Gastroenterology - 01. Gastroesophageal Reflux Disease (Courses in Therapeutics and Disease State Management).ppt

Author: Monica L. Skomo, B.S., Pharm.D., BCACP, CTTS; Assoc. Prof. of Pharmacy Practice; Dir. of Assessment and Educational Strategies; Duquesne University School of Pharmacy
http://accesspharmacy.mhmedical.com/LearningModuleGroup.aspx?id=8
Copyright © 2017 McGraw-Hill Education. All rights reserved
Gastroenterology:
Gastroesophageal Reflux Disease
Courses in Therapeutics and Disease State Management

Learning Objectives (Slide 1 of 2)
• Define GERD and describe the various stages of disease severity
• Describe the etiology of GERD and risk factors associated with
the disease
• Discuss typical symptoms, atypical symptoms, alarm symptoms,
aggravating factors and complications associated with GERD
• Describe how GERD is diagnosed and the role of endoscopy
• Discuss the various pharmacologic approaches for the treatment
of GERD

Learning Objectives (Slide 2 of 2)
• Review the roles of the H2-antagonists and proton pump inhibitors
in the treatment of GERD and prevention of its recurrence
• Describe non-pharmacologic and lifestyle measures that may be
beneficial in the reduction of symptoms of reflux disease
• Given a GERD patient history, be able to recommend appropriate
pharmacologic and nonpharmacologic therapies and explain the
rationale behind your decision
• Discuss drug adverse effects and monitoring parameters for drugs
and GERD

Required and Recommended Reading
May D, Thiman M, Rao SC. Gastroesophageal Reflux
Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR,
Wells BG, Posey L. eds. Pharmacotherapy: A
Pathophysiologic Approach, 10e New York, NY: McGraw-
Hill; 2017.

GERD Definitions
• GERD (Gastroesophageal Reflux Disease)
– A condition that occurs when refluxed stomach contents lead to troublesome symptoms
and/or complications
– Episodic pyrosis (heartburn) that is not frequent enough or painful enough to be
considered bothersome by the patient is not included in the above consensus GERD
definition
• Pyrosis frequency of more than 2 times per week is sometimes used as a criteria for GERD
• Chronic symptoms or mucosal damage produced by the abnormal reflux of gastric
contents into the esophagus.
• Symptoms of GERD vary in severity, duration, and frequency.
• When the esophagus is repeatedly exposed to refluxed material for prolonged
periods of time, inflammation of the esophagus (esophagitis) occurs, and in some
cases it can progress to erosion of the squamous epithelium of the esophagus
(erosive esophagitis) and may lead to other complications.

Epidemiology (Slide 1 of 2)
• Heartburn is the most frequent clinical complaint
– Reported to occur at least once daily in 10%
– 20% weekly;
– 44% monthly of U.S. adults
– $5 billion for OTC/Rx per year
• Most frequently occurs in adults over 40 years of age
• Incidence in similar between men and women

Epidemiology (Slide 2 of 2)
• About 50% of pregnant women will experience GERD
• Can also occur in infants
• Prevalence depends on geographic region but is highest
in Western countries

Risk Factors
• Obesity (BMI ≥ 30)
• Alcohol use
• Smoking
• Excessive caffeine intake
• Respiratory diseases

Key Factors in the Development of GERD
(Slide 1 of 2)
• A decrease in lower esophageal sphincter (LES) pressure
• Decreased clearance of gastric contents from the
esophagus
• Decreased mucosal resistance in the esophagus

Key Factors in the Development of GERD
(Slide 2 of 2)
• Composition of reflux contents “extra acidic”
– Gastric fluid that has a pH < 4 is extremely caustic to the
esophageal mucosa.
• Decreased gastric emptying (increased gastric emptying
time)
• Certain anatomic features
– Most commonly a hiatal hernia

Pathophysiology of GERD (Role of the Lower
Esophageal Sphincter)
• Link: Figure of comparison of esophageal high-resolution
manometry
• Link: Figure of pathophysiology of esophageal reflux
disease (LES, lower esophageal sphincter)

Hiatal Hernia
• A hiatal hernia occurs when a portion of the stomach
protrudes through the diaphragm into the chest
– Causes a disruption in the normal anatomic barriers between
the stomach and the esophagus
• Link: Figure of radiographic anatomy of the
gastroesophageal junction

GERD Symptoms
• GERD symptoms are often grouped in 3 categories
– Typical or “classic” esophageal symptoms
– Alarm or complicated symptoms
• May be indicative of GERD complications
– Atypical or extraesophageal symptoms

Typical or “Classic” Symptoms
• Pyrosis (heartburn)
– Hallmark symptom
– A substernal feeling of warmth or burning rising up from the
abdomen that may radiate to the neck
• Regurgitation/Belching
• Acid brash/Hypersalivation
• Chest pain (non cardiac in nature)

Alarm (Complicated) Symptoms
• Any of these symptoms warrant immediate referral for
testing
– Dysphagia
– Odynophagia
– Bleeding
– Unexplained weight loss
– Choking
– Chest pain (if could be cardiac in nature)

Extraesophageal Symptoms/Manifestations (Atypical
Symptoms)
• These symptoms have an association with GERD but
causality should only be considered if a concomitant
esophageal symptoms are present
– Chronic cough
– Asthma-like symptoms
• About 50% of those with asthma have GERD
– Laryngitis/Hoarseness
– Recurrent sore throat
– Dental enamel erosion

GERD
• GERD is often described on either esophageal symptoms or
esophageal tissue injury
– Symptom-based GERD syndromes (with or without esophageal
tissue injury)
– Tissue injury-based GERD syndromes (with or without esophageal
symptoms)
• Extraesophageal GERD syndromes may also occur
• GERD is also sometimes described in terms of the absence
or presence of esophageal erosions
– Non-erosive reflux disease (NERD)
– Erosive reflux disease (ERD)

Symptom-Based GERD Syndromes
• May or may not have esophageal tissue injury
• Have typical or “classic” esophageal symptoms
• May have alarm symptoms particularly if GERD
complications (see next section) are present

Tissue-Injury Based GERD Syndromes
• Examples of esophageal tissue injury include the presence of
any of the following:
– Esophagitis (inflammation of the esophagus)
– Erosions (erosion of the squamous epithelium of the esophagus)
– Strictures
– Barrett’s esophagus
– Esophageal adenocarcinoma
• May present with alarm symptoms particularly if have GERD
complications
• May or may not have typical or classic symptoms

Extraesophageal GERD Syndromes
• Present with extraesophageal or atypical symptoms
• May or may not have typical esophageal symptoms
• Extraesophageal symptoms have an association with GERD,
but causality should only be considered if a concomitant
esophageal GERD syndrome is also present
• Extraesophageal manifestations of GERD are being
recognized with increasing frequency.
• GERD may be either a causative or exacerbating factor in up
to 50% of patients who experience these symptoms.

Aggravating Factors
• Recumbency
• Increased intra-abdominal pressure
• Reduced gastric motility
• Decreased LES tone or pressure
• Direct mucosal irritation

Decrease in LES Pressure
• Examples of foods that decrease LES pressure
– Fatty foods, peppermint, spearmint, chocolate, coffee, cola, tea,
garlic, onions, chili peppers
• Examples of medications that decrease LES pressure
– Anticholinergics, barbiturates, benzodiazepines, caffeine,
dihydropyridine calcium channel blockers, dopamine, estrogen,
ethanol, narcotics, nicotine, nitrates, progesterone, theophylline

Direct Mucosal Irritation
• Examples of foods that are direct irritants to the
esophageal mucosa
– Spicy foods, orange juice, tomato juice, coffee
• Examples of medications that are direct irritants to the
esophageal mucosa
– Oral bisphosphonates, aspirin, iron, NSAIDs, quinidine,
potassium

Foods and Medications that May Worsen GERD Symptoms
Foods/Beverages Medications
Decreased Lower Esophageal Sphincter Pressure
Fatty meal Anticholinergics
Carminatives (peppermint, spearmint) Barbiturates
Chocolate Caffeine
Coffee, cola, tea Dihydropyridine calcium channel blockers
Garlic Dopamine
Onions Estrogen
Chili peppers Nicotine
Alcohol (wine) Nitrates
Progesterone
Tetracycline
Theophylline
Direct Irritants to the Esophageal Mucosa
Spicy foods Aspirin
Orange juice Bisphosphonates
Tomato juice Nonsteroidal antiinflammatory drugs (NSAIDs)
Coffee Iron
Tobacco Quinidine
Potassium chloride

Complications of GERD
• Esophagitis
– Link: Figure of EGD demonstrating linear red streaks with a central
white streak extended up the esophagus in peptic regurgitant
esophagitis
• Erosions and ulceration of the esophageal mucosa
• Strictures of the esophagus
– Secondary to fibrous tissue deposition after long standing erosion
• Barrett’s esophagus
– Present in about 10% of those with GERD
– Most prevalent in white males in Western countries
• Esophageal adenocarcinoma

Barrett’s Esophagus (Slide 1 of 2)
• Barrett’s esophagus occurs when the normal squamous
cell epithelium in the esophagus converts to a columnar
cell epithelium (intestinal-type epithelium)
• More common in men than women
• Barrett’s esophagus does not cause specific symptoms
but the reflux does

Barrett’s Esophagus (Slide 2 of 2)
• Those with Barrett’s esophagus develop adenocarcinoma
of the esophagus at a rate of 0.12% per year
– Gender ratio for esophageal adenocarcinoma is 8:1
(male:female)
• Patients must be monitored via endoscopy to evaluate
changes in cell type and conversion to adenocarcinoma

Complications of GERD (Photos)
Link: Photos of endoscopic appearance of peptic
esophagitis, a peptic stricture, Barrett’s metaplasia, and
adenocarcinoma

GERD Diagnosis/Diagnostic Tests (Slide 1 of 4)
• Clinical History
– Patient’s description of typical or classic GERD symptoms such
as pyrosis, is often enough to consider GERD as an initial
diagnosis (uncomplicated GERD)
• Empiric trial of proton pump inhibitor (PPI) therapy
– ACG (American College of Gastroenterology) guidelines state
that it is reasonable to assume a GERD diagnosis in patients
who respond to appropriate therapy

• Endoscopy
– Endoscopy is the technique of choice to identify complications of
GERD such as ulcerations, erosions, Barrett’s esophagus, etc.
– Biopsy of the esophageal tissue is needed to identify and diagnose
Barrett’s esophagus and esophageal adenocarcinoma
– Many patients with GERD (presenting with typical or atypical
symptoms) will have normal appearing esophageal mucosa on
endoscopy
– Usually not part of the work-up except in certain subsets of patients
(alarm symptoms, those refractory to treatment, etc.)

• Ambulatory pH Monitoring
– Identifies patients with excessive esophageal acid exposure
and helps determine if symptoms are acid related
– Useful in patients not responding to acid-suppression therapy
• Barium Radiography
– Not routinely used to diagnose GERD due to a lack of
sensitivity and specificity
– Can detect hiatal hernia

• Patients presenting with extraesophageal or atypical
symptoms should be reviewed on a case-by-case basis to
be considered for testing
• Alarm symptoms always warrant further testing

Therapeutic Approach to GERD
• The initial treatment used is determined by the patient’s
condition:
– Frequency of symptoms
– Degree of symptoms
– Presence and/or degree of esophagitis
– Presence of complications

Goals of Treatment
• Alleviate or eliminate acute symptoms
• Decrease frequency of recurrence
• Promote healing if esophageal tissue injury is present
• Prevent complications

General Treatment Approach
• Initial therapy in patients who present with typical GERD symptoms
should include patient-directed (self-care) therapy (antacids, OTC
H2-antagonist, or OTC PPIs) and lifestyle modifications
• Those who do not respond to patient-directed therapy and lifestyle
modifications after 2 weeks should seek medical attention and are
usually started on empiric therapy consisting of an acid suppression
agent such as a proton pump inhibitor (PPI)
• Those who do not respond to empiric acid suppression therapy or
have alarm symptoms should undergo testing such as an endoscopy

Nonpharmacologic Therapies
• Lifestyle modifications
– Should be incorporated into the management of GERD regardless of the
severity of disease
– Lifestyle modifications should be tailored to an each individual patient’s
needs
• Anti-reflux surgery
– Used as a last resort option in select patients
• When long-term pharmacologic therapy is undesirable
• Who have refractory GERD
• Have complications
• Endoscopic therapies
– Results have been disappointing and hence are not usually recommended

Lifestyle Modifications (Slide 1 of 2)
• Weight loss (if the patient is overweight or obese)
• Elevation of the head of the bed 6 to 8 inches
• Eat smaller, more frequent meals (as opposed to larger
meals less frequently)
• Include protein-rich meals in diet (increases LES
pressure)

Lifestyle Modifications (Slide 2 of 2)
• Avoid eating 3 hours prior to sleeping or lying down
• Avoid foods or medications that exacerbate GERD
• Avoid alcohol
• Tobacco cessation

Endoscopic Interventions
• Stretta Procedure
– Stretta is an endoscopically guided radiofrequency (RF) energy delivery
system. The device is guided down the esophagus and RF energy is
delivered to tissues via catheters/needles. RF energy is thought to
improve GERD symptoms by increasing collagen deposition at the LES,
increasing muscle wall thickness and reconstituting the barrier to the
reflux of gastric contents.
• LINX Reflux Management System (FDA approved March 2012)
– A series of titanium beads each with a magnetic core connected together
with a wire to form a ring shape.
– Implanted in the LES
– The force of the magnetic beads provides additional strength to a keep a
weak LES closed.

Therapeutic Interventions in the Management
of GERD
Link: Figure of therapeutic interventions in the
management of gastroesophageal reflux disease

Pharmacologic Agents Used in the Treatment of
GERD
• Antacids and alginic acid products
• H2-receptor antagonists (HRA)
• Proton pump inhibitors (PPIs)
• Promotility agents

Antacids (Slide 1 of 2)
• MOA
– Neutralize hydrochloric acid in the stomach, which results in an increase
in gastric pH
• Agents
– Magnesium hydroxide
– Aluminum hydroxide
– Calcium carbonate
• Adverse effects
– Diarrhea (magnesium hydroxide)
– Constipation (aluminum hydroxide and calcium carbonate)
– Alterations in mineral metabolism
– Acid-base disturbances

Antacids (Slide 2 of 2)
• Monitoring
– Periodic calcium and phosphate levels if on chronic antacid therapy
• Patient counseling
– Antacids can decrease the levels of numerous other drugs including
tetracyclines, digoxin, iron supplements, fluroquinolones, and
ketoconazole.
• Patients should separate antacids and other medications by at least 2 hours
– Patients with renal impairment should not use aluminum or
magnesium containing antacids unless directed by their physician
– Onset of relief is less than 5 minutes and duration of relief is 20 to
30 minutes

Composition and Acid Neutralizing Capacities of Popular Antacid Preparations
PRODUCT Al(OH)3
a Mg(OH)2
a CaCO3
a SIMETHICONEa ACID NEUTRALIZING
CAPACITYb
Tablets
Gelusil 200 200 0 25 10.5
Maalox Quick Dissolve 0 0 600 0 12
Mylanta Double Strength 400 400 0 40 23
Riopan Plus Double
Strength
Magaldrate, 1080 20 30
Calcium Rich Rolaids 80 412 0 11
Tums EX 0 0 750 0 15
Liquids
Maalox TC 600 300 0 0 28
Milk of Magnesia 0 400 0 0 14
Mylanta Maximum
Strength
400 400 0 40 25
Riopan Magaldrate, 540 0 15
aContents, milligrams per tablet or per 5 ml.
bAcid neutralizing capacity, milliequivalents per tablet or per 5 ml.
The U.S. marketplace for antacids is fluid. The current trend of "reusing" well-known brand names to introduce new products that contain an active ingredient different from expected is a source of confusion that can
present a danger to patients. Medication safety experts encourage clinical practitioners to refer to the active ingredient(s) in conjunction with the proprietary (brand) name when selecting OTC products.

Antacid-Alginic Acid Combination
• MOA
– The antacid neutralizes stomach acid and the alginic acid is a
foaming agent that creates a viscous solution that floats on top
of the stomach contents and may be protect the esophagus
from refluxed stomach acid
• Agents
– Aluminum hydroxide/Magnesium carbonate/Alginic acid
(Gaviscon)

H2-Receptor Antagonists (Slide 1 of 2)
• MOA
– Competitive inhibition of histamine at H2 receptors of gastric
parietal cells which inhibits gastric acid secretion
• Agents
– Cimetidine (Tagamet)
– Famotidine (Pepcid)
– Nizatidine (Axid)
– Ranitidine (Zantac)

H2-Receptor Antagonists (Slide 2 of 2)
• Adverse effects
– Headache, somnolence, fatigue, dizziness, constipation, diarrhea
• Monitoring
– Monitor for CNS effects (rare) in those over 50 years old or in those
with renal or hepatic impairment
– If taking once a day, it is preferable to take the dose at bedtime
– Onset of relief is 30 to 45 minutes and duration of relief is 4 to 10
hours

Proton Pump Inhibitors (PPIs) (Slide 1 of 3)
• MOA
– Blocks acid secretion by inhibiting gastric H+/K+ adenosine triphosphatase found
on the secretory surface of gastric parietal cells
– Results in a long-lasting anti-secretory effect that can maintain gastric pH levels
above 4
• Agents
– Dexlansoprazole (Dexilant)
– Esomeprazole (Nexium)
– Lansoprazole (Prevacid)
– Omeprazole (Prilosec)
– Omeprazole/sodium bicarbonate (Zegerid)
– Pantoprazole (Protonix)
– Rabeprazole (Aciphex)

• Common adverse effects
– Headache, dizziness, somnolence, diarrhea, constipation,
flatulence, abdominal pain, nausea
• Serious adverse effects
– Increased risk of Clostridium difficile infections
– Increase risk of community-acquired pneumonia
• Long-term adverse effects (> 1 year)
– Hypomagnesemia
– Bone fractures
– Vitamin B12 deficiency

• Monitoring
– Appearance of diarrhea (frequency and type of diarrhea episodes)
– Periodic magnesium levels (if long-term therapy)
– Routine bone density studies (DXA scans)
• If other risk factors for osteoporosis or bone fractures present
– Preferable to take a PPI 30 to 60 minutes before a meal (mainly
breakfast)
– If a second dose is needed, take prior to the evening meal
– Onset of relief is 2 to 3 hours and the duration of relief is 12 to 24
hours

Evaluate the Risks versus Benefits of
Long-Term PPI Use (Slide 1 of 2)
• Long-term PPI use has been associated with increased
risk of:
– Fractures
– Infections such as C. Diff and pneumonia (expand)
– Hypomagnesemia
– Vitamin B12 deficiency

Evaluate the Risks versus Benefits of
Long-Term PPI Use (Slide 2 of 2)
• Long-term PPI use MAY BE associated with increased
risk of:
– Dementia
– Renal disease
– Cardiovascular disease

Promotility Agents
• Promotility agents, such as metoclopramide and
bethanechol, have been used as adjunct therapy to acid
suppression agents such as PPIs in patients who have a
known motility defect
• However, they are not generally recommended to be used
for GERD treatment due to their limited effectiveness and
undesirable adverse effect profiles

Pharmacologic Therapy (Slide 1 of 3)
• Patient directed therapy (Self-care) is appropriate for
intermittent, mild pyrosis and is managed using over-the-
counter products such as antacids, OTC H2-receptor
antagonists, and OTC proton pump inhibitors (PPIs)
• Link: Table on Therapeutic Approach to GERD in Adults

Pharmacologic Therapy (Slide 2 of 3)
• Symptomatic relief of uncomplicated GERD is treated with
prescription H2-receptor antagonists or prescription PPIs
at the following doses and durations:
• Refer to Link: Table on Therapeutic Approach to GERD
in Adults

Pharmacologic Treatment (Slide 3 of 3)
• Healing of erosive esophagitis or treatment of patients
presenting with moderate to severe symptoms or
complications
• Refer to Link: Table on Therapeutic Approach to GERD
in Adults

PPIs v. H2-Receptor Antagonists
• Symptomatic improvement as well as endoscopic healing
rates are higher for the PPIs compared to the H2-receptor
antagonists
• PPIs are therefore preferred over H2-receptor antagonists
in patients with erosive disease, moderate to severe
symptoms, or with complications

Maintenance Therapy (Slide 1 of 2)
• What patients should receive maintenance therapy?
– Those with symptomatic relapse following discontinuation of the
drug or a decrease in dose.
• If NERD/uncomplicated GERD, try to manage with on-demand or
intermittent PPI therapy or H2-receptor antagonists

Maintenance Therapy (Slide 2 of 2)
• What patients should receive maintenance therapy?
– Those with a history of complications (e.g. Barrett’s esophagus,
strictures, hemorrhage, ulcerations, etc.)
• Long-term maintenance therapy with PPIs at the lowest possible dose
– Can consider intermittent or on demand PPI therapy in some circumstances

PPIs and Rebound Acid Secretion (Slide 1 of 2)
• There have been reports of rebound acid secretion when
PPIs are abruptly discontinued.
– This can happen when PPIs are used for as little as 2 months
(and of course when they are used longer)
– These hyperacidity symptoms include dyspepsia and heartburn
• Often attributed to a relapse of the disorder (e.g. GERD), but it can
even happen in patients who didn’t have these symptoms to start with

PPIs and Rebound Acid Secretion (Slide 2 of 2)
• Tapering strategies for patients experiencing rebound acid
secretion
– (1) Taper PPI over 4 to 6 weeks
• First lower the dose of the PPI
• Then extend the PPI dosing interval to every other day then every 3rd
day
• An H2-antagonist or antacid can be used for symptoms on “off days” as
needed
– (2) Suggest a switch to an H2-antagonist with antacids used as
needed for several weeks then discontinue

Patients with Extraesophageal (Atypical) GERD
(Slide 1 of 2)
• GERD can be considered as a potential co-factor in
patients with asthma, chronic cough, or laryngitis
– Careful evaluation of non-GERD causes should be undertaken
in all of these patients
• Patients with atypical symptoms may need higher doses
of acid suppression therapy with longer treatment duration
compared to those patients with typical symptoms

Patients with Extraesophageal (Atypical) GERD
(Slide 2 of 2)
• A PPI trial is recommended to treat extraesophageal
symptoms in patients who have typical GERD symptoms
as well
• Reflux monitoring should be considered before a PPI trial
in patients with extraesophageal symptoms who do not
have typical GERD symptoms

Pediatric Patients (Slide 1 of 2)
• A suspected cause of reflux in infants is a
developmentally immature LES
• Many infants have reflux with little or no clinical
consequence
– This uncomplicated reflux usually manifests as regurgitation or
spitting up
– Usually responds to supportive therapy
• Chronic vomiting associated with GERD must be carefully
evaluated and distinguished from other causes

Pediatric Patients
• Careful consideration should be given before a medication is
recommended
• When a medication is deemed necessary, ranitidine dosed at
2 to 4mg/kg twice a day is often used
• PPIs are increasing being used in children older than 1 year
– Lansoprazole, esomeprazole, and omeprazole are indicated for
treating symptomatic and erosive GERD in children > 1 year old
– See next slide for dosing ranges
• Omeprazole has been used off-label in children less than 1
year old at a dose of 1mg/kg/day

PPIs in Children > 1 year of age
• Lansoprazole
– 15mg per day is recommended for children weighing < 30kg
– 30mg per day is recommended for children weighing > 30kg
• Esomeprazole
– Dosed 10 to 20mg a day for children 1 to 11 years old
– Dosed at 20 to 40mg a day for children 12 to 17 years old
• Omeprazole
– 5mg daily in children weighing between 5 and 10kg
– 10mg daily in children weighing between 10 and 20kg
– 20mg daily in children weighing ≥ 20kg

Elderly Patients
• Many elderly patients have decreased defense
mechanisms such as decreased saliva production
• PPI therapy may be warranted for those > 60 years of age
with symptomatic GERD
– They have superior efficacy and have once a day dosing
– Long-term risk of bone fractures is a concern and elderly
patients should be monitored appropriately
• Elderly are at higher risk of being sensitive to possible
CNS effects of H2-receptor antagonists

Patients with Refractory GERD
• Refractory GERD should be considered in patients who have
not responded to a standard course of twice a day PPI
therapy
• The majority of patients with refractory symptoms experience
nocturnal acid breakthrough
• Switching to a different PPI may be effective in some patients
• Adding an H2-receptor antagonist at bedtime for nocturnal
symptoms is reasonable but the effect may decrease over
time due to tachyphylaxis with H2-receptor antagonists

References (Slide 1 of 3)
• May D, Thiman M, Rao SC. Gastroesophageal Reflux
Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG,
Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach,
10e New York, NY: McGraw-Hill; 2017.
• Mills JC, Stappenbeck TS. Gastrointestinal Disease. In: Hammer
GD, McPhee SJ. eds. Pathophysiology of Disease: An Introduction
to Clinical Medicine, Seventh Edition. New York, NY: McGraw-Hill;
2013.
• Kahrilas PJ, Hirano I. Diseases of the Esophagus. In: Kasper D,
Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison's
Principles of Internal Medicine, 19e. New York, NY: McGraw-Hill;
2015.

• Wallace JL, Sharkey KA. Pharmacotherapy of Gastric Acidity,
Peptic Ulcers, and Gastroesophageal Reflux Disease. In:
Brunton LL, Chabner BA, Knollmann BC. eds. Goodman &
Gilman's: The Pharmacological Basis of Therapeutics, 12e.
New York, NY: McGraw-Hill; 2011.
• Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis
and management of gastroesophageal reflux disease. Am J
Gastroenterol 2013; 108: 308-328.
• Schoenfeld AJ, Grady D. Adverse effects associated with
proton pump inhibitors. JAMA Internal Medicine 2016; 176(2):
172-174.

• Micromedex Solutions. Truven Health Analytics, Inc. Ann
Arbor, MI. Accessed October 15, 2016.
• Lexicomp Online®, Lexi-Drugs®, Hudson, Ohio: Lexi-
Comp, Inc. Accessed October 15, 2016.

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