The
digestive tract is the disassembly line of the body where food is broken down
into less complex subunits and the food nutrients become available to the body.
From the mouth to the anus the digestive tract is approximately 30 feet long
(Marieb, 2001). It is made up of the oral cavity, pharynx, esophagus, stomach,
small intestine, and large intestine (Marieb, 2001). The intestinal tract's
main functions are to breakdown nutrients and transfer those nutrients and
water from the external environment to the internal environment where the
circulatory system delivers them to cells (Marieb, 2001).
The
process of digestion begins with chewing. Chewing mechanically breaks up food
into smaller pieces that can be swallowed. The salivary glands secrete a mucous
solution into the mouth that moistens and lubricates food particles. Saliva
contains amylase, an enzyme that begins to digest carbohydrates (Marieb,
2001).
The
pharynx and esophagus provide the pathway by which ingested food and drink
reach the stomach. Peristalsis (a wavelike muscular contraction) moves food
down the esophagus into the stomach (Marieb, 2001). Once food reaches the
stomach, it is stored, dissolved and partially digested into a solution of
hydrochloric acid: enzymes and food particles that are called chyme (Marieb,
2001). Then the stomach pushes the fluid and partially digested food into the
duodenum and small intestine to be further digested and absorbed (Marieb,
2001). The large intestine stores the material undigested by the small
intestine and concentrates it by absorbing water (Marieb, 2001). Each part of
the digestive tract plays an important role in the digestion of food.
Stomach
Acid Production:
The
parietal cell is responsible for the secretion of protons as hydrochloric acid
into deep invaginations of the cell membrane called canaliculi (Marieb, 2001).
These are continuous with the gastric lumen (Marieb, 2001). It does this by use
of the H+/K+ATPase contained in the “proton pump”. The
proton pump is composed of two protein subunits (Barrison, 2001). The larger,
catalytic subunit is made up of 1033 amino acids and the smaller; glycosylated
subunit has 291 amino acids (Barrison, 2001). The catalytic subunit has a large
cytoplasmic element, a small intramembrane domain and a very small
extracytoplasmic piece (Barrison, 2001). The glycosylated subunit has a small
cytoplasmic element, a single membrane-spanning helix and a large, glycosylated
extracytoplasmic domain (Barrison, 2001). The pump exchanges H+ for
K+ when a K-Cl transport pathway is parallel to the pump (Barrison,
2001).
When the cell is at rest, proton pumps reside in the cytoplasm in
tubulovesicular membranes. When acetylcholine, histamine, or gastrin, proton
pumps stimulate the parietal cell and K-Cl conductance channels are transported
to and then fused into the canalicular membrane. The cell can then begin the
active transport of protons to produce gastric acid (Barrison, 2001).
The production of gastric acid begins with the generation of H+. Intracellular
CO2 and H2O combine in a reaction catalyzed by carbonic
anhydrase to form H2CO3. This dissociates into H+
and HCO3-. HCO3- is extruded into
the interstitial fluid where it is exchanged for another anion: Cl- (Marieb,
2001). This maintains the intercellular pH. Cl- and K+
are transported into the lumen of the canaliculus by the K-Cl transport pathway
(Barrison, 2001). The proton pump then exchanges intracellular H+
for the K+ in the canaliculi. Because the H+ creates an osmotic
gradient across the cell membrane, H2O diffuses out of the parietal
cell into the gastric lumen (Barrison, 2001). This allows the cell to maintain
its internal pH and concentration of cellular constituents while producing a
very low gastric pH. There are three pathways leading to acid production by the
parietal cells: the acetylcholine, gastrin, and histamine receptor pathways
(Marieb, 2001). These three pathways are in constant interaction and overlap
with each other. Acetylcholine is secreted at the sight, smell and taste of
food; gastrin and histamine are released when there is food in the stomach. The
binding of acetylcholine, gastrin, or histamine to a specific receptor on the
parietal cell initiates process that produces stomach acid (Marieb, 2001).
The
sight, smell, and taste of food cause salivation and stimulation of the vagus
nerve that release acetylcholine (Marieb, 490). When acetylcholine binds to its
receptor, the parietal cell’s calcium ion channels open. This allows calcium
ions to move into the cell. The intracellular increase in calcium concentration
activates the intracellular protein phosphokinases (Marieb, 2001). The increase
in active protein phosphokinases results in the translocation of H+-K+-ATPase
to the secretory canaliculus, where the extracellular aspect of the pump is
exposed to potassium ions. The proton pump exchanges potassium ions for
hydrogen ions. Chloride ions diffuse across the parietal cell membrane, via
chloride channels, from the bloodstream to the secretory canaliculus where they
combine with protons to form hydrochloric acid (Marieb, 2001).
Protein in the stomach chemically stimulates the
release of gastrin from G-cells located in the gastric pits of the stomach
mucosa. Stretching of the stomach’s rugae, folds in the stomach triggers
stretch sensors in the stomach. The sensors inform the brain the stomach is
full and then release acetylcholine from the vagus nerve. This further
stimulates the G cells to produce gastrin. Gastrin travels through the
bloodstream and binds to the gastrin receptor on the parietal cells, located in
the gastric gland. When gastrin binds to its receptor the parietal cell’s
calcium ion channels open, allowing calcium ions to enter the cell. The intracellular
increase in calcium activates the intracellular protein phosphokinases. The
increase in active protein phosphokinase stimulates the proton pump increasing
acidity as in the acetylcholine pathway (Marieb, 2001).
Almost
everyone experiences a little acid reflux, particularly after meals. Acid
reflux irritates the walls of the esophagus, inducing a secondary peristaltic
contraction of the smooth muscle, and may produce the discomfort or pain known as
heartburn. Most episodes of acid reflux are asymptomatic.
After
a meal, the lower esophageal sphincter (LES) usually remains closed. When it
relaxes, it may allow acid and food particles to reflux into the esophagus. The
lower esophageal sphincter is a ring of thick circular, smooth muscle. At rest,
the LES maintains a high-pressure between 15 and 30 mm Hg above stomach
pressures. The LES relaxes before the esophagus contracts and allows food to
pass through to the stomach. After food passes into the stomach, the LES
constricts to prevent the contents from regurgitating into the esophagus. The
LES of many individuals with GERD either does not shut completely or the
control of opening and closing malfunctions.
The
inability for individuals with GERD to effectively clear their esophagus is
another factor that increases esophageal acid exposure. Although peristalsis
occurs, esophageal clearance is ineffective because of decreased amplitude of
secondary peristaltic waves (Bytzer, 2003). Patients with pathologic reflux
often experience many episodes of short-duration reflux and/or several
prolonged episodes where the acid may stay in the esophagus for up to several
hours.
Although
the duration of esophageal acid exposure correlates with the frequency of symptoms,
as well as the extent and severity of esophageal mucosa injury, the degree of
mucosa damage can be accelerated if luminal pH is less than 2, or if pepsin or
conjugated bile salts are present in the refluxate. Pathologic conditions
associated with GERD include erythema, isolated erosion, confluent erosions,
circumferential erosions, deep ulcers, esophageal stricture, replacement of
normal esophageal epithelium with abnormal epithelium, pulmonary aspiration,
chronic cough and reflux laryngitis. A physician can diagnose and evaluate the
severity of GERD (Bytzer, 2003).
GERD
is caused by a combination of conditions that increase the presence of acid
reflux in the esophagus. These conditions include transient LES relaxation,
decreased LES resting tone, impaired esophageal clearance, delayed gastric
emptying, decreased salivation and impaired tissue resistance. Other factors
that may increase the frequency of the symptoms of GERD in some patients
include smoking, caffeine, chocolate, fatty foods, overeating with gastric
distention, tight clothing, the presence of a hiatal hernia and certain
medications (Fass, 2003).
Saliva,
which has a pH of 7.8 to 8.0, is rich in bicarbonate and can normally
neutralize the residual acid coating the esophagus after a secondary
peristaltic wave. Swallowing allows the saliva to enter the esophagus to buffer
the acid. Decreasing salivation can contribute to the duration of esophageal
acid exposure (Fass, 2003).
Tissue
resistance in the esophagus consists of the cell membranes and intercellular
functional complexes. These protect against acid injury by limiting the rate of
hydrogen ions diffusing into the epithelium. The esophagus also produces
bicarbonate, to buffer the acid, and mucus, which forms a protective barrier on
the epithelial surface. The resistance of the esophageal mucosa to acid damage
is much less than that of the stomach lining. When esophageal damage occurs,
there is too much acid and pepsin present for a given level of mucosa
protection. The pepsin in the acid refluxate can damage the esophagus by
digesting epithelial protein and cause ulcers (Fennerty, 2002).
Transient
LES relaxation (TLESR) is the mechanism by which reflux occurs in healthy
people. Most individuals with GERD have a normal resting LES tone. TLESRs are
the dominant cause of reflux in these individuals, occurring in up to 82% of
reflux episodes (Fass, 2003). TLESRs is the relaxing of the LES. This
relaxation causes acid to reflux. If the sphincter remains relaxed, more and
more acid is admitted into the esophagus with a higher frequency (Fass, 2003).
No medication exists to treat GERD by preventing transient LES relaxation only
surgery (Harris, 2003).
If
gastric emptying is delayed, the gastric fluid volume is increased. Delayed
gastric emptying is believed to contribute to a small proportion of GERD cases
by increasing the amount of fluid available for reflux. The increase in gastric
fluid volume also increases the pressure in the stomach. When the pressure
becomes greater than 30 mmHg, the LES can no longer suppress the fluid and it
refluxes (Fennerty, 2002).
The excessive
reflux in patients with GERD overwhelms the intrinsic mucosa defense
mechanisms. This results in many symptoms. The most common symptom of GERD is
heartburn. Besides the discomfort of heartburn, reflux results in symptoms of
esophageal inflammation, such as odynophagia (pain on swallowing) and dysphagia
(difficult swallowing) (Fennerty, 2002). The acid reflux may also cause
pulmonary symptoms such as coughing, wheezing, asthma, aspiration pneumonia and
interstitial fibrosis; oral symptoms such as tooth enamel decay, gingivitis,
halitosis and water brash; throat symptoms such as a soreness, laryngitis,
hoarseness and earache (Fennerty, 2002).
Nexium (esomeprazole)
The active ingredient in Nexium is esomeprazole, a
proton pump inhibitor (PPI) that works by binding to parietal cells in the
stomach and inhibiting the release of protons into the stomach which reduces
the amount of stomach acid produced (Levine, 2002). Nexium is used to treat a
wide range of patients, including both the newly diagnosed and patients
switched from other therapies. Nexium is used to treat the (GERD) where acid
from the stomach escapes into the esophagus causing inflammation and heartburn
(a burning feeling rising from the stomach or lower chest up towards the neck).
Nexium also treats ulcers in the stomach or upper part of the intestine
associated with infection by the bacterium "Helicobacter pylori",
which is treated by a combination of esomeprazole and antibiotics. However,
gastroesophageal reflux disease will be exclusively covered in this paper.
Nexium
works by binding irreversibly to the hydrogen/potassium APTase in the proton
pump (Dev Bardhan, 2003). The binding to the pump disables the transport of
proton into the stomach; this is achieved by blocking or closing the transport
channel (Dev Bardhan, 2003). Because the proton pump is the final pathway for
secretion of hydrochloric acid by the parietal cells in the stomach, its
inhibition dramatically decreases the secretion of protons that produce
hydrochloric acid in the stomach and alters the gastric pH (Barrison,
2001).
In
the liver a number of enzymes for metabolizing chemicals in the blood are
found. One family of enzymes is called the cytochrome P450 system. There are
two important liver enzymes from the cytochrome P450 family involved in Nexium
metabolism, CYP2C19, which is called sip2C19, and the other is CYP3A4, which is
called sip3A4 (Quigley, 2003).
Most
CYP450 enzymes in humans are located in the liver, where nearly all-chemical
metabolism occurs. These enzymes catalyze many types of reactions. The most
important being hydroxylation. The goal of all of the reactions is to make
chemicals more water-soluble so that the kidneys can excrete them. While the
CYP450 enzyme usually inactivates chemicals, they can change inactive compounds
into active compounds (Quigley, 2003).
Chemicals
that inhibit a certain CYP450 are not necessarily those metabolized by that
enzyme, and chemicals that are metabolized by an enzyme do not necessarily
inhibit it. Thus, drug-drug interactions are related to the effect of
concurrent use of those drugs on the CYP450 enzyme family. In addition, some
drugs are metabolized by more than one CYP450 enzyme, so predicting the effects
of the simultaneous use of another drug may become more complex. Finally, drugs
that are a mix of isomers often are metabolized as two separate drugs (Quigley,
2003).
Conclusion
Heartburn
and other symptoms of GERD have been relieved through the use of Nexium, a
proton pump inhibitor (DeVault, 2002). Many things can cause GERD, though
Nexium does not fix the problem it does reduce discomfort and pain (DeVault,
2002). The main symptom of GERD is heartburn: the reflux of acid from the
stomach up the esophagus. This causes irritation as the refluxant burns the
esophageal lining. Nexium reduces the amount of acid produced in the stomach
and therefore reduces the amount of acid in the refluxant, reducing discomfort
and pain.
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Koni Stone