Peptic ulcer disease (PUD):
a condition in which there is a discontinuity
in the entire thickness of the gastric or duodenal mucosa that persists as a
result of acid and pepsin in the gastric juice.
In the stomach, mucus and bicarbonate,
stimulated by the local generation of prostaglandins, protect the gastric
mucosa.
If
these defences are disrupted, a gastric or duodenal ulcer may form.
Infection with Helicobacter pylori and
use of NSAIDs also play a key role in the pathogenesis of acid-peptic diseases
and these factors should be considered in treatment and prevention
of PUD
Nonsteroidal
anti-inflammatory drug (NSAID) use,
Infection
with gram-negative Helicobacter pylori,
Increased
hydrochloric acid secretion, and
Inadequate mucosal defense against gastric
acid.
Treatment and prevention
of PUD
Accomplished
either by:
Reducing
secretion of gastric acid with the use of H2-receptor antagonists or
PPIs,
Enhancing mucosal protection with agents such
as misoprostol and sucralfate,
Eradicating
the H. pylori infection.
Gastro-esophageal reflux
disease (GERD)
Occurs when protective barriers to the reflux
of gastric contents into the esophagus fail.
Reflux of gastric contents into the oesophagus
may result in dyspepsia and erosive esophagitis.
Treatment approaches to GERD
Treatment is directed at:
Decreasing
gastric acidity,
Enhancing
the lower esophageal sphincter pressure,
Stimulating esophageal motility.
Physiology of gastric
secretions
Gastric acid secretion by parietal cells of the
gastric mucosa is stimulated by:
acetylcholine, histamine, and gastrin
Binding
of Ach (M3) and gastrin on the parietal cell receptors results in an
increase in cytosolic calcium which stimulates protein kinases that stimulate
acid secretion from the H+/K+ ATPase on the canalicular surface.
The
H+/K+-ATPase secretes H+ in exchange for K+ into the lumen of the stomach.
Physiology of gastric secretions (cont’d)
Special endocrine cells of the stomach, known
as enterochromaffin-like (ECL) cells have receptors for Ach and gastrin and are
the source of histamine.
Histamine binds to the H2 receptors on the
parietal cells resulting in activation of adenylyl cyclase
This
leads to an increase in intracellular second messenger cAMP.
Activation of cAMP dependent protein kinases
results in stimulation of H+-K+ pump.
Gastric and oesohageal defenses against acidity
The high acid concentration in the gastric
lumen requires defence mechanisms to protect the esophagus and the stomach.
The primary esophageal defense is the lower
esophageal sphincter which prevents reflux of acidic gastric contents into the
esophagus.
Gastric and oesohageal defenses against acidity
The stomach protects itself from acid damage by
a number of mechanisms:
The most important defense is the secretion of
a mucus layer that protects gastric epithelial cells.
Gastric
mucus is soluble when secreted but quickly forms an insoluble gel that coats
the mucosal surface of the stomach, slows ion diffusion, and prevents mucosal
damage by macromolecules such as pepsin.
Mucus
production is stimulated by prostaglandins E2 and I2, which also directly
inhibit gastric acid secretion by parietal cells.
Therefore
alcohol, aspirin, and other drugs that inhibit prostaglandin formation decrease
mucus secretion and predispose to the development of peptic ulcer disease.
Gastric and oesohageal defenses against acidity
Another mucosal defense is the secretion of
bicarbonate ions by superficial gastric epithelial cells.
Bicarbonate
neutralizes the acid in the region of the mucosal cells, thereby raising pH and
preventing acid-mediated damage.
Gastric and oesohageal defenses against acidity
There is also an elaborate system for
regulating the amount of acid secreted by the stomach. Gastric luminal pH is a
sensitive regulator of acid secretion.
Proteins
in food provide buffering in the lumen; consequently, the gastric luminal pH is
usually above 3 after a meal.
However,
if the buffering capacity of protein is exceeded or if the stomach is empty,
the pH of the gastric lumen will fall below 3. When this happens,the endocrine
cells (D cells) in the antrum secrete somatostatin, which inhibits the release
of gastrin and, thus, gastric acid secretion.
Another
mechanism for inhibiting gastric acid secretion is acidification of the
duodenal lumen.
Acidification stimulates the release of
secretin, which inhibits the release of gastrin, and several peptides,
collectively known as enterogastrones (e.g. cholecystokinin, gastrin releasing
peptide), which are released by intestinal endocrine cells.
Agents used in PUD and GERD:
Proton Pump Inhibitors (PPIs)
Proton pump inhibitors are the most potent
inhibitors of the gastric H+/K+ pump.
In therapeutic doses they decrease both the
basal and stimulated production of gastric acid by 80-95%.
PPIs: Mechanism of action
All PPIs are prodrugs with an acid-resistant
enteric coating to protect them from premature degradation by gastric acid.
The coating is removed in the alkaline
duodenum, and the prodrug, a weak base, diffuses into the parietal cells of the
stomach and accumulate on the luminal side of parietal cells acidic secretory canaliculi.
At the parietal cell canaliculus, the
prodrug is converted to the active form,
which reacts with a cysteine residue of the H+/K+-ATPase, forming a stable
covalent bond.
This results in irreversible inactivation of
the pump molecule.
PPIs: Mechanism of action
Acid secretion resumes only after new pump
molecules are synthesized and inserted into the luminal membrane,
PPIs thus provide a prolonged (up to 24–48
hour) suppression of acid secretion, despite the much shorter plasma half-lives
(0.5–2 hours) of the parent compounds.
Since these drugs block the final step in acid
production, they are very effective in acid suppression regardless of other
stimulating factors.
PPIs: Pharmacokinetics
In a fasting state, only 10% of proton pumps
are actively secreting acid and susceptible to inhibition.
Therefore proton pump inhibitors should be
administered approximately 1 hour before a meal so that the peak serum
concentration coincides with the maximal activity of proton pump secretion.
The drugs have a short serum half-life of about
1.5 hours but the duration of acid inhibition lasts up to 24 hours due to the
irreversible inactivation of the proton pump.
PPIs: Pharmacokinetics
At least 18 hours are required for synthesis of
new H+/K+ ATPase pump molecules.
Because not all proton pumps are inactivated
with the first dose of medication, up to 3–4 days of daily medication are
required before the full acid inhibition is achieved.
Similarly, after stopping the drug, it takes
3–4 days for full acid secretion to return.
PPIs: Pharmacokinetics
Once in the small bowel, PPIs are rapidly
absorbed, highly protein bound, and extensively metabolized by hepatic CYPs,
particularly CYP2C19 and CYP3A4.
Proton pump inhibitors undergo rapid first-pass
and systemic hepatic metabolism and have negligible renal clearance.
Dose reduction is not needed for patients with
renal insufficiency or mild to moderate liver disease but should be considered
in patients with severe liver impairment.
Although other proton pumps exist in the body,
the H+/K+ ATPase exists only in the
parietal cell and is distinct structurally and functionally from other H+
transporting enzymes.
PPIs: Adverse effects
The most common are nausea, abdominal pain,
constipation, flatulence, and diarrhea.
Myopathy, arthralgias, headaches, and rashes
also have been reported.
Hypergastrinemia is more frequent and more
severe with PPIs than with H2- receptor antagonists.
This
hypergastrinemia may predispose to rebound hypersecretion of gastric acid upon
drug discontinuation.
PPIs: Drug Interactions
Omeprazole inhibits the metabolism of warfarin,
phenytoin, diazepam, and cyclosporine. However, drug interactions
are not a problem with the other PPIs.
Prolonged therapy with agents that suppress
gastric acid, such as the PPIs and H2 antagonists, may result in low vitamin
B12, because acid is required for its absorption.
Increasing gastric pH increases the potential
for incomplete absorption of calcium carbonate products.
An
effective option would be to use calcium citrate as a source of calcium by
patients taking prolonged acid-suppressing medications. The absorption of the
citrate salt is not affected by gastric pH.
PPIs: Drug Interactions
Loss of gastric acidity from chronic PPI
treatment may affect the bioavailability of such drugs as ketoconazole,
ampicillin esters, and iron salts.
Chronic therapy with PPIs has been linked to
increased frequency of hip fractures which are secondary to decreased
absorption of calcium.
PPIs: Therapeutic uses
PPIs are used principally to promote healing of
gastric and duodenal ulcers
Used to treat gastroesophageal reflux disease
(GERD), including erosive esophagitis, that is either complicated or
unresponsive to treatment with H2- receptor antagonists.
PPIs
also are the mainstay in the treatment of pathological hypersecretory
conditions such as the Zollinger-Ellison syndrome.
PPIs: Therapeutic uses
PPIs are also used for treatment and prevention
of recurrence of NSAID-associated gastric ulcers in patients who continue NSAID
use
They are also used for reducing the risk of duodenal ulcer
recurrence associated with H. pylori infections.
H2-Receptor Antagonists
These agents inhibit acid production by
reversibly competing with histamine for binding to H2–receptors on basolateral
membranes of parietal cells to prevent histamine induced stimulation of gastric
acid secretion.
They are
less potent than proton pump inhibitors but still suppress 24-hour gastric acid
secretion by ~70%.
The H2 -receptor antagonists predominantly
inhibit basal acid secretion, which accounts for their efficacy in suppressing
nocturnal acid secretion.
Because
the most important determinant of duodenal ulcer healing is the level of
nocturnal acidity, evening dosing of H2- receptor antagonists is usually adequate.
Examples include cimetidine, ranitidine,
famotidine and nizatidine. These drugs are available for oral administration
while intravenous and intramuscular preparations of cimetidine, ranitidine, and
famotidine are also available.
H2-Receptor Antagonists:
Pharmacokinetics
H2-receptor antagonists are rapidly absorbed after oral administration, with
peak serum concentrations within 1–3 hours.
Therapeutic levels are achieved rapidly after
intravenous dosing and are maintained for 4–5 hours (cimetidine), 6–8 hours
(ranitidine), or 10–12 hours (famotidine).
Unlike proton pump inhibitors, only a small
percentage of H2-receptor antagonists are protein-bound.
The kidneys excrete these drugs and their
metabolites by filtration and renal tubular secretion.
It is
therefore important to reduce doses of H2 receptor antagonists in patients with
decreased creatinine clearance.
Pharmacokinetics: Cimetidine
Cimetidine and the other H2 antagonists are
given orally, distribute widely throughout the body (including into breast milk
and across the placenta), and are excreted mainly in the urine
Cimetidine normally has a short serum
half-life, which is increased in renal failure.
Approximately 30% of a dose of cimetidine is
slowly inactivated by the liver's microsomal mixed-function oxygenase system
and can interfere with the metabolism of
many other drugs; the other 70 percent is excreted unchanged in the urine.
The dosage of all these drugs must be decreased
in patients with hepatic or renal failure.
Cimetidine inhibits cytochrome P450 and can
slow metabolism (and, thus, potentiate the action) of several drugs (for
example, warfarin, diazepam, phenytoin, quinidine, carbamazepine, theophylline,
and imipramine; , sometimes resulting in serious adverse clinical effects.
Pharmacokinetics: Ranitidine
Compared to cimetidine, ranitidine is longer
acting and is five- to ten-fold more potent.
Ranitidine has minimal side effects and does
not produce the antiandrogenic or prolactin-stimulating effects of cimetidine.
Unlike
cimetidine, it does not inhibit the mixed-function oxygenase system in the
liver and,thus, does not affect the concentrations of other drugs.
Pharmacokinetics: Famotidine
Famotidine is similar to ranitidine in its
pharmacologic action,
However, it is 20 to 50 times more potent than
cimetidine, and 3 to 20 times more potent than ranitidine.
Pharmacokinetics: Nizatidine
Nizatidine is similar to ranitidine in its
pharmacologic action and potency.
In contrast to cimetidine, ranitidine, and
famotidine, which are metabolized by the liver, nizatidine is eliminated
principally by the kidney.
Because little first-pass metabolism occurs
with nizatidine, its bioavailability is nearly 100 percent.
No intravenous preparation is available.
H2-Receptor Antagonists:
Therapeutic uses
Peptic ulcers:
All
four agents are equally effective in promoting healing of duodenal and gastric
ulcers.
However,
recurrence is common after treatment with H2 antagonists is stopped (60-100%
per year).
Patients
with NSAID-induced ulcers should be treated with PPIs, because these agents
heal and prevent future ulcers better than H2 antagonists.
H2-Receptor Antagonists: Therapeutic uses
Acute stress ulcers:
These
drugs are useful in managing acute stress ulcers associated with major physical
trauma in high-risk patients in intensive care units.
They
are usually injected intravenously.
H2-Receptor Antagonists: Therapeutic uses
Gastroesophageal reflux disease:
Low
doses of H2 antagonists (sold OTC) appear to be effective for prevention and
treatment of heartburn (gastroesophageal reflux).
However,
about 50 percent of patients do not find benefit, and PPIs are now used
preferentially in the treatment of this disorder.
Because
H2-receptor antagonists act by stopping acid secretion, they may not relieve
symptoms for at least 45 minutes.
Antacids
more efficiently, but temporarily, neutralize secreted acid already in the
stomach.
Finally,
tolerance to the effects of H2 antagonists can be seen within 2 weeks of
therapy.
H2-Receptor antagonists:
Adverse effects
The H2 -receptor antagonists are generally well
tolerated, with a low (<3%) incidence of adverse effects. These include:
Diarrhea , headache, drowsiness, fatigue,
muscular pain, and constipation.
Less common adverse effects include those
affecting the CNS (confusion, delirium, hallucinations, slurred speech, and
headaches), which occur primarily with intravenous administration or in elderly
subjects.
H2-Receptor antagonists: Adverse effects
Cimetidine can also have endocrine effects
because it acts as a non-steroidal antiandrogen.
The
effects include galactorrhoea in women and gynecomastia, reduced sperm count
and impotence in men.
This
occurs because at high doses cimetidine
decreases testosterone binding to the androgen receptor and inhibits CYP
1B1 that hydroxylates estradiol.
H2 receptor antagonists have been associated
with various blood dyscrasias including granulocytopaenia, thrombocytopenia and
pancytopaenia.
H2-Receptor antagonists: Drug Interactions
Cimetidine is partly metabolized by CYP 450
system.
Therefore
co-administered drugs such as warfarin, benzodiazepines and theophylline which
are also metabolized by this system may accumulate if their doses are not
adjusted.
Ranitidine,
famotidine and nizatidine do not alter CYP 450 metabolism of drugs and are also
not associated with gynaecomastia.
Tolerance to acid-suppressing medications
Tolerance to the acid-suppressing effects of H2
receptor antagonists results in diminished therapeutic effect with prolonged
use.
Tolerance can develop within 3 days of starting
treatment and may be resistant to increased doses.
Diminished sensitivity may result from the
effect of the secondary hypergastrinemia to stimulate histamine release from ECL
cells.
Although PPIs cause even greater elevations of endogenous
gastrin,they do not cause this
phenomenon because their site of action is distal to the action of histamine on
acid release.
Rebound
hyperacidity with acid-suppressing medications
Rebound increases in gastric acidity can occur
when either of these drug classes is discontinued.
Therefore the drug should be tapered gradually
or other alternatives such as antacids should be used after discontinuing H2
-receptor antagonists or PPIs.
Agents that enhance mucosal defense:
prostaglandin analogs
prostaglandin analogs
PG A, E and PG I inhibit gastric acid secretion and also
stimulate mucus and bicarbonate secretion by the gastric mucosa (cytoprotective
effect).
They bind to the PG E Receptor 3 (EP3 receptor)
which is a GPCR on parietal cells and stimulate the Gi pathway, thereby
decreasing intracellular cyclic AMP and gastric acid secretion.
Since NSAIDs diminish prostaglandin formation
by inhibiting cyclooxygenase, synthetic prostaglandin analogs are used to
reduce NSAID-induced mucosal damage.
Prostaglandin analogs:
Misoprostol
Misoprostol
is a synthetic analog of PGE1 which is used in prevention of
NSAID-induced gastric ulceration.
The degree of inhibition of gastric acid
secretion by misoprostol is directly related to dose.
Oral
doses of 100–200 μg significantly inhibit basal acid secretion (up to 95%
inhibition) or food-stimulated acid secretion (up to 85% inhibition).
The
usual recommended dose for ulcer prophylaxis is 200 μg four times a day.
Pharmacokinetics: Misoprostol
Misoprostol is rapidly absorbed after oral
administration and then is rapidly and extensively de-esterified to form
misoprostol acid, the principal and active metabolite of the drug.
Some of this conversion may occur in the
parietal cells.
A single
dose inhibits acid production within 30 minutes.
Pharmacokinetics: Misoprostol
The therapeutic effect peaks at 60–90 minutes
and lasts for up to 3 hours.
Food and antacids decrease the rate of
misoprostol absorption, resulting in delayed and decreased peak plasma
concentrations of the active metabolite.
The free
acid is excreted mainly in the urine, with an elimination half-life of about
20–40 minutes.
Adverse effects: Misoprostol
Like other prostaglandins, misoprostol produces uterine contractions and is
contraindicated during pregnancy.
Dose-related diarrhea and nausea are the most
common adverse effects and limit the use of this agent.
Misoprostol can cause clinical exacerbations of
inflammatory bowel disease and should be
avoided in patients with this disorder.
Therapeutic uses: Misoprostol
Misoprostol , as well as some PPIs, is approved
for prevention of gastric ulcers induced by NSAIDs.
It is
less effective than H2 antagonists and the PPIs for acute treatment of peptic
ulcers.
Although
misoprostol has cytoprotective actions, it is clinically effective only at
higher doses that diminish gastric acid secretion.
Routine
prophylactic use of misoprostol may not be justified except in patients who are
taking NSAIDs and are at high risk of NSAID-induced ulcers, such as the elderly
or patients with ulcer complications.
Mucosal protective agents
They are also known as cytoprotective
compounds,
They
have several actions that enhance mucosal protection mechanisms, thereby
preventing mucosal injury, reducing inflammation, and healing existing ulcers.
They include sucralfate and bismuth
subsalicylate
Mucosal protective agents:
Sucralfate
This complex of aluminum hydroxide and sulfated
sucrose binds to positively charged groups in proteins of both normal and
necrotic mucosa.
By forming complex gels with epithelial cells,
sucralfate creates a physical barrier
that impairs diffusion of HCl and prevents degradation of mucus by pepsin and
acid.
Mucosal protective agents:
Sucralfate
It also stimulates prostaglandin release as
well as mucus and bicarbonate output, and it inhibits peptic digestion.
By these mechanisms, sucralfate effectively
heals duodenal ulcers and is used in long-term maintenance therapy to prevent
their recurrence.
Mucosal protective agents: Sucralfate
Little of the drug is absorbed systemically.
It is very well tolerated, but it can interfere
with the absorption of other drugs by binding to them.
This agent does not prevent NSAID-induced
ulcers, nor does it heal gastric ulcers.
Sucralfate: Therapeutic uses
Because increased gastric pH may be a factor in
the development of nosocomial pneumonia in critically ill patients, sucralfate
may offer an advantage over proton pump inhibitors and H2 receptor antagonists
for the prophylaxis of stress ulcers.
Due to its unique mechanism of action,
sucralfate also has been used in several other conditions associated with
mucosal inflammation or ulceration that may not respond to acid suppression
e.g. oral mucositis due to radiation and bile reflux gastropathy.
Sucralfate: Dosing considerations
Since it is activated by acid, sucralfate
should be taken on an empty stomach 1 hour before meals.
The use
of antacids within 30 minutes of a dose of sucralfate should be avoided.
The usual dose of sucralfate is 1 g four times
daily for active duodenal ulcer or 1 g twice daily for maintenance therapy.
Sucralfate: Adverse effects
The most common side effect of sucralfate is
constipation (~2%).
As some aluminum can be absorbed, sucralfate
should be avoided in patients with renal failure who are at risk for aluminium
overload.
Aluminium
-containing antacids should also not be combined with sucralfate in these
patients.
The “sticky” nature of the viscous gel produced
by sucralfate in the stomach also may lead to the formation of bezoars in some
patients especially in patients with underlying gastroparesis.
Sucralfate: Drug interactions
Sucralfate forms a viscous layer in the stomach
that may inhibit absorption of other drugs, including phenytoin, digoxin,
cimetidine, ketoconazole, and fluoroquinolone antibiotics.
Sucralfate therefore should be taken at least
2 hours after the administration of other drugs.
Mucosal protective agents:
Bismuth subsalicylate
Bismuth subsalicylate
Preparations of this compound effectively heal
peptic ulcers.
In addition to their antimicrobial actions,
they:
inhibit the activity of pepsin,
increase
secretion of mucus, and
interact
with glycoproteins in necrotic mucosal tissue to coat and protect the ulcer
crater.
Antacids
Antacids are weak bases that react with gastric
acid to form water and a salt, thereby diminishing gastric acidity.
Because pepsin is inactive at a pH greater than
4, antacids also reduce pepsin activity.
The rationale for use of antacids in PUD is
based on the fact that buffering of H+ in the stomach permits
healing.
Antacids: Sodium bicarbonate
NaHCO3 (e.g. baking soda, Alka Seltzer) reacts
rapidly with HCl to produce carbon dioxide and NaCl.
Formation of carbon dioxide results in gastric
distention and belching.
Unreacted alkali is readily absorbed,
potentially causing metabolic alkalosis when given in high doses or to patients
with renal insufficiency.
Sodium
chloride absorption may exacerbate fluid retention in patients with heart
failure, hypertension, and renal insufficiency.
Antacids: Calcium carbonate
CaCO3: (e.g. Actal Tums, Os-Cal) is less soluble and
reacts more slowly than sodium bicarbonate with HCl to form carbon dioxide and
CaCl2.
However, the release of CO2 can cause belching, nausea, abdominal
distention, and flatulence.
Antacids: magnesium or aluminium hydroxide containing Formulations
These react slowly with HCl to form magnesium
chloride or aluminum chloride and water.
Because no gas is generated, belching does not
occur.
Metabolic alkalosis is also uncommon because
of the efficiency of the neutralization reaction.
Antacids: magnesium or aluminium hydroxide containing Formulations
Because unabsorbed magnesium salts may cause an
osmotic diarrhea and aluminum salts may cause constipation, these agents are
commonly administered together (eg,
Gelusil, Maalox, Mylanta) to minimize the impact upon bowel function.
Both magnesium and aluminum are absorbed and
excreted by the kidneys.
Hence,
patients with renal insufficiency should not take these agents for long
periods.
Role of simethicone in antacid preparations
Simethicone is
a surfactant that may decrease foaming and hence oesophageal reflux,
For this reason, it is included in many antacid
preparations.
Antacids: Therapeutic uses
For uncomplicated ulcers, antacids are given
orally 1 and 3 hours after meals and at bedtime.
For severe symptoms or uncontrolled reflux,
antacids can be given as often as every 30–60 minutes.
If
tablets are used, they should be thoroughly chewed for maximum effect.
Antacids: Pharmacokinetics
Antacids are cleared from the empty stomach in
~30 minutes.
However, the presence of food is sufficient to
elevate gastric pH to about 5 for ~1 hour and to prolong the neutralizing
effects of antacids for 2–3 hours.
Antacids: Adverse effects
Antacids vary in the extent to which they are
absorbed, and hence in their systemic effects.
Antacids
that contain Al3+, Ca2+, or Mg2+ are absorbed less completely than those containing NaHCO3.
With
normal renal function, the modest accumulations of Al3+and Mg2+do not pose a
problem.
However in renal insufficiency, absorbed
Al3+can contribute to osteoporosis, encephalopathy, and proximal myopathy.
Antacids: Adverse effects
About 15% of orally administered Ca2 +is
absorbed resulting in a transient hypercalcemia.
Although
this is not a problem in normal patients, the hypercalcemia from as little as
3–4 g of CaCO3 per day can be problematic in patients with uremia.
Antacids: Drug Interactions
By altering gastric and urinary pH, antacids
may affect a number of drugs by altering rates of dissolution and absorption,
bioavailability, and renal elimination.
e.g.,
thyroid hormones, allopurinol, and imidazole antifungals)
Antacids: Drug Interactions
Al3+and Mg2+antacids chelate other drugs
present in GI tract, forming insoluble complexes that pass through the GI tract
without absorption.
Thus,
concurrent administration of antacids and drugs intended for systemic absorption
should be avoided.
Most
interactions can be avoided by taking antacids 2 hours before or after
ingestion of other drugs.
Antimuscarinic agents
Muscarinic receptor stimulation increases GIT
motility and secretory activity.
A cholinergic antagonist, such as dicyclomine,
can be used as an adjunct in the management of PUD and Zollinger-Ellison
syndrome, particularly in patients who are refractory to standard therapies.
However, its many side effects (for example,
cardiac arrhythmias, dry mouth, constipation, and urinary retention) limit its
use.
Other acid suppressants and cytoprotective
agents
Rebamipide exerts a cytoprotective effect both by
increasing prostaglandin generation in gastric mucosa and by scavenging reactive
oxygen species.
Ecabet which
increases the formation of PGE2 and PGI2,is also
used for ulcer therapy.
Carbenoxolone, a derivative of glycyrrhizic acid found in
licorice root, has been used with modest success for ulcer therapy .Its exact
mechanism of action is not clear, but it may alter the composition and quantity
of mucin.
Unfortunately,
carbenoxolone inhibits the type 2 isozyme of 11β-hydroxysteroid dehydrogenase, which protects the mineralocorticoid
receptor from activation by cortisol in the distal nephron.
It
therefore causes hypokalemia and hypertension due to excessive
mineralocorticoid receptor activation.
Therapeutic strategies for specific acid-peptic
disorders.
The success of acid-suppressing agents in a
variety of conditions is critically dependent upon their ability to keep
intragastric pH above a certain target, generally pH 3–5.
This target varies to some extent with the
disease being treated.
Treatment of GERD
In some individuals GERD can cause severe erosive esophagitis.
Serious
sequelae include stricture formation and Barrett’s metaplasia
(replacement of squamous by intestinal columnar epithelium), which, in turn, is
associated with a small but significant risk of adenocarcinoma.
Most of the
symptoms of GERD are due to erosive
effects of the refluxed gastric content on the esophageal epithelium
thus providing the rationale for suppression of gastric acid.
The goals of GERD therapy are complete
resolution of symptoms and healing of esophagitis.
Treatment of GERD
PPIs are
more effective than H2 receptor antagonists in achieving these goals.
Healing
rates after 4 weeks and 8 weeks of therapy with PPIs are ~80% and 90%,
respectively, while the corresponding healing rates with H2 receptor
antagonists are 50% and 75%, respectively.
Strictures
associated with GERD also respond better to proton pump inhibitors than to H2
receptor antagonists.
Unfortunately,Barrett’s
esophagus, which is a complication of GERD is usually refractory to therapy, as neither acid
suppression nor antireflux surgery has been shown to produce regression of metaplasia or to
decrease the incidence of tumors.
Antacids are recommended only for the patient
with mild, infrequent episodes of heartburn.
Treatment of GERD in pregnancy
Mild cases of GERD during pregnancy should be
treated conservatively.
Antacids
or sucralfate are considered the first-line drugs.
If
symptoms persist, H2 receptor antagonists can be used, with ranitidine having
the most established safety record in this setting.
PPIs are reserved for women with intractable
symptoms or complicated reflux disease.
In
these situations, lansoprazole is preferred based on animal data and available
experience in pregnant women.
Treatment of PUD
Peptic
ulcer disease is usually a result of an imbalance between mucosal
defense factors (bicarbonate, mucin, prostaglandin) and injurious factors (acid
and pepsin).
H. pylori and exogenous agents such as NSAIDs
interact in complex ways to cause an ulcer.
Up to
60% of peptic ulcers are associated with H. pylori infection of the stomach.
The
effects NSAIDs are usually mediated systemically through suppression of COX-1
in the mucosa and decreased production of the cytoprotective prostaglandins
PGE2 and PGI2.
Treatment of PUD
Although both PPIs and H2-receptor antagonists
are effective in duodenal ulcers, PPIs relieve symptoms of duodenal ulcers and
promote healing more rapidly than do H2 receptor antagonists.
Peptic ulcer
is a chronic disease, and recurrence within 1 year is expected in the majority
of patients who do not receive prophylactic acid suppression.
Treatment of PUD
Because H. pylori plays a major role in the
majority of peptic ulcer, antibiotics are used to eliminate this organism from
the stomach.
Intravenous pantoprazole or lansoprazole are
used in patients with acute bleeding
ulcers.
These
agents result in maximal acid suppression which accelerates healing of the
underlying ulcer.
Treatment of H.pylori infection
H. pylori, a gram-negative bacillus, has been
associated with over 90% of duodenal ulcers and 80% of gastric ulcers.
Eradication of this infection is standard care
in patients with gastric and duodenal ulcers.
The ideal regimen should achieve a cure rate of >90%.
Treatment of H.pylori infection
Current studies demonstrate that the highest
eradication rates are achieved by 1 week of triple therapy consisting of a PPI
and two specified antibiotics.
The most effective 1 week twice daily regimens
have been shown to be:
(OCA)
Omeprazole 20mg, clarithromycin 500mg and amoxicillin 1g
(OCM)Omeprazole
20mg, clarithromycin 250mg and metronidazole 400mg.
Treatment of H.pylori infection
Omeprazole may be replaced with any of the
other PPIs.
Ranitidine bismuth citrate (RBC) is a chemical
entity which incorporates bismuth into the ranitidine molecule and was designed
for H.pylori eradication.
RBC-based
triple therapies have been shown to have
equal efficacy to PPI-based therapies.
H2-receptor antagonists have been shown to be
less effective than PPIs in triple therapy regimens.
Treatment of NSAID-related
ulcers
Chronic NSAID users have a 2–4% risk of
developing a symptomatic ulcer, GI bleeding or perforation.
Ideally, NSAIDs should be avoided in patients
with an ulcer.
Healing of ulcers despite continued NSAID use
is possible with the use of acid-suppressant agents, usually at higher doses
and for a considerably longer duration than standard regimens (e.g., 8 weeks or
longer).
Treatment of NSAID-related ulcers
PPIs are
superior to H2-receptor antagonists and misoprostol in promoting the healing of
active ulcers (healing rates of 80–90% for proton pump inhibitors versus 60–75%
for the H2 receptor antagonists) and in preventing recurrence of gastric and
duodenal ulcers in the setting of continued NSAID administration.
Treatment of stress-related ulcers
Stress ulcers are ulcers of the stomach or
duodenum that occur in the context of a profound illness or trauma requiring
intensive care.
The aetiology of stress-related ulcers differs
from that of other peptic ulcers because it involves acid and mucosal ischemia.
Because
of limitations on the oral administration of drugs in many patients with
stress-related ulcers, intravenous H2 receptor antagonists and PPIs are used to
reduce the incidence of GI hemorrhage due to stress ulcers.
Treatment of Zollinger-Ellison Syndrome
This syndrome consists of a triad of :
non-β
islet cell tumours of pancreas or duodenal gastrinomas that contain and release gastrin ,
gastric
acid hypersecretion and
severe ulcer disease.
Surgical resection of the gastrinoma may be
curative.
Medical management consists of high dose PPIs
(usually given at twice the routine dosage for peptic ulcers).
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