Gastroesophageal Reflux Disease:
Pathophysiology and Treatments Available
Pankaj Rakha1*, Raj Kumar1,
Supriya1, Nidhi1, Manju Nagpal2 and Gitika
Arora3
1Rajendra
3NCRD’s Sterling Institute of Pharmacy, Navi
Mumbai.
ABSTRACT:
Gastroesophageal
reflux disease (GERD) is primarily a motility disorder. Escape of gastric
contents into the esophagus occurs as a consequence of an incompetent
gastroesophageal barrier. This barrier is weakened in the presence of an
abnormally functioning Lower Esophageal Sphincter (LES). This review is focused
on the epidemiology, pathophysiology and treatments of gastro-oesophageal
reflux disease.
KEY WORDS: Reflux, proton pump inhibitors, H2
receptor antagonists, radiofrequency.
INTRODUCTION
Gastroesophageal
reflux disease (GERD) is defined as any symptomatic
clinical condition presumed to result from esophageal exposure to gastric
contents. It is the retrograde movement of gastric contents from the
stomach into the esophagus. GERD is a condition in
which the oesophagus becomes irritated or inflamed because of acid backing up
from the stomach. It results in heart burn, regurgitation and possible
esophageal mucosal damage (reflux esophagitis)1. When esophagus is repeatedly exposed to refluxed material for prolonged periods
of time, inflammation of the esophagus (reflux esophagitis) occurs and in some
cases it can progress to erosion of squamous epithelium of the esophagus
(erosive esophagitis). Approximately
40%–60% of patients with symptoms of gastroesophageal reflux disease have
esophageal erosions when evaluated endoscopically2.
Complications of long term reflux may include the
development of strictures, Barrett’s esophagus or adrenocarcinoma of esophagus.
However, erosive esophagitis and other complications of gastroesophageal
reflux disease occur more frequently in elderly people3 . The body has
also ways to protect itself from the harmful effects of reflux and acid
for e.g. most reflux occurs during the day, when individuals are upright. In
the upright position the refluxed liquid is more likely to flow back down in to
the stomach due to effect of gravity. Gravity, swallowing and saliva are
important protective mechanism for the esophagus, but they are effective only
when individuals are in the upright position. At night, during sleep, gravity
is not in effect, swallowing stops, and the secretion of saliva is reduced.
Therefore the reflux that occurs at night is more likely to result in acid
remaining in esophagus longer and causing greater damage to esophagus. GERD is
a chronic condition once it begins, it usually is lifelong. Because it
is a chronic relapsing condition, lifestyle modifications combined with
maintenance therapy are recommended for its treatment, as most patients will
experience a recurrence of symptoms if drug therapy is discontinued.
EPIDEMIOLOGY:
GERD is the fourth most common
gastrointestinal disease that affects a large proportion of adult population.
The incidence of GERD is estimated at 6% per year4. The impairment
in quality of life is similar to that occurring in patients with cardiac
diseases..
The epidemiology
of GERD has been a subject of much interest in recent years5. GERD
occurs both in adults and children and its symptoms have a great impact on the quality of life. In western populations,
25% of people report having heartburn at least once a month, 12% at least once
per week, and 5% describe daily symptoms6. In east Asian
populations, prevalence is much lower with 11% reporting heartburn at least
once per month, 4% weekly and 2% having daily symptoms7. There is a
paucity of information about the prevalence of heartburn in other geographical
regions, but symptoms of gastroesophageal reflux disease are uncommon in non-
western populations. GERD is also very difficult
to assess because many patients do not seek medical treatment and symptoms do
not always correlate well with severity of disease8.
PATHOPHYSIOLOGY:
The main factor in the development of GERD is the
retrograde movement of acid or other noxious substances from the stomach into
the esophagus9. Although reflux is a normal physiologic process, it
can become a pathologic one when injury to esophageal, oropharyngeal and
laryngeal tissue occurs10. The factors involved in the development
of this pathologic process are LES pressure, esophageal clearance, mucosal
integrity and gastric emptying. These are main physiologic mechanisms that
protect the esophageal lining from the injury and their compromise can result
in the symptoms of reflux disease. These factors
are discussed as follows:
LES Pressure:
LES is a segment of smooth muscle in the distal
esophagus that tonically contracts so that the pressure in this area is at
least 15mm Hg above intragastric pressure11. This mechanism acts as
a physiological barrier to prevent gastric contents from refluxing into the
esophagus12. Cholinergic innervation is important in maintaining the
tone of LES. The sphincter relaxes in response to esophageal peristalsis to
allow the passage of food, liquid or saliva into the stomach. There are brief
periods when the sphincter relaxes when there is no swallowing or esophageal
peristalsis and these events are termed as Transient Lower Oesophageal
Sphincter Relaxation (TLOSRs)13. TLOSRs take place through
acetylcholine and nitric oxide neurotransmission14.
Esophageal Clearance:
Damage produced by GERD is partially
dependent on duration of contact between the gastric contents and esophageal
mucosa15. This contact time is in turn dependent on the rate at
which the esophagus clears the noxious materials as well as the frequency of
reflux. Three forces which help in removing acidic contents from the esophagus
are - gravity, esophageal peristalsis and salivation16. Gravity
propels acidic contents through the esophagus more efficiently. The coupling of
salivation with esophageal peristalsis helps in clearing acidic stomach
contents. Bicarbonate from saliva acts to neutralize the acid that is refluxed
into esophagus.
Mucosal Resistance:
This term encompasses pre epithelial, epithelial and
post epithelial defenses17. Pre epithelial defenses consist of mucus
and bicarbonate that physically impeds and buffer the acid, although these
defenses are not well developed in esophagus13. The epithelial
defenses consist of tight and physiologic mechanisms that extrude acid from the
endothelial cell. The main post epithelial defense is by the blood flow which
delivers protective substances such as oxygen, nutrients and bicarbonates and
removes deleterious substances such as hydrogen ions and carbon dioxide19.
Gastric Emptying:
Delayed gastric emptying can contribute to
gastroesophageal reflux. An increase in gastric volume may increase both the
frequency of reflux and the amount of gastric fluid available to be refluxed.
Patients with gastroesophageal reflux, particularly infants may have a
defect-antral motility. The delay in emptying may promote regurgitation of
feedings, which might in turn contribute to two common complications of
Gastroesophageal reflux disease in infants i. e. failure to thrive and
pulmonary aspiration 20.
PHARMACOLOGIC TREATMENTS AVAILABLE:
Antacids: Antacids are often used as first line
therapy in patients with mild to moderate GERD21. These work by
neutralizing acidic gastric juices secreted by parietal cells, resulting in
intragastric pH >4.0. At this pH, the conversion of pepsinogen into pepsin
is reduced 22. Also, neutralization of gastric fluids leads to
increased LES pressure. If taken after meals as opposed to an empty stomach,
antacids can reduce gastric acidity for upto 3 hours because they only neutralize
existing acid thus revealing symptoms rather than prevention of acid secretion.
Patients who require frequent use of antacids for chronic symptoms should be
treated with acid- suppression therapy because their illness is considered more
significant. These need to be administered several times a day because of their short duration of action. Antacids or their
combinations may cause gastrointestinal adverse events (diarrhea or
constipation), alteration in mineral metabolism and acid base disturbances
depending on the salt included in the product.
For example, magnesium salts cause diarrhea due to their osmotic effect,
whereas both calcium and aluminum containing antacids have been reported to
cause constipation23. Antacids interact with a variety of drugs by
altering gastric pH, increasing urinary pH, adsorbing medications to their surfaces, providing a physical barrier to the
absorption or forming insoluble complexes with other medications. Antacids are
recommended only for patients with mild periodic symptoms. A European study has
also recommended calcium or magnesium-based antacids to be used in pregnancy
because of their safety record24.
H2 receptor antagonists:
H2 receptor antagonists are effective in
treating patients with mild to moderate GERD. The H2 receptor
antagonists (Cimetidine, Ranitidine, Famotidine and Nizatidine) competitively
and reversibly inhibit histamine at H2 receptor located on the
gastric parietal cells resulting in reduced gastric acid secretion25.
H2 receptor antagonists are appropriate for the prevention of
symptoms such as heartburn, however these doses are not adequate in patients
with evidence of esophagitis26. For non erosive diseases, H2
receptor antagonists are generally given at a standard dose twice daily.
Although the H2 receptor antagonists are relatively benign drugs,
adverse effects have been reported including headache, dizziness, fatigue,
diarrhea, thrombocytopenia and rashes27. Drug interactions are most
common with Cimetidine, a medication that inhibits most isozymes of the
Cytochrome P-450 system. Compared with the more potent Proton Pump Inhibitors (PPIs) H2 receptor antagonists
provide the advantage of prompt relief of heartburn and can be administered as
supplement to improve nocturnal gastric acid control in GERD patients taking
PPIs28.
Proton Pump Inhibitors (PPIs):
These are superior to H2 receptor
antagonists; both in their ability to control
symptoms and to heal esophagitis in patients with GERD29. PPIs are
the most potent acid suppressants available today30. These agents
bind irreversibly and non-competitively to the H+/K+ ATPase
pump thereby inhibiting the acid secretion. The PPIs act by interfering with
this final step in acid secretion31.
Due to their long duration of action, these agents can be administered
every 24 hours, with potentially improved adherence to treatment. It has been
proved that patients with non cardiac chest pain respond to PPIs better than to
placebo32. The most common side effects reported with the PPIs in
clinical trials included nausea, diarrhea, constipation, abdominal pain,
headache and dizziness33.
PPIs are currently the most effective agents available for gastric acid
suppression.
Promotility Agents:
GERD is partially characterized by a disorder of
motility. Promotility agents include Metoclopramide, Bethanechol and Cisapride.
Metoclopramide is a Dopamine antagonist that promotes motility by increase in
(i) LES tone (ii) peristalsis in stomach (leading to increased emptying) and
(iii) peristalsis in the duodenum leading to a reduced transit time. Healthcare
providers often are reluctant to prescribe these medications because they have
fairly significant side effects like anxiety, depression, insomnia,
hallucination34. Bethanechol is a cholinergic agent that increases
LES tone but it has been associated with side effects such as blurred vision,
abdominal cramps, sweating, lachrymation, headache and gastrointestinal
discomfort.
NON PHARMACOLOGICAL TREATMENT:
Lifestyle Modifications:
Patients with GERD may experience symptoms after the
ingestion of a large, fatty or spicy meal. They may also experience reflux at
night while in a recumbent position, because during this time, swallowing,
saliva production, and esophageal peristalsis are decreased or virtually absent35.
Lifestyle modifications should be encouraged in all patients with GERD. The
most common lifestyle changes that a patient should be educated about include:
a)
Maintain
a Healthy body weight.
b)
Avoid
large meals and eating with three hours of bed time.
c)
Avoidance
of foods, medications that exacerbate GERD.
d)
Stop
smoking.
e)
Elevation
of the Head of the bed.
f)
Avoid
alcohol.
g)
Limit
fatty or greasy foods, chocolates, coffee, caffeine and other irritating foods.
h)
Maintain
good posture, especially while seated.
i)
Avoid
working out, bending or stopping on a full stomach.
SURGICAL TREATMENT:
Surgery is never the first option for treating GERD.
Changes in lifestyle and habits, non prescription antacids and prescription
medications all must be tried before resorting to surgery. Surgical fundoplication
can correct the cause of the disease and prevent the need for long term
medication. Testing should be done in selected patients who might benefit from
surgery. It includes esophageal manometry, upper gastrointestinal endoscopy,
24h esophageal pH monitoring and gastric emptying studies36.
Patients with persistent GERD symptoms while receiving
PPIs therapy (i.e. PPI failures) should be referred for surgical treatment only
if their symptoms have been documented as associated with acid or non acid reflux,
because patients with symptoms not related to reflux are unlikely to benefit
from surgery. Contraindications to performing surgical interventions are major
esophageal motility abnormalities i.e. achalasia, scleroderma and severe
ineffective esophageal motility.
MISSCELLANEOUS:
The Stretta procedure or delivery of radiofrequency
energy to the LES is a new endoscopic technique of treating reflux37.
The system works by endoscopically identifying the LES and measuring the
distance from the incisors38. The device acts to ablate nerves in the lower esophagus and cardia of the
stomach which relaxes the LES. A catheter (20 Fr) with a balloon at the tip is
passed orally and positioned at the LES. The balloon is deployed and four small
metallic prongs on the edge of the balloon are imbedded into the esophageal
wall. Radiofrequency energy is applied to create small thermal lesions while
keeping the mucosa safe with water cooling. Intramuscular scar tissue built up
in 3 to 6 months post Stretta, which functions to bolster the lower esophageal
sphincter function39. Endoscopic injection of materials into the
gastroesophageal junction was first reported by O’Connor and Lehman in 10
patients. They used Bovine collagen and demonstrated the augmentation of LES
and reduction in symptoms of reflux40. There may be new hope for
GERD sufferers from magnetic beads. A device called as LINX reflux management
system is made of flexible band of magnetic beads. This device is placed during
a 20-30 minute laparoscopic surgical procedure. The beads are made up of
permanent rare earth magnets encased in titanium. Each band is sized to fit the
individual patient. The band stretches to allow food to pass, but prevents the
reflux of acid. For many years, acid suppressive therapy has been at the fore
front of treating gastroesophageal reflux disease. Yet, despite the advent of
the PPIs, some patients continue to experience persistent GERD symptoms. LES
was once thought to be the main structure providing a pressure barrier between
the esophagus and the stomach. Therapeutic options for such patients are
currently limited. Preclinical research has identified a number of drug targets
through which TLESRS can be modulated, and the gamma amino butyric acid (GABA)
receptor has emerged as one of the most promising one41. More recent
studies have shown that it consists of two subunits: GABAa and GABAb
that assemble as a hetero dimer in neuronal cell membrane42. The
GABAb receptor is coupled negatively to adenylyl cyclase and voltage
gated calcium channels and positively to inwardly rectifying potassium channels43.
It exerts an inhibitory effect on neuronal transmission by opening the
potassium channels and closing the potassium
channels, with the former mechanism appearing to predominate in vagal afferent.
Studies with baclofen, a well known agonist of this receptor, have demonstrated
that reflux inhibition is a valid concept in the clinical setting in that
reducing the incidence of GERD symptoms.
Fig. 1: Algorithm for the treatment of patients with gastroesophageal
reflux disease. EGD: esophagogastroduodenoscopy; OTC: over the counter; H2-RA:
histamine 2- receptor antagonist; PPI: proton pump inhibitor
CONCLUSION:
GERD is a chronic condition that affects a large
population of the adult population. It involves the breakdown of the
physiologic mechanisms that protect the lining of the esophagus including LES
pressure, gastric motility, mucosal integrity and esophageal clearance. The
chronic relapsing nature of GERD continues to propel the investigation into
therapies that are cost effective as well as therapeutically successful. The
most effective medical treatment targets gastric acid suppression, allowing
healing of the erosive/ peptic erosion and controlling the symptoms. For the
medical treatment of GERD, PPIs are potent acid suppressants with favorable
side effects and long term efficacy and safety. Surgery should be offered to
patients with GERD as an alternative to long term anti reflux medication.
Careful selection of appropriate surgical candidate is important and the
possibility of developing new or recurrent symptoms requiring medications
should be disclosed to the patients.
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Received on 14.01.2010
Accepted on 15.02.2010
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Research J. Pharmacology and
Pharmacodynamics 2(2): March –April 2010: 160 -164