Antonius Nugraha Widhi Pratama, Apt.

Bag Farmasi Klinik dan Komunitas

Fakultas Farmasi
Universitas Jember
 Reference:
Koda-Kimble, M.A., 2008. Applied
therapeutics: the clinical use of
drugs. Lippincott Williams &
Wilkins.

DiPiro, J.T., Talbert, R.L., Yee, G.C.,

Matzke, G.R., Wells, B.G., Posey,
L.M., 2008. Pharmacotherapy: A
Pathophysiologic Approach.
McGraw-Hill Medical.

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 Section 1

INTRODUCTION

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 Introduction
Common medical Exposure of refluxed material,
disorder in various long period
specialties
GERD: symptoms or
mucosal damage that
results from abnormal Inflammation of the esophagus
(reflux esophagitis)
reflux of the stomach
contents into the
esophagus.
In some cases progress to
erosive esophagitis

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 Introduction

Atypical (or extraesophageal) GERD: GER

associated with disease processes in organs other
than the esophagus, such as the lungs or larynx.

Severe reflux symptoms associated with normal

endoscopic findings are referred to as
“symptomatic GERD,” nonerosive reflux disease
(NERD), or endoscopy-negative reflux disease
(ENRD).

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 Introduction

Complications of long-term reflux may include the

development of strictures, Barrett’s esophagus, or
adenocarcinoma of the esophagus.

Many patients suffering from mild GERD do not go

on to develop erosive esophagitis and are often
managed with lifestyle changes, antacids, and
nonprescription histamine-2 (H2)-receptor
antagonists or nonprescription proton pump
inhibitors.

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 Epidemiology

GERD occurs in all ages, most common: older than

age 40 years.
Mortality associated with GERD is rare, BUT give
significant impact on quality of life.

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 Pathophysiology

The key factor in the development of GERD is the

abnormal reflux of gastric contents from the
stomach into the esophagus.

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 Pathophysiology

In some cases, gastroesophageal reflux is associated

with defective lower esophageal sphincter (LES)
pressure or function.
 Decrease in gastroesophageal sphincter (LES) pressures
related to
a) spontaneous transient LES relaxations,
b) transient increases in intraabdominal pressure, or
c) an atonic LES, all of which may lead to the development
of gastroesophageal reflux.

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 Pathophysiology

Problems with other normal mucosal defense

mechanisms, such as anatomic factors, esophageal
clearance, mucosal resistance, gastric emptying,
epidermal growth factor, and salivary buffering, may
also contribute to the development of GERD.
Aggressive factors:
 gastric acid,
 pepsin,
 bile acids, and
 pancreatic enzymes.

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 Complications

Several complications:
 esophageal strictures,
 Barrett’s esophagus, and
 adenocarcinoma of the esophagus.

May lead to esophageal bleeding

 the blood loss is usually chronic and low grade in nature,
 anemia may occur.

NSAID or aspirin: additional risk factor to the

development or worsening of GERD complications.
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 Complications
Esophageal stricture,
common in the distal
esophagus and are
generally 1 to 2 cm in
length

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 Complications
Barrett’s esophagus:
the reparative process
Replacement of the
squamous epithelial
lining of the esophagus
by specialized
columnar-type
epithelium.
More likely to occur in
those patients with a
long history (years) of
symptomatic reflux.
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 Complications

Cancer of esophagus

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 Clinical Presentations

Type of symptoms: (a) typical, (b) atypical, or (c)

alarm.
The severity of the symptoms
 does not always correlate with the degree of esophagitis,
 does correlate with the duration of reflux.
Patients with nonerosive disease may have
symptoms as severe as those with endoscopic
findings.

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 Clinical Presentations: Symptoms

Typical symptoms Atypical symptoms Alarm symptoms

• May be aggravated by • In some cases, these • These symptoms may

activities that worsen extraesophageal be indicative of
gastroesophageal symptoms may be the complications of GERD
reflux such as only symptoms such as Barrett’s
recumbent position, present, making it esophagus, esophageal
bending over, or eating more difficult to strictures, or
a meal high in fat. recognize GERD as the esophageal cancer.
• Heartburn cause, especially when • Continual pain
• Water brash endoscopic studies are • Dysphagia
(hypersalivation) normal.
• Odynophagia
• Belching • Nonallergic asthma
• Unexplained weight
• Regurgitation • Chronic cough loss
• Hoarseness • Choking
• Pharyngitis
• Chest pain
• Dental erosions

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 Clinical Presentations: Diagnosis

Useful tests in diagnosing GERD include

 endoscopy,
 ambulatory reflux monitoring, and
 manometry.

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 Clinical Presentations: Diagnosis

Endoscopy: preferred technique for assessing

 esophagitis,
 Identifying Barrett’s esophagus, and
 diagnosing complications.
Enables visualization and biopsy of the esophageal
mucosa.
Highly specific test, BUT not extremely sensitive.
 In mild cases of GERD, the esophageal mucosa may
appear relatively normal.
 In addition, noninflammatory GERD and major motor
disorders may be missed by endoscopy.

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 Section 2

TREATMENT

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 Desired Outcomes

Reversing the various pathophysiologic

abnormalities.
Goals:
 alleviate or eliminate the patient’s symptoms;
 decrease the frequency or recurrence and duration of
gastroesophageal reflux;
 promote healing of the injured mucosa; and
 prevent the development of complications.

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 Desired Outcomes

Specifically, therapy is directed at

 decreasing the acidity of the refluxate;
 decreasing the gastric volume available to be refluxed;
 improving gastric emptying;
 increasing LES pressure;
 enhancing esophageal acid clearance; and
 protecting the esophageal mucosa.

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 General Approach to Treatment

The treatment of GERD is categorized into one of

the following modalities:
 lifestyle modifications and patient-directed therapy with
antacids, nonprescription H2-receptor antagonists, and/or
nonprescription proton pump inhibitors;
 pharmacologic intervention with prescription-strength
acid suppression therapy; and
 interventional therapies (antireflux surgery or endoscopic
therapies).

Evidence-based treatment recommendations – see

Dipiro, JT, 2008
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 General Approach to Treatment
Step-up Approach
 Starting with noninvasive
lifestyle modifications and
patient-directed therapy,
and progressing to
pharmacologic
management or
interventional approaches.
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Step-down Approach
 Starting with a proton
pump inhibitor given once
or twice daily instead of an
H2-receptor antagonist,
and then stepping down to
the lowest degree of acid
suppression needed to
control symptoms, is also
effective.
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 General Approach to Treatment

Patients do not respond to lifestyle modifications

and patient directed therapy after 2 weeks? 
medical attention and are generally started on
empiric therapy consisting of an acid-suppression
agent.

Promotility agents are not as effective as acid-

suppression agents. The availability of a promotility
agent that has an acceptable adverse effect profile is
lacking.

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 General Approach to Treatment

Promotility agents + acid-suppression drugs  only

modest improvements in symptoms over standard
doses of H2-receptor antagonists and should not be
routinely recommended.

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 General Approach to Treatment

Mucosal protectants, such as sucralfate, have a very

limited role in the treatment of GERD.
Maintenance therapy is generally necessary to
control symptoms and to prevent complications.
GERD that is refractory to adequate acid
suppression is rare. In these cases, the diagnosis
should be confirmed through further diagnostic
tests before longterm, high-dose therapy or
interventional approaches (antireflux surgery or
endoscopic therapies) are considered.

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 Nonpharmacologic Therapy

Lifestyle Modifications
A patient should be educated about include
 weight loss;
 elevation of the head of the bed;
 consumption of smaller meals and not eating 3 hours prior
to sleeping;
 avoidance of foods or medications that exacerbate GERD;
 smoking cessation; and
 avoidance of alcohol

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 Nonpharmacologic Therapy

Interventional Approaches
Surgical intervention is a viable maintenance
alternative for selected patients with well-
documented GERD.
Goal of antireflux surgery:
 to reestablish the antireflux barrier,
 to position the lower esophageal sphincter within the
abdomen where it is under positive (intraabdominal)
pressure, and
 to close any associated hiatal defect.

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 Nonpharmacologic Therapy

Interventional Approaches: Endoscopic Therapies

Several new endoscopic approaches for the
management of GERD include endoscopic sewing
devices and endoluminal application of
radiofrequency heat energy resulting in tissue injury
or nerve ablation (the Stretta procedure). These
techniques are FDA-approved, but their exact role in
the management of GERD has yet to be determined.

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 Pharmacologic Therapy

Patient-directed therapy with nonprescription

antacids, H2-receptor antagonists, or proton pump
inhibitors and
Prescription-strength acid suppression therapy or
promotility medications.

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 Pharmacologic Therapy

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Pharmacologic Therapy: Nonprescription Drugs

Patient-directed therapy
Nonprescription H2-receptor antagonists
 cimetidine, famotidine, nizatidine, and ranitidine
 effective in lowering gastric acid when taken prior to
meals and decrease GERD symptoms associated with
exercise.
 much longer duration of action compared with antacids.
Antacids: slightly faster onset of action,
PPI omeprazole: a dose of 20 mg per day is indicated
for short-term (14 days) treatment of heartburn.

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Pharmacologic Therapy: Acid Suppression Therapy

H2-Receptor Antagonists (Cimetidine, Famotidine,

Nizatidine,and Ranitidine)
H2-receptor antagonists in divided doses are
effective in treating patients with mild to moderate
GERD. The majority of the trials assessing the
efficacy of standard doses of H2-receptor
antagonists indicate that symptomatic
improvement is achieved in an average of 60% of
patients after 12 weeks of therapy. However,
endoscopic healing rates tend to be lower, an
average of 50%.

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Pharmacologic Therapy: Acid Suppression Therapy

H2-Receptor Antagonists (Cimetidine, Famotidine,

Nizatidine,and Ranitidine)
Because all of the H2-receptor antagonists have
similar efficacy, selection of the specific agent to use
in the management of GERD should be based on
factors such as differences in pharmacokinetics,
safety profile, and cost. In general, the H2-receptor
antagonists are well tolerated.

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Pharmacologic Therapy: Acid Suppression Therapy

Proton Pump Inhibitors (Esomeprazole,

Lansoprazole,Omeprazole, Pantoprazole, and
Rabeprazole)
PPI superior to H2RA in treating moderate to severe
GERD.
FDA-approved doses (per day) of proton pump
inhibitors are omeprazole 20 mg, esomeprazole 20
mg, lansoprazole 30 mg, rabeprazole 20 mg, and
pantoprazole 40 mg.
Symptomatic relief is seen in approximately 83% of
patients after 8 weeks treated with a proton pump
inhibitor, whereas the endoscopic healing rate at 8
weeks is 78%.
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Pharmacologic Therapy: Acid Suppression Therapy

A few trials have compared proton pump inhibitors

to each other. In general, healing rates at 4 weeks
and 8 weeks are similar; lansoprazole and
rabeprazole, however, may relieve symptoms faster
after the first dose when compared to omeprazole.
The proton pump inhibitors are usually well
tolerated; however, potential adverse effects include
headache, dizziness, somnolence, diarrhea,
constipation, nausea, and vitamin B12 deficiency.

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Pharmacologic Therapy: Acid Suppression Therapy

Drug interactions with omeprazole are of particular

concern in patients who are considered “slow
metabolizers,” which is more common in the Asian
population, but also found in approximately 3% of
the caucasian population. Like omeprazole, the
metabolism of esomeprazole may also be altered in
patients with this polymorphic gene variation.
Patients on potentially interacting drugs, such as
warfarin, should be monitored closely for potential
problems.

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Pharmacologic Therapy: Acid Suppression Therapy

The proton pump inhibitors degrade in acidic

environments and are therefore formulated in a
delayed-release capsule or tablet formulation.
Lansoprazole, esomeprazole, and omeprazole
contain enteric-coated (pH-sensitive) granules in a
capsule form.
For patients who are unable to swallow the capsule,
or for pediatric patients, the contents of the
delayed-release capsule can be mixed in applesauce
or placed in orange juice. If a patient has a
nasogastric tube, the contents of an omeprazole
capsule can be mixed in 8.4% sodium bicarbonate
solution.
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Pharmacologic Therapy: Acid Suppression Therapy

The newest dosage form is omeprazole in a

nonprescription delayed-release tablet and a
combination product with sodium bicarbonate in an
immediate-release capsule and oral suspension
(Zegerid).

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Pharmacologic Therapy: Acid Suppression Therapy

Patients should be instructed to take their proton

pump inhibitor in the morning, 15 to 30 minutes
before breakfast, to maximize efficacy, because
these agents inhibit only actively secreting proton
pumps.
Patients with nocturnal symptoms may benefit from
taking their proton pump inhibitor prior to the
evening meal. If dosed twice daily, the second dose
should be administered approximately 10 to 12
hours after the morning dose and prior to a meal or
snack.

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 Pharmacologic Therapy: Promotility Agents

Promotility agents may be useful as an adjunct to

acid suppression therapy in patients with a known
motility defect (e.g., LES incompetence, decreased
esophageal clearance, delayed gastric emptying).
Unfortunately, all available promotility agents are
fraught with undesirable side effects and are not
generally as effective as acid suppression therapy.
Extrapyramidal effects, sedation, and irritability are
common with bethanechol and metoclopramide.
Cisapride, Metoclopramide, Bethanechol

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 Pharmacoeconomic Considerations

The proton pump inhibitors are generally more

expensive than the H2-receptor antagonists or
promotility agents. Omeprazole’s generic and over-
the-counter availability makes this less of an issue.
However, the most expensive therapy is the one
that is ineffective. If the H2-receptor antagonist
does not accomplish the treatment goals, then it
costs more because the patient must be retreated.

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 Pharmacoeconomic Considerations

Decision analysis has been used to evaluate the

cost-effectiveness of lifestyle modifications and/or
patient-directed therapy alone or combined with
omeprazole 20 mg daily or ranitidine 150 mg twice
daily for patients with persistent symptomatic
GERD.
Although the retail cost of omeprazole was highest
among the treatments evaluated, it was the most
cost-effective strategy and was associated with the
lowest overall cost. Studies also show that proton
pump inhibitors improve quality-of-life measures in
symptomatic patients with erosive esophagitis.
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 Conclusions

Gastroesophageal reflux disease is a common

disease that classically presents as heartburn. The
pathophysiology of reflux is complex, involving both
aggressive factors (acid, pepsin, bile acids,
pancreatic enzymes, and prostaglandins) and
defense mechanisms (anatomic factors, LES
pressure, esophageal clearance, and gastric
emptying).
Therapeutic modalities are designed to minimize
the aggressive factors and/or augment the defense
mechanisms.

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 Section 3

SPECIAL POPULATIONS

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 Pediatric Patients with GERD

± 18% of the infant population

Promotility agent + acid suppression agent  work
the fastest
 Promotility agent: metoclopramide
 Unfortunately, cisapride removed from market

 Acid supressor: ranitidine 2 mg/kg BID

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 Pediatric Patients with GERD

PPI: lansoprazole vs omeprazole?

Lanzoprazole
 15 mg OD for <=30kg
 30 mg OD for > 30 kg
 Indicated for treating symptomatic and erosive GERD in
pediatric patients (> 1 year)
Omeprazole
 1 mg/kg/day OD or BID
 Not FDA approved for use in children, but has evidence

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 Elderly/Geriatric Patients with GERD

Decreased host defense mechanisms, such as saliva

production
Often these patients do not seek medical attention
because they feel their symptoms are part of the
normal aging process

They may present with atypical symptoms such as

chest pain, asthma, hoarseness, coughing,
wheezing, poor dentition, or jaw pain. Decreased GI
motility is a common problem in elderly patients.

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 Elderly/Geriatric Patients with GERD

No good promotility agent available

 Cisapride removed
 Metoclopramide: bad CNS effect
H2RA  bad CNS effect
PPI
 Once daily
 most useful treatment, especially beneficial in the elderly

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