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• Gastroesophageal reflux disease (GERD) refers to symptoms or mucosal damage
resulting from the abnormal retrograde movement of gastric contents from the
stomach into the esophagus. . It is primarily the result of transient relaxation of the
•When the esophagus is repeatedly exposed to refluxed material for prolonged
periods, inflammation of the esophagus (reflux esophagitis) can occur and in
some cases it progresses to erosion of the squamous epithelium (erosive
•Severe reflux symptoms associated with normal endoscopic findings are referred
to as “symptomatic GERD,” non erosive reflux disease, or endoscopy- negative
reflux disease.
 Protective mechanisms such as esophageal peristalsis and
bicarbonate-rich saliva quickly return the acidic pH to
 GERD develops when alterations in reflux result in
symptoms, mucosal injury, or both.
 Esophageal injury occurs with continued exposure of the
mucosa to gastric acid and results in inflammation that can
progress to ulceration (erosive esophagitis).
 GERD is a chronic disease that affects patients across all age
groups with equal distribution between men and women.
 The prevalence of GERD appears to be greater in the
Western population with patients presenting with more
clinically important disease and complications than in Eastern
countries (especially Asian populations) where GERD is
 When considering the symptoms of GERD, such as
heartburn and acid regurgitation, the overall
prevalence in the United States is approximately 45%.
 In Western populations, 25% of patients report heartburn
monthly, 12% weekly, and 5% describe daily symptoms.
 It has also been estimated that 7% of the U.S. population
have complicated GERD associated with erosive
 Up to 75% of patients who undergo endoscopic
procedures due to symptoms associated with GERD have
normal esophageal findings.
 These patients are identified as having functional heartburn,
nonerosive reflux disease (NERD), or endoscopy-negative
reflux disease (ENRD).
 Other patients with GERD have symptoms that occur outside
of the esophagus which are considered atypical or
extraesophageal manifestations of GERD.
 Extraesophageal manifestations may be present with or
without accompanying typical symptoms (e.g., heartburn).
 Extraesophageal manifestations have been estimated to
occur in about 80% of patients with at least weekly
symptoms of GERD.
Extraesophageal disorders in GERD
 Noncardiac chest pain
 laryngeal diseases
 Laryngitis
 pulmonary diseases
chronic cough
recurrent bronchitis
sleep apnea
pulmonary fibrosis
 subglottic stenosis
 laryngeal cancer
 other ENT (ear, nose,
throat) disorders
 Sinusitis
 Otitis media
 Pharyngitis
 dental erosion
Etiology and Risk Factors
 Increased contact of the acidic refluxate with the esophageal
 Dietary and lifestyle factors, drugs, and certain medical and
surgical conditions.
 Lowering the LES pressure (e.g., nitrates, progesterone, foods
high in fat, mint, chocolate) or having a direct irritating effect on the
esophageal mucosa (e.g., citrus, tomatoes, bisphosphonates).
 Increased intra-abdominal pressure has been associated with
overeating, coughing, and bending or straining to lift heavy objects as
well as tight-fitting clothing.
Life style
 Smoking – Inhibits saliva, may also increase acid
production & weaken the LES.
 Certain exercising & bending – that may increase the
abdominal pressure.
 Wearing of tight clothing – increases the abdominal
 Lying flat after a meal – relaxes the muscles making
susceptibility for reflux.
 Fatty, greasy foods - take longer to digest keeping food in the
stomach longer.
 Peppermint, spearmint, and chocolate weaken the LES.
 Carbonated and alcoholic beverages increase the acidity in the
 Large meal portions – produce large acid levels.
 Citrus, onions, and acid from tomatoes can be irritating to the
“Medications that relax the LES”
 Benzodiazepines
 Anticholinergics
 Theophylline
 Potassium supplements
 Narcotics containing codeine.
 Calium channel Blockers
 Nitroglycerine
 Iron supplements
 Fosamax
 Erythromycin
 Childhood GERD appears to continue into adolescence
and adulthood.
 Although most infants develop physiological
regurgitation, or spitting up, the majority (95%) will
have abatement of symptoms by 1.0 to 1.5 years of age.
 However, infants with persisting symptoms beyond 2
years of age are at risk of developing complicated
 Pregnancy has also been associated with an increased
incidence of GERD with 30% to 50% of pregnant women
complaining of heartburn; however, in patients without a
previous diagnosis of GERD, the symptoms resolve when
the child is born.
 The mechanisms for GERD in pregnancy are related to
 a) the hormonal effects of progesterone and estrogen,
which lower LES pressure, and
 b) increasing intra-abdominal pressure
 Certain medical and surgical conditions such as
 Gastroparesis,(A condition that affects the stomach muscles and
prevent proper stomach emptying)
 Scleroderma, (Chronic hardening and tightening of the skin and
connective tissues)
 Long-term placement of nasogastric tubes may also be associated
with GERD.
 The eradication of H. pylori infection may increase the risk
of GERD symptoms and esophagitis.
Quality Of Life (QOL)
 Patients with GERD may have a decrease in quality of life.
 When comparing quality of life in patients with GERD to those
with other chronic medical diseases, the quality of life in GERD
patients was between patients with psychiatric disorders and
patients with mild heart failure.
 The pathophysiology of GERD is associated with
 Defects in transient relaxations of the LES,
 Esophageal acid clearance and buffering capabilities,
 Anatomy,
 Gastric emptying,
 Mucosal resistance and
 with exposure of the esophageal mucosa to aggressive factors
(gastric acid, pepsin, and bile salts) leading to esophageal damage.
Transient Relaxations of the Lower
Esophageal Sphincter
 The LES, when in a resting state, remains at a high pressure
(10–30 mmHg) to prevent the gastric contents from entering
into the esophagus.
 Pressures are lowest during the day and with meals and
highest at night.
 Transient relaxations of the LES are short periods of sphincter
relaxation that are different from those that occur with
swallowing or peristalsis.
 They occur due to vagal stimulation in response to gastric
distension from meals (most common), gas, stress, vomiting,
or coughing and can persist >10 seconds.
 A small percentage of patients may also have a continuously
weak and hypotensive LES (decreased LES resting tone).
 Stress reflux increases intra-abdominal pressure and may blow
open the hypotensive LES.
 When LES pressures remain constantly low, the risk for serious
complications (e.g., erosive esophagitis) increase dramatically.
 Scleroderma, which is related to fibrosis of smooth muscle,
may reduce LES tone and increase the potential for GERD.
Esophageal Acid Clearance and
Buffering Capabilities
 Although the number of reflux events and quantity of refluxate
are notable, it is the duration of time the mucosa is in contact
with these noxious substances that determines esophageal
damage and complications.
 More than 50% of patients diagnosed with severe esophagitis have
decreased acid clearance from the esophagus.
 Peristalsis is the primary mechanism by which acid refluxate is
removed from the esophagus.
 Other mechanisms include swallowing, esophageal distension
in response to refluxate, and gravity (which is only effective when
the patient is in an upright position).
 Saliva plays an important role in the neutralization of
gastric acid within the esophagus.
 Its bicarbonate-rich content buffers the residual acid that
remains in the esophagus after peristalsis.
 However, saliva is only effective on small amounts of gastric
acid, as patients with larger volumes of acid refluxate may not
have the neutralizing capacity in saliva necessary to protect
the esophagus. Swallowing increases the rate of saliva
production and esophageal acid clearance.
 The reduction of swallowing that occurs during sleep is
associated with nocturnal GERD.
 Patients with decreased saliva production (e.g., elderly,
patients taking medication with anticholinergic effects, and
those with certain medication conditions such as xerostomia
or Sjogren's syndrome) may also be at increased risk of
developing GERD.
Anatomic Abnormalities
 Hiatal hernia (protrusion of the upper portion of the stomach into
the thoracic cavity due to weakening in the diaphragmatic muscles) is
frequently described as a cause of GERD, but its causal relationship
remains uncertain.
 Although hiatal hernia is associated with a greater degree of esophagitis,
strictures, and Barrett's metaplasia, not all patients with hiatal hernia
develop symptoms or complications.
 This may be related to the size of the hiatal hernia and its effect on LES
 Hypotensive LES in combination with hiatal hernia increases the
likelihood of reflux and complicated disease
Gastric Emptying
 Delayed gastric emptying increases the volume of gastric fluid
remaining within the stomach that is available for reflux and is
associated with gastric distension.
 Although delayed gastric emptying is present in up to 15% of patients
with GERD, a causal relationship has not been established.
 Because some patients such as those with diabetic gastroparesis also
have GERD, the association between delayed gastric emptying and
GERD cannot be overlooked.
Mucosal Resistance
 The capability of the esophageal mucosa to endure contact with and
withstand injury from gastric refluxate (acid and pepsin) is a
substantial determinate for the development of GERD.
 When considering the mucosal resistance within the esophagus
compared with that of the stomach and duodenum, the esophagus is
less resistant to damage from gastric acid.
 However, mucosal resistance in the esophagus is composed of many
defensive factors working in tandem to prevent esophageal injury.
 The esophagus also secretes a protective mucous layer and
 This creates an environment in the esophagus of a higher pH than that of
the stomach. The pH in the esophagus is normally about 7-8, whereas
the pH in the stomach is generally 2-4.
 Enhanced blood flow in response to an acidic environment within the
esophagus improves tissue oxygenation, provides nutrients, and helps
to maintain a normal acid–base balance.
 Esophageal injury also occurs when the concentration of acid and
pepsin exceed the protection afforded by mucosal resistance
Aggressive Factors Associated With
Esophageal Damage
 The gastric refluxate, which is composed primarily of gastric acid
and pepsin, is the primary aggressive factor associated with GERD.
 The development and degree of mucosal damage is dependent on the
pH and contents of the refluxate as well as the total exposure time of
refluxate with the esophageal mucosa.
 A pH <4 is usually required to produce injury to the esophageal
mucosa, but as the refluxate becomes more acidic, the mucosal
damage is accelerated.
 The addition of pepsin (which is converted from secreted pepsinogen
in an acidic pH) to the acidic refluxate will markedly increase the
propensity of the refluxate to compromise mucosal resistance and
increases the potential for esophageal bleeding.
 Duodenogastric reflux or alkaline reflux containing bile acids
and pancreatic juices may also contribute to esophagitis.
 Because gastric and duodenogastric reflux are often
concomitantly present, their actions may be additive in causing
esophageal damage.
 The duration of total exposure time of the esophagus to the
refluxate is the primary mechanism involved in the development
of GERD and its complications.
 The longer the duration of exposure time, the greater the
possibility of severe disease, including progression to Barrett's
Eradication of Helicobacter pylori
 The relationship between H. pylori infection and GERD remains
 Early studies suggest that H. pylori eradication is associated with
increased gastric acidity and subsequent development of erosive
 In contrast, it appears that H. pylori may be protective against GERD
symptoms and related complications.
 This is presumably due to the microorganisms ability to decrease the
acidity of the refluxate, as it does not appear to affect the functional
defense mechanisms of the esophagus.
 Although H. pylori testing in patients with GERD is not standard
practice, if the patient is tested and found to be H. pylori positive,
eradication is recommended
The 3 mechanisms of the lower esophageal
sphincter (LES) which prevent backflow are:
 Pressure in the LES is greater than that of the stomach.
 High levels of Acetylcholine, a neurotransmitter
increases constriction of the LES.
 Gastrin, a hormone also increases constriction of the LES.
Some conditions that can interfere with the
mechanisms of the Lower Esophageal Sphincter
 OBESITY - excess weight puts extra pressure on the stomach &
 Pregnancy – results in greater pressure on the stomach & also has a
higher level of progesterone. This hormone relaxes many muscles,
including the LES.
 ASTHMA – it is unsure why, but, is believed that the coughing leads to
pressure changes on the diaphragm.
 HIATAL HERNIA – which is the following topic.
 There are specialized cells deep in the stomach lining that affect the rate
of acid production.
 The primary cells which contribute to acid production are known as parietal
 Each gastric parietal cell contains about 1 million acid pumps.
 The primary function of the activated pumps are to exchange hydrogen
ions from the parietal cells to potassium using energy derived from
splitting ATP.
 The stomach produces an average of 2 liters of HCL a day, which in
combination with the protein-splitting enzyme pepsin, breaks
down chemicals in food.
 Complications of long-term reflux may include the
development of
 Erosive esophagitis (up to 47%)
 Strictures (>30%),
 Barrett’s esophagus (10% to 15% ), or
 Adenocarcinoma of the esophagus.
• The hallmark symptom of gastroesophageal reflux and esophagitis is heartburn, or
pyrosis. It is classically described as a substernal sensation of warmth or burning that
may radiate to the neck. It is waxing and waning in character and is often aggravated
by activities that worsen gastroesophageal reflux (e.g., recumbent position, bending
over, eating a high-fat meal). Other symptoms include water brash (hypersalivation),
belching, and regurgitation.
• Atypical symptoms include nonallergic asthma, chronic cough, hoarseness,
pharyngitis, dental erosions, and chest pain that mimics angina.
• Inadequately treated GERD may lead to complications from long-term acid
exposure such as continual pain, dysphagia, and odynophagia. Other severe
complications include esophageal strictures, hemorrhage, Barrett’s esophagus, and
esophageal adenocarcinoma.
Clinical Presentation
A normal upper esophagoscopy
The Los Angeles Classification System for the
endoscopic assessment of reflux oesophagitis
 One or more mucosal breaks no longer than 5 mm, non of
which extends between the tops of the mucosal folds
The Los Angeles Classification System for the
endoscopic assessment of reflux oesophagitis
One or more mucosal breaks more than 5 mm long, none of
which extends between the tops of two mucosal folds
The Los Angeles Classification System for the
endoscopic assessment of reflux oesophagitis
Mucosal breaks that extend between the tops of two or more mucosal
folds, but which involve less than 75% of the oesophageal
The Los Angeles Classification System for the
endoscopic assessment of reflux oesophagitis
 Mucosal breaks which involve at least 75% of the
oesophageal circumference
Endoscopic view of GERD complications
 Therapeutic Goals
 to alleviate symptoms, promote esophageal healing,
prevent recurrence, provide cost-effective
pharmacotherapy, and avoid long-term complications.
 One long-term consequence is Barrett's esophagus, or Barrett's
metaplasia, which is identified in 10% to 15% of GERD patients
on endoscopic evaluation.
 This premalignant condition may predispose the patient to
esophageal adenocarcinoma.
 Patients with Barrett's esophagus have a 30- to 125-fold greater
risk of developing esophageal cancer than an age-matched
Nonpharmacologic Measures and SelfDirected Treatment
 Lifestyle and dietary modifications comprise the initial step in
managing patients with GERD
 Lifestyle modifications are aimed at reducing acid exposure within
the esophagus by increasing LES pressure, decreasing
intragastric pressure, improving esophageal acid clearance,
and avoiding specific agents that irritate the esophageal
 There is evidence to support several modifications that reduce
esophageal gastric acid exposure and symptoms.These include
raising the head of the bed 6 to 8 inches by using blocks
sleeping in a left lateral decubitus position; and
weight loss, which also decreases intra-gastric pressure.
Avoiding large meals within 3 hours of bedtime or lying down in the
supine position may also decrease symptoms.
 Antacids
 Antacids are useful only in the relief of mild symptoms
associated with GERD.
 Because of their short duration of action and inability
to heal erosive esophagitis, they are not an option
for treating moderate to severe GERD.
H2-Receptor Antagonists
 The H2RAs are effective in treating patients with mild to moderate
 but response rates vary with the severity of disease, the dose of the drug,
and the duration of therapy.
 The H2RAs are considered equally effective when used in equipotent
doses for symptomatic relief and esophageal healing.
 They are effective in reducing nocturnal symptoms but only
modestly effective in relieving meal-related symptoms, as they
only block one mechanism of parietal cell activation (the H2 receptor).
 The H2RAs relieve symptoms in about 50% to 60% of patients treated
after 12 weeks of continuous therapy and are superior to placebo.
 Increasing the H2RA dose may not improve symptoms in
some patients.
 Esophageal healing requires higher doses
 Esophageal healing rates with the H2RAs are reported to be
about 50% after 8 to 12 weeks of treatment, but rates will vary
depending on the degree of esophagitis.
 For example, endoscopic healing rates in trials with high-dose
H2RAs were approximately 60% to 90% in patients with grades I
and II esophagitis but were only 30% to 50% in patients with
more severe disease (grades III and IV esophagitis).
 When a H2RA is used to heal the esophagus, higher daily dosages
and prolonged treatment (8–12 weeks) are required.
Proton Pump Inhibitors
 The PPIs are the drugs of choice for patients with frequent
moderate to severe GERD symptoms and esophagitis because they
provide more rapid relief of symptoms and esophageal healing than
do the H2RAs.
 Act by Inhibits the gastric acid pump, H+/K+ ATPase &
are prodrugs
 When used in recommended dosages, all of the PPIs provide similar
rates of symptom relief and esophageal healing.
 Their superior efficacy, when compared with the H2RAs, is related
to their ability to maintain an intragrastric pH >4 for a long
duration time (up to 24 hours/day vs. up to 10 hours with a
 Typically, PPIs are taken once daily 30 to 60 minutes before
breakfast, but if a second dose is required, it should be taken
prior to the evening meal.
 A large meta-analysis of 16 trials confirms that PPIs are
superior to the H2RAs for achieving rapid and complete
relief of GERD symptoms.
 Complete symptom relief (within 4–12 weeks) was
achieved in 77.4% of patients taking a PPI versus 47.6% of
those taking and H2RA (p <0.0001).
 Healing also occurred more quickly with PPI therapy in
that by week two, 63.4% of patients had healed with the
PPI, while it took 12 weeks with the H2RAs for 60.2% of
patients to heal.
 Another large meta-analysis, which evaluated over 33
randomized trials, demonstrated similar results with 81.7%
of patients healed at 8 weeks with a PPI versus 52.0% with a
 Esophageal healing among the five PPIs appears to be
equivalent, as about 85% to 90% of patients achieve complete
healing at 8 weeks in numerous head-to-head trials with equivalent
 One meta-analysis, which compared esophageal healing rates
among omeprazole 20 mg, lansoprazole 30 mg,
pantoprazole 40 mg, and rabeprazole 20 mg (each given
once daily), reported no statistical difference.
 However, all of the PPIs were superior to ranitidine 300 to
600 mg/day.
 The ability of a high-dose PPI to reverse Barrett's
metaplasia remains controversial.
 Although studies have demonstrated islands of normal
squamous epithelium returning, no data have determined
that this is associated with a risk reduction in
 In fact, others have suggested that this return of normal
mucosa may actually mask carcinogenic changes occurring
deeper in the gastric mucosa.
 Improvement of quality of life has also been evaluated
in patients receiving PPI therapy in the management of
 A recent study comparing esomeprazole with ranitidine
over a period of 6 months showed a significant
improvement in both physical functioning and sleep
with the PPI therapy.
Prokinetic Agents
 Two prokinetic agents, metoclopramide and bethanechol,
may be effective in the management of GERD.
 Both drugs stimulate the motility of the upper GI tract
without altering gastric acid secretion and increase LES
 Although these drugs may provide relief of symptoms, they
are ineffective in healing erosive esophagitis unless they
are combined with a H2RA or PPI.
 Prokinetics are not widely used to treat GERD, because
they are not as effective as other treatments and are
associated with numerous side effects.
 Prokinetics are reserved for patients who are refractory to
other available treatment options or who have delayed
gastric emptying.
 Sucralfate appears to be effective in treating mild cases of
GERD and possibly mild esophagitis but is not effective
in the management of severe disease.
 Given better options at this time, sucralfate is rarely used in
the management of GERD.
 The PPIs are considered the drugs of choice for
patients with frequent or severe GERD symptoms,
or who have complicated disease, because of their potent
inhibition of gastric acid secretion.
Maintenance Therapy
 GERD is chronic disease. Up to 80% of patients with severe
esophagitis and 15% to 30% with less severe disease have a
symptomatic relapse within 6 months after discontinuing treatment.
 The goal of maintenance therapy is to keep the patient
symptom-free and prevent potentially life-threatening
 Continuous maintenance therapy with a daily PPI is more
effective than a H2RA, with reported relapse rates of 25% and 50%,
 Thus, PPIs are the drugs of choice for maintaining remission in
patients with healed esophagitis.
On-Demand Pharmacotherapy
 The use of intermittent (on-demand) courses of PPI therapy
(2–4 weeks) have been suggested as being potentially beneficial in
patients with GERD.
 One trial, which compared continuous maintenance therapy with
esomeprazole 20 mg daily versus on-demand therapy with the
same drug and dose in patients with healed erosive esophagitis,
reported that continuous therapy was superior to on-demand
therapy (81% vs. 58%, respectively) in maintaining endoscopic
remission at 6 months.
 Although numerous studies with a variety of PPIs have
demonstrated patient satisfaction with on-demand therapy,
systemic review of 17 trials evaluating the use of ondemand therapy indicates that intermittent therapy
should only be considered in patients with mild,
nonerosive disease.
Combination of a Proton Pump Inhibitor
and H2-Receptor Antagonists
 The addition of a H2RA at bedtime to a once or twice daily PPI
regimen is sometimes used for patients who continue to have
nocturnal symptoms, although the evidence to support this
combination remains inconclusive.
 The rational for this practice is based on evidence that suggests a
period of nocturnal acid breakthrough (defined as intragastric pH <4
for longer than 1 hour during the night) in a significant number of
patients despite twice-daily PPI therapy, suggesting that histamine
release may have an important function in nocturnal acid
 One study suggests that the addition of a H2RA to a twice-daily PPI
regimen resulted in a statistically significant reduction in nocturnal
acid breakthrough during the sleeping hours.
 This trial, however, evaluated only a single bedtime dose of a H 2RA
and did not consider the tachyphylaxis that can occur with
continuous use.
 A more recent trial using a twice-daily PPI regimen with
continuous use of a H2RA for 4 weeks demonstrated no difference
in nocturnal acid suppression, suggesting that tolerance does play
an important role in the use of H2RAs for this indication.
Nonerosive Reflux Disease
 Up to 75% patients with typical GERD symptoms who undergo
endoscopy will not have evidence of esophagitis or complicated disease.
 These patients are described as having functional heartburn, NERD or
ENRD and usually undergo 24-hour ambulatory pH monitoring to
determine whether abnormal reflux is present despite a negative
 A trial of a PPI is usually indicated despite no esophageal findings, as
many patients will respond to this therapy.
 Further medical evaluation is usually required if a patient does not
respond to PPI therapy despite a doubling of the daily dose.
Asthma and Gastroesophageal Reflux
 GERD may play a role in the pathophysiology of asthma.
 Reports suggest that concomitant GERD occurs in 34% to 89%
of the asthmatic population.
 Two theoretical mechanisms exist as to how GERD can
potentially exacerbate asthma symptoms.
 The reflex theory proposes that symptoms result from the direct
irritation of the vagus nerve when refluxate comes into contact with
the esophageal mucosa, resulting in reflex bronchospasm.
 In contrast, the reflux theory proposes that aspiration of
refluxed acid into the lungs causes caustic injury of tissue
within the bronchial tree, resulting in asthmatic symptoms.
 An important meta-analysis of trials that evaluated the effects
of antireflux therapy on patients with asthma indicates that
asthma symptoms improved in 69% of patients, that the use
of asthma medications was reduced by 62%, and that only
26% of the subjects showed improvement in evening peak
expiratory flow rate.
 All other pulmonary function tests (PFTs) showed little or no
change with antireflux therapy.
 However, this meta-analysis only evaluated studies of up to 8
weeks in duration.
 A recent trial with esomeprazole 40 mg daily for 3 months
demonstrated improvements in PFTs and a decreased use of shortacting rescue bronchodilators in asthmatics with GERD compared
with asthmatics without GERD.
 One-third of the patients in the GERD group were also able
reduce their dose of inhaled corticosteroid and remained stable.
New Treatments
Cholecystokinin2 receptor
antagonists (CCK2)
Potassium competitive acid
blockers (P-CABs)
 Cholecystokinin2 receptor antagonists
Block the CCK2 receptors inhibiting
acid secretion
Still in clinical trials
Best use in combination with PPI’s
 Potassium competitive acid blockers (P-CABs)
 Target H+/K+ ATPase
 Ionically binds to the proton pump
 Specific for the K+ binding region and prevents
acid secretion
 Binds reversibly
 Still in clinical trials
Treatment for H. pylori
• Amoxicillin + clarithromycin +
proton pump inhibitor
• Metronidazole + clarithromycin +
proton pump inhibitor
• Bismuth subsalicylate + metronidazole
+ tetracycline + proton pump
editor: The McGraw-Hill Companies, Inc. ; 2008.
2. Joseph T. DiPiro P, Executive Dean and Professor,
South Carolina College of Pharmacy, University of
South Carolina. Pharmacotherapy A Pathophysiologic
Approach. Seventh Edition ed.: McGraw-Hill; 2008.
3. Koda-Kimble MAY, Lloyd Yee. Applied Therapeutics:
The Clinical Use Of Drugs, 9th Edition. Koda-Kimble
MAY, Lloyd Yee, editor: Copyright ©2009 Lippincott
Williams & Wilkins; 2009.