • Generally well tolerated
• Helicobacter pylori eradication • Possible interaction with clopidogrel (controversial)
• Zollinger-Ellison syndrome • Increased incidence of osteoporosis-associated bone fractures of hip, wrist, or spine
• Diarrhea
• Interstitial nephritis
Histamine 2 Receptor Antagonists
Cimetidine • Gastric ulcer (to promote healing) • No longer recommend for treating active ulcers
Famotidine • Duodenal ulcer (to promote healing) • Generally well tolerated
Nizatidine • Gastroesophageal reflux disease
Ranitidine
Mucosal Defensive Agents
Misoprostol • Ulcer prophylaxis • Rarely used because of side effects
• Cannot be used in women of childbearing potential
• Diarrhea
• Marketed in combination with diclofenac
Sucralfate • Ulcer prophylaxis • Generally well tolerated
• Constipation
Antacids • Acid reflux • OTC; generally well tolerated
• Esophagitis • Na+ and AL+3 loads: potential problems in CV and renal disease

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