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Chapter 32: Pharmacotherapy of Gastric Acidity, Peptic Ulcers, and Gastroesophageal

Reflux Disease

INTRODUCTION
This chapter will be most useful after having a basic understanding of the material in Chapter 45, Pharmacotherapy
of Gastric Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease in Goodman & Gilman's The Pharmacological
Basis of Therapeutics, 12th Edition. In addition to the material presented here, the 12th Edition contains:

A description of the physiology of gastric secretion

Therapeutic strategies for the treatment of specific acid-peptic disorders

Table 45-2 which shows the composition and acid neutralizing capacities of popular antacid preparations

LEARNING OBJECTIVES

Identify the sites in the gastric parietal cell where drugs act to suppress acid secretion.

Describe the mechanism of action of proton pump inhibitors, H2 receptor antagonists, and
prostaglandin analogs to suppress gastric acid secretion.

Describe the limitations to the use of H2 receptor antagonists in chronic acid suppression.

Identify potential drug interactions with proton pump inhibitors and H 2 receptor antagonists.

Describe the mechanism of action of drugs that enhance gastric cytoprotection.

Describe the recommendations for therapy of gastroesophageal reflux disease (GERD) and
peptic ulcer disease.

Understand the role of Helicobacter pylori infection in peptic ulcer disease and the therapeutic
principles for its eradication.

Describe appropriate therapy for NSAID-induced ulcers.

DRUGS INCLUDED IN THIS CHAPTER

Cimetidine (TAGAMET, others)
Famotidine (PEPSID, others)
Nizatidine (AXID, others)
Rabeprazole (ACIPHEX)

Dexlansoprazole (KAPIDEX)
Lansoprazole (PREVACID)
Omeprazole (PRILOSEC, others)
Ranitidine (ZANTEC, others)

Esomeprazole (NEXIUM)
Misoprostol (CYTOTEC)
Pantoprazole (PROTONIX)
Sucralfate (CARAFATE, others)

MECHANISMS OF ACTION OF DRUGS USED TO TREAT GASTRIC ACID

DISEASES
DRUG CLASS

H2 Receptor
Antagonists

Proton Pump
Inhibitors

DRUGS

MECHANISM OF ACTION

Cimetidine
Ranitidine
Famotidine
Nizatidine

Competes with histamine for binding to H2 receptors on the

basolateral membrane of parietal cells (see Figure 32-1)

Lansoprazole

The activated form binds covalently with sulfhydryl groups

on cysteine in the H+,K+-ATPase located on the luminal
membrane of the parietal cell to suppress acid secretion
(see Figure 32-1)

Pantoprazole
Omeprazole

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DRUG CLASS

DRUGS

MECHANISM OF ACTION

Esomeprazole
Dexlansoprazole
Rabeprazole

Prostaglandin
Analog
Cytoprotective
Agent

Misoprostol
Sucralfate

Binds to the EP3 receptor on parietal cells decreasing cyclic AMP

and gastric acid secretion (see Figure 32-1)
Forms a viscous, sticky polymer that adheres to epithelial cells
and ulcer craters and is cytoprotective

Antacids

Various over-theNeutralize gastric acid

counter (OTC) products

Bismuth

Various OTC products

Binds to the base of ulcers and promotes mucin and

bicarbonate production

CASE 32-1
A 42-year-old woman is seen because of worsening heartburn during the past week. She was
first diagnosed with GERD 1 month ago and treatment was begun with cimetidine 400 mg
once daily. Two weeks later the cimetidinedosage was increased to 400 mg twice daily.

a. What is the reason for the worsening of her GERD symptoms?

Cimetidine is an H2 receptor antagonist and tolerance to acid suppressing effects of
these drugs has been shown to develop as early as 2 to 5 days after beginning
treatment. One mechanism for this phenomenon is secondary to the
hypergastrinemia that stimulates histamine release and overcomes the H2 receptor
blockade.
b. What are the mechanisms of action of H2 receptor blockers and proton
pump inhibitors?
The mechanisms of action of these drugs is shown in Figure 32-1. The H2 receptor
blockers suppress gastric acid secretion by competing with histamine for binding to
H2 receptors on the basolateral membrane of parietal cells. The structural similarity
of the H2 receptor antagonists and histamine is shown in Figure 32-2.
The proton pump inhibitors are prodrugs that require activation in an acid
environment (see Figure 32-3). The activated form binds covalently with sulfhydryl
groups on cysteine in the H+,K+-ATPase located on the luminal membrane of the
parietal cell. Despite the short plasma half-lives (0.5-2 h) of the parent drug, acid
suppression continues for 24 to 48 hours or until new pump molecules are
synthesized.

c. What is a rational approach to her treatment?

A rational choice would be to switch her to a proton pump inhibitor. Although these
drugs can also cause a hypergastrinemia, it does not result in tolerance because the
inhibition occurs at the H+,K+-ATPase which is the final step in gastric acid
secretion. Figure 32-4 shows the general guidelines for medical management of
GERD.

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d. If the patient is switched to a proton pump inhibitor, of what adverse

effects should she be warned?
Proton pump inhibitors are metabolized by hepatic CYPs and they may interfere with
the elimination of other drugs cleared by this route. Chronic treatment with proton
pump inhibitors decreases the absorption of vitamin B12. The loss of gastric acidity
may affect the bioavailability of drugs, most notably iron salts. This may result in an
iron deficiency anemia.

FIGURE
32-4
General
guidelines
for the
medical

management of gastroesophageal reflux disease (GERD). Only medications that suppress

acid production or that neutralize acid are shown.
CASE 32-2
A 56-year-old man is diagnosed with duodenal ulcer complicated by H. pylori infection. He
has been treated with amoxicillin for 2 weeks, but his symptoms of stomach pain persist.

a. Why has his therapeutic regimen not been effective? What

problems might be the result of this therapeutic regimen?
H. pylori, a gram negative rod, has been associated with gastritis and subsequent
development of gastric and duodenal ulcers, gastric adenoma, and gastric B-cell

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lymphoma. Single antibiotic therapy for H. pyloriinfection is not effective for

eradication and may result in bacterial resistance that is more difficult to treat than
the initial infection.

b. What would you recommend for the treatment of his condition?

A common therapeutic approach would be to use a proton pump inhibitor
plus clarithromycin plus eithermetronidazole or amoxicillin for 14 days. Another
common approach would be to use a proton pump inhibitor
plus metronidazole plus bismuth plus tetracycline.

c. What is the most common problem observed with your

recommended regimen?
The most common problem observed with these therapeutic regimens is poor patient
compliance due to the number of medications that must be taken each day and to
medication-related side effects.
Table 32-1 Therapy of Helicobacter pylori Infection
Triple therapy 14
days: Proton pump inhibitor
+ clarithromycin 500 mg
plus metronidazole 500 mg
oramoxicillin 1 g twice a day
(tetracycline 500 mg can be
substituted
for amoxicillin or metronidazole
)

Quadruple therapy 14
days: Proton pump inhibitor
twice a day
+ metronidazole 500 mg three
times daily
plusbismuth subsalicylate 525
mg + tetracycline 500 mg four
times daily

H2 receptor antagonist twice a

day plus bismuth subsalicylate
525 mg + metronidazole 250
mg + tetracycline500 mg four
times daily

DOSAGES:
Proton pump inhibitors:
Omeprazole: 20 mg
Lansoprazole: 30 mg
Rabeprazole: 20 mg
Pantoprazole: 40 mg
Esomeprazole: 40 mg

H2 receptor antagonists:
Cimetidine: 400 mg
Famotidine: 20 mg
Nizatidine: 150 mg
Ranitidine: 150 mg

CASE 32-3
A 64-year-old man is referred because of stomach pain. He has been
diagnosed with osteoarthritis and has been taking a COX-1 inhibitor for the
past 3 months. Workup shows that he has a duodenal ulcer that you suspect
is a result of his NSAID use.
a. Describe the pathogenesis of NSAID-induced ulcers.
NSAIDs diminish prostaglandin formation by inhibiting cyclooxygenase. This effect
can result in enhanced gastric acid secretion (prostaglandins may lower gastric acid
secretion). In addition, prostaglandins stimulate gastric mucin production that
provides a cytoprotective effect to the gastric mucosa which is diminished by NSAIDs.

b. What are your therapeutic options?

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One option is to change this patient to an NSAID that is a selective inhibitor of COX-2,
although this may not completely eliminate the risk of ulcer formation. Another
option is to try misoprostol although it has numerous gastrointestinal side effects and
4-times-daily dosing is inconvenient. Finally, NSAID-induced ulcers can be managed
with acid suppression using either an H2 receptor antagonist or proton pump inhibitor.
Proton pump inhibitors can effectively heal active ulcers and prevent recurrence in
the setting of continued NSAID administration.

KEY CONCEPTS

Proton pump inhibitors are superior to H2 receptor antagonists for acid suppression in
patients with GERD and peptic ulcers.

Tolerance to the acid-suppressing effects of the H2 receptor antagonists is commonly

observed and limits their continuous use.

H. pylori is effectively eradicated with a combination of acid-suppressing drugs and

multiple antibiotics administered for 10 to 14 days.

NSAID-induced ulcers can be effectively treated with a proton pump inhibitor even
during continued NSAID administration.

SUMMARY: DRUGS USED TO TREAT GASTRIC ACIDITY, PEPTIC ULCERS, AND GASTROESOPHAGEAL REFLUX
DISEASE

CLASS AND
SUBCLASSES

H2 Receptor
Antagonists

NAMES

Cimetidine
Ranitidine

Diarrhea,
Promote healing headache,
drowsiness,
of gastric and
duodenal ulcers, fatigue,
muscular
treatment of
uncomplicated pain, and
constipation
GERD, and to
prevent
occurrence of
Tolerance
stress ulcers
occurs with
long-term use

Same
as cimetidine
Same
Nizatidine
as cimetidine
Treatment of
Omeprazole gastric and
duodenal ulcers
Famotidine

Proton Pump
Inhibitors

CLINICAL USES

TOXICITIES
UNIQUE;
COMMON
CLINICALLY
IMPORTANT

Same
as cimetidine
Same
as cimetidine
Nausea,
flatulence,
abdominal

Inhibition of hepatic
CYPs Delirium and
confusion with IV use
in elderly patients
Gynecomastia in men
Galactorrhea in
women

No inhibition of
hepatic CYPs
No inhibition of
hepatic CYPs
Metabolized by
hepatic CYPs and may

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CLASS AND
SUBCLASSES

NAMES

CLINICAL USES

TOXICITIES
UNIQUE;
COMMON
CLINICALLY
IMPORTANT

Esomeprazol
e
Lansoprazole

and GERD

pain,
constipation

Pantoprazole
Rabeprazole

Prostaglandin
Misoprostol
Analog

Cytoprotective
Sucralfate
Agents

Bismuth

Prevention of
NSAID-induced
mucosal injury

Treatment of
peptic ulcer
disease

Diarrhea

affect other drugs that

are metabolized by
hepatic CYPs
Decreased absorption
of folic acid, vitamin
B12, and iron salts

Clinical exacerbation
of inflammatory bowel
disease
Contraindicated in
pregnancy

Avoid in patients with

renal failure
Constipation

May inhibit the

absorption of other
drugs

Treatment of
peptic ulcer
Bismuth subsalicylate
particularly in
Black tongue
OTC products
is associated with
patients with H. and stools
salicylate poisoning
pyloriinfection
(see Table 32-1)