PHARMACOTHERAPY

OF
GASTROESOPHAGEAL
REFLUX DISEASE
(GERD)
FARMAKOTERAPI I

BY
JASTRIA PUSMARANI, S. FARM., M. SC.,
APT
JASTRIA PUSMARANI, M.SC.,APT 09/10/2017 1
• The stomach consists of three distinct
anatomical regions, each of which possesses
specialized functional processes
• The cardia, which is the uppermost portion of
the stomach at the junction between the
esophagus and stomach, is responsible for the
mucus secretion that protects against the acid
milieu of the stomach.
• The parietal cells, which are responsible for
gastric acid and intrinsic factor (required for
vitamin B12 absorption) secretion.
JASTRIA PUSMARANI, M.SC.,APT 09/10/2017 2
• the peptic (chief) cells, which secrete
pepsinogen (a precursor to pepsin).
• Pepsinogen, under acidic conditions in the
stomach, is converted to pepsin (a
proteolytic enzyme), which is responsible
for breaking down protein.
• The antrum makes up the final 10% to 20%
of the stomach.
• It contains the G cells, which secrete the
hormone gastrin, which through a
feedback mechanism stimulates acid
secretion by the parietal cell. 3
JASTRIA PUSMARANI, M.SC.,APT 09/10/2017
• Three stimuli (neurologic, physical, and
hormonal) trigger the parietal cell to
secrete acid.
• Neurologic impulses, from the central
nervous system (CNS) and initiated by the
sight, smell, and taste of food, travel along
cholinergic pathways to stimulate the
release of acetylcholine, which arrives via
nerve endings and activates the
muscarinic receptor on the parietal cell. 9
• Ingested food causes gastric distention,
which triggers the release of acetylcholine
and also stimulates G cells within the
antrum to produce gastrin.
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• Elevated intragastric pH also stimulates
the production of gastrin.
• Gastrin works via a feedback mechanism
which, although produced in response to
elevated pH, can be inhibited by low
gastric pH.
• The stomach is protected from
overproduction of gastric acid by the
release of somatostatin from antral D cells,
which signal the G cell to stop producing
gastrin.10
• Gastrin enters the blood and arrives at the
parietal cell, where it binds to the gastrin
receptor.
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• Acetylcholine and gastrin promote the release
of histamine from the mast cell which then bind
to the histamine H2-receptor on the parietal
cell.
• Histamine release is associated with both
postprandial and nocturnal acid secretion
• The gastrin, histamine H 2, and muscarinic
receptors are located on the basolateral
membrane of the parietal cell
• This activates the hydrogen-potassium
adenosine triphosphatase (H +/K+-ATPase) or
proton pump to move into position in the
secretory canaliculus located in the apical
membrane of the parietal cell.
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• The proton pump is an ion transport
pathway that transports hydrogen ions out
of the cytoplasm and into the secretory
canaliculus, where they are exchanged for
potassium ions that enter the parietal cell
via the opposite ion channel.
• In the secretory canaliculus, the hydrogen
ion combines with chloride from the blood
to form hydrochloric acid (HCl), which is
then released from the secretory
canaliculus into the gastric acid lumen. 11
• The proton pump is the final common
pathway for gastric acid secretion. 9,11
JASTRIA PUSMARANI, M.SC.,APT 09/10/2017 7
 GASTROINTESTINAL ANATOMIC
REGIONS

JASTRIA PUSMARANI, M.SC.,APT 09/10/2017 8

JASTRIA PUSMARANI, M.SC.,APT 09/10/2017 9
 DEFINITION
• Gastroesophageal reflux disease (GERD)
occurs when refluxed stomach contents lead to
troublesome symptoms and/or complications.
• Episodic heartburn that is not frequent or
painful enough to be bothersome
• Gastroesophageal reflux disease (GERD)
refers to symptoms or mucosal damage that
result from abnormal reflux of gastric contents
into the esophagus.
• Gastroesophageal reflux  the retrograde
movement of gastric contents from the
stomach into the esophagus.
JASTRIA PUSMARANI, M.SC.,APT 09/10/2017 10
• GERD can be divided into three distinct
categories: erosive esophagitis, non-erosive
reflux disease, and Barrett’s esophagus.

JASTRIA PUSMARANI, M.SC.,APT 09/10/2017 11

EROSIVE ESOPHAGITIS
• Erosive esophagitis occurs when the
esophagus is repeatedly exposed to
refluxed material for prolonged periods
• The inflammation that occurs
progresses to erosions of the squamous
epithelium.

JASTRIA PUSMARANI, M.SC.,APT 09/10/2017 12

NON-EROSIVE REFLUX
DISEASE
• Non-erosive reflux disease, also referred
to as “symptomatic”
• GERD or endoscopy-negative reflux
disease, is associated with severe reflux
symptoms with normal endoscopic
findings.

JASTRIA PUSMARANI, M.SC.,APT 09/10/2017 13

BARRETT’S ESOPHAGUS
• Barrett’s esophagus is more likely to
occur in patients with a long history
(years) of symptomatic reflux and may
be a risk factor for developing
adenocarcinoma of the esophagus.

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 PATHOPHYSIOLOGY
• The key factor is abnormal reflux of gastric
contents from the stomach into the
esophagus.
• In some cases, reflux is associated with
defective lower esophageal sphincter (LES)
pressure or function.
• Patients may have decreased LES pressure
from spontaneous transient LES
relaxations, transient increases in
intraabdominal pressure, or an atonic
LES.
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 NEXT...
• Problems with other normal mucosal
defense mechanisms may contribute to
development of GERD, including :
• abnormal esophageal anatomy,
• improper esophageal clearance of gastric
fluids,
• reduced mucosal resistance to acid,
• delayed or ineffective gastric emptying,
• inadequate production of epidermal
growth factor, and
• reduced salivary buffering of acid.
JASTRIA PUSMARANI, M.SC.,APT 09/10/2017 16
 NEXT...
• Esophagitis occurs when the esophagus is
repeatedly exposed to refluxed gastric
contents for prolonged periods  erosion of
the squamous epithelium of the esophagus
(erosive esophagitis).
• Substances that promote esophageal
damage upon reflux into the esophagus
include gastric acid, pepsin, bile acids, and
pancreatic enzymes.
• Complications from long-term acid exposure
include esophagitis, esophageal strictures,
Barrett esophagus, and esophageal
JASTRIA PUSMARANI, M.SC.,APT 09/10/2017 17
adenocarcinoma
JASTRIA PUSMARANI, M.SC.,APT 09/10/2017 18
ENDOSCOPIC IMAGES OF THE
ESOPHAGUS

JASTRIA PUSMARANI, M.SC.,APT 09/10/2017 19

 CLINICAL PRESENTATION
• Symptom-based GERD (with or without
esophageal tissue injury) typically presents
with heartburn, usually described as a
substernal sensation of warmth or burning
rising up from the abdomen that may radiate
to the neck.
• It may be waxing and waning in character and
aggravated by activities that worsen reflux
(eg, recumbent position, eating a high-fat
meal).
• Other symptoms are:
• water brash (hypersalivation),
• belching, and
JASTRIA PUSMARANI, M.SC.,APT
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09/10/2017
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ALARM SYMPTOMS THAT MAY INDICATE
COMPLICATIONS
• Dysphagia,
• Odynophagia,
• Bleeding, and
• Weight loss.

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GOALS OF TREATMENT
• The goals 
• Reduce or eliminate symptoms,
• Decrease frequency and duration of
gastroesophageal reflux,
• Promote healing of injured mucosa,
and
• Prevent development of
complications.

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• Therapy is directed toward:
decreasing 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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THERAPY
• Non Pharmacology
• Pharmacology

JASTRIA PUSMARANI, M.SC.,APT 09/10/2017 25

 NONPHARMACOLOGIC TREATMENT OF
GERD WITH LIFESTYLE MODIFICATIONS
• Elevate the head of the bed (increases
esophageal clearance).
• Use 6- to 8-inch blocks under the head of
the bed.
• Sleep on a foam wedge
• Dietary changes
• Avoid foods that may decrease lower
esophageal sphincter pressure (fats,
chocolate, alcohol, peppermint, and
spearmint)
JASTRIA PUSMARANI, M.SC.,APT 09/10/2017 26
 NEXT...
• Avoid foods that have a direct irritant effect on
the esophageal mucosa (spicy foods, orange
juice, tomato juice, and coffee)
• Include protein-rich meals in diet (augments
lower esophageal sphincter pressure)
• Eat small meals and avoid eating immediately
prior to sleeping (within 3 h if possible)
(decreases gastric volume)
• Weight reduction (reduces symtoms)
• Stop smoking (decreases spontaneous
esophageal sphincter relaxation)
• Avoid alcohol
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THERAPY PHARMACOLOGY
• Pharmacotherapy of Drugs used to Treat
Acid-Related Disorders
 Antacids and Alginic Acid
 H2-Receptor Antagonists
 Proton Pump Inhibitors
 Sucralfate
 Misoprostol
 Bismuth Salts

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JASTRIA PUSMARANI, M.SC.,APT 09/10/2017 29
 Antacids and Alginic Acid
• Antacids  used to relieve mild and
infrequent symptoms associated with acid-
related diseases.
• They act  by neutralizing gastric acid and
thus increasing intragastric pH.
• Antacids are very quick acting and
modestly elevate intragastric pH within
minutes, but their duration of action is
short (about 30 minutes on an empty
stomach).
• The duration of action can be extended to
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• Antacids are available as individual salts or as
combination of salts of magnesium, aluminum,
calcium, or sodium.
• Aluminum- and magnesium-containing salts are
also able to bind bile salts. 12
• Aluminum salts may enhance mucosal protection
by increasing mucosal prostaglandins,
stimulating mucus and bicarbonate secretion
and enhancing microvascular blood flow.
• Antacids also inhibit the action of pepsin.

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H2-RECEPTOR ANTAGONISTS
• H2-Receptor Antagonists
• cimetidine,
• ranitidine,
• famotidine, and
• Nizatidine
• H2RAs  competitively and selectively
inhibit the action of histamine on the H 2
receptors of the parietal cells, thus
reducing both basal and stimulated
gastric acid secretion
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• Oral absorption from the small intestine is rapid,
and peak drug concentrations usually are
achieved within 1 to 3 hours after administration
• Cimetidine has demonstrated weak
antiandrogenic effects, and
• its use in high doses (hypersecretory
conditions)  gynecomastia and impotence in
men.
• H2RAS + KETOCONOZALOE Failure antifungi of
ketoconazole

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PROTON PUMP INHIBITORS
• PPIs are highly specific inhibitors of
gastric acid secretion and
• PPIs
• omeprazole,
• lansoprazole,
• rabeprazole,
• pantoprazole, and esomeprazole.

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• Potential long-term adverse effects 
• enteric infections,
• vitamin B12 deficiency,
• hypomagnesemia, and
• bone fractures.
• PPIs + ketoconazole or itraconazole
• can decrease the absorption ketoconazole
or itraconazole
• Patients should take oral PPIs in the morning
15 to 30 minutes before breakfast or their
largest meal of the day to maximize
efficacy,  inhibit actively secreting proton
pumps.
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• PPIs have been associated with an
increased risk of infections (e.g.,
pneumonias, enteric infections) possibly
due to the ability of the microorganisms
ability to survive in a less acidic
environment.
• Long-term PPI use in older patients on high
dosages increased risk of hip fractures 
inhibition of calcium absorption by PPI-
induced hypochlorhydia
• A decrease in vitamin B12 (cyanocobalamin)
 in patients with long-term PPI use
because gastric acid is required to
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MUCOSAL PROTECTANTS
• Sucralfate, a nonabsorbable aluminum salt
of sucrose octasulfate
• Sucralfate  promotes gastric mucosal
protection by shielding ulcerated tissue
from aggressive factors such as acid,
pepsin, and bile salts.
• The drug has minimal systemic absorption
and does not possess antisecretory
activity.

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• Sucralfate may also have other protective
actions related to the stimulation of
mucosal prostaglandins.
• The bioavailability of oral fluoroquinolones,
warfarin, phenytoin, levothyroxine,
ketoconazole, amitriptyline, and
theophylline may be reduced when
concomitantly administered with
sucralfate.
• Because of these interactions, sucralfate
should be given at least 2 hours after
these medications.
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MISOPROSTOL
• Misoprostol, a synthetic prostaglandin E 1
analog, is the only prostaglandin analog
• Misoprostol acts primarily by enhancing
mucosal defense mechanisms.9
• It produces cytoprotective effects by
• stimulating the production of mucus and
bicarbonate,
• improving mucosal blood flow, and
• reducing mucosal cell turnover similar to
the effects of endogenous prostaglandin.
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• Misoprostol also produces a dose-dependent
inhibition of gastric acid, but even at high
doses, it is less than that of the H 2RAs.
• The use of misoprostol is limited because of
its potential to cause a dose-dependent
diarrhea (in up to 30% of patients) and
abdominal cramping.9
• Taking the drug with meals may help to
reduce the diarrhea.
• Misoprostol is an abortifacient because of its
uterotrophic effects.
• it is contraindicated in women who are
pregnant who take it for a GI indication
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