DRUGS IN TREATING

PEPTIC ULCER DISEASE

(PHA 308)
DR. KAZEEM ADEOLA OSHIKOYA
 BACKGROUND
• Peptic ulcer disease can involve the stomach or
duodenum.
• Clinically, it may difficult to differentiate between gastric
and duodenal, although some findings may be suggestive.
• Epigastric pain is the most common symptom of both
gastric and duodenal ulcers, characterized by a gnawing or
burning sensation and that occurs after meals—classically,
shortly after meals with gastric ulcers and 2-3 hours
afterward with duodenal ulcers.
• In uncomplicated peptic ulcer disease, the clinical
findings are few and nonspecific.
• “Alarm features" that warrant prompt
gastroenterology referral include bleeding, anemia,
early satiety, unexplained weight loss, progressive
dysphagia or odynophagia, recurrent vomiting, and a
family history of gastrointestinal (GI) cancer.
• Patients with perforated peptic ulcer disease usually
present with a sudden onset of severe, sharp
abdominal pain.
• In most patients with uncomplicated peptic ulcer
disease, routine laboratory tests usually are not helpful;
instead, documentation of peptic ulcer disease depends
on radiographic and endoscopic confirmation.
• Testing for H pylori infection is essential in all patients
with peptic ulcers.
• Rapid urease tests are considered the endoscopic
diagnostic test of choice.
• Of the noninvasive tests, fecal antigen testing is more
accurate than antibody testing and is less expensive
than urea breath tests but either is reasonable.
• A fasting serum gastrin level should be obtained in
certain cases to screen for zollinger-Ellison syndrome.
• Most patients with peptic ulcer disease are treated
successfully with cure of H pylori infection and/or
avoidance of nonsteroidal anti-inflammatory drugs
(NSAIDs), along with the appropriate use of
antisecretory therapy.
• The recommended primary therapy for H pylori infection
is proton pump inhibitor (PPI)–based triple therapy.
• These regimens result in a cure of infection and ulcer
healing in approximately 85-90% of cases.
• Ulcers can recur in the absence of successful H
pylori eradication.
• In patients with NSAID-associated peptic ulcers,
discontinuation of NSAIDs is paramount, if it is
clinically feasible.
• For patients who must continue with their NSAIDs, proton
pump inhibitor (PPI) maintenance is recommended to
prevent recurrences even after eradication of H pylori.
• Prophylactic regimens that have been shown to
dramatically reduce the risk of NSAID-induced gastric and
duodenal ulcers include the use of a prostaglandin analog
or a PPI.
• Maintenance therapy with antisecretory medications (eg,
H2 blockers, PPIs) for 1 year is indicated in high-risk
patients.
PATHOPHYSIOLOGY OF PEPTIC ULCER
DISEASE
• Peptic ulcers are defects in the gastric or duodenal
mucosa that extend through the muscularis mucosa.
• The epithelial cells of the stomach and duodenum
secrete mucus in response to irritation of the epithelial
lining and as a result of cholinergic stimulation.
• The superficial portion of the gastric and duodenal
mucosa exists in the form of a gel layer, which is
impermeable to acid and pepsin.
• Other gastric and duodenal cells secrete bicarbonate,
which aids in buffering acid that lies near the mucosa.
• Prostaglandins of the E type (PGE) have an important
protective role, because PGE increases the production
of both bicarbonate and the mucous layer.
• In the event of acid and pepsin entering the epithelial
cells, additional mechanisms are in place to reduce
injury.
• Within the epithelial cells, ion pumps in the basolateral cell
membrane help to regulate intracellular PH by removing
excess hydrogen ions.
• Through the process of restitution, healthy cells migrate to
the site of injury.
• Mucosal blood flow removes acid that diffuses through the
injured mucosa and provides bicarbonate to the surface
epithelial cells.
• Under normal conditions, a physiologic balance exists
between gastric acid secretion and gastroduodenal mucosal
defense.
• Mucosal injury and, thus, peptic ulcer occur when the
balance between the aggressive factors and the
defensive mechanisms is disrupted.
• Aggressive factors, such as nonsteroidal anti-
inflammatory drugs (NSAIDs), H pylori infection,
alcohol, bile salts, acid, and pepsin, can alter the
mucosal defense by allowing the back diffusion of
hydrogen ions and subsequent epithelial cell injury.
• The defensive mechanisms include tight intercellular
junctions, mucus, bicarbonate, mucosal blood flow,
• The gram-negative spirochete H. pylori was first linked to
gastritis in 1983.
• Since then, further study of H pylori has revealed that it is a
major part of the triad, which includes acid and pepsin, that
contributes to primary peptic ulcer disease.
• The unique microbiologic characteristics of this organism,
such as urease production, allows it to alkalinize its
microenvironment and survive for years in the hostile acidic
environment of the stomach, where it causes mucosal
inflammation and, in some individuals, worsens the severity
of peptic ulcer disease.
• When H pylori colonizes the gastric mucosa, inflammation
usually results.
• The causal association between H pylori gastritis and duodenal
ulceration is now well established in children and adult.
• H pylori infection is associated with high levels of gastrin and
pepsinogen and reduced levels of somatostatin.
• In H pylori infected patients, exposure of the duodenum to acid
is increased.
• Virulence factors produced by H pylori, including urease,
catalase, vacuolating cytotoxin, and lipopolysaccharide, have
been described.
• Most patients with duodenal ulcers have impaired
duodenal bicarbonate secretion, which has also proven to
be caused by h pylori because its eradication reverses the
defect.
• The combination of increased gastric acid secretion and
reduced duodenal bicarbonate secretion lowers the PH in
the duodenum, which promotes the development of
gastric metaplasia (i.e, the presence of gastric epithelium
in the first portion of the duodenum).
• H pylori infection in areas of gastric metaplasia induces
duodenitis and enhances the susceptibility to acid
injury, thereby predisposing to duodenal ulcers.
• Duodenal colonization by H pylori was found to be a
highly significant predictor of subsequent
development of duodenal ulcers.
 H. PYLORI TRAETMENT
• The 2017 American College of Gastroenterology (ACG)
guidelines for the treatment of H pylori infection strongly
recommend 10-14 days of quadruple therapy with :
• Bismuth, a PPI, tetracycline, and a nitroimidazole.
• An alternative strongly recommended option is 10-14
days of concomitant PPI, clarithromycin, amoxicillin, and
a nitroimidazole.
• PPI–based triple therapy was the previous
recommendation.
• These regimens result in a cure of infection and ulcer
healing in 〰️ 85-90% of cases.
• Ulcers can recur in the absence of successful H
pylori eradication.
• Dual therapies; an alternative regimens for treating H
pylori infection, are usually not recommended as first-
line therapy, because of a variable cure rate that is
significantly less than the cure rate achieved with triple
 TRIPLE REGIMENS
• PPI-based triple therapy regimens for H pylori consist of a
PPI, amoxicillin, and clarithromycin for 7-14 days.
• A longer duration of treatment (14 d vs 7 d) appears to be
more effective and is currently the recommended
treatment.
• Amoxicillin should be replaced with metronidazole in
penicillin-allergic patients only, because of the high rate of
metronidazole resistance.
• In patients with complicated ulcers caused by H pylori,
treatment with a PPI beyond the 14-day course of
antibiotics and until the confirmation of the
eradication of H pylori is recommended.
• Polymorphisms in the host CYP2C19 gene and
antibiotic-resistance attributes of H pylori isolates
appear to influence the outcome of triple therapy.
• CYP2C19 affects peptic ulcer healing, H
pylori eradication, and PPI therapeutic efficacy.
• When a patient’s CYP2C19 genotype is unknown, H
pylori eradication may be achieved with
fluoroquinolones/metronidazole/clarithromycin-
based triple therapies.
• PPI-based triple therapies are a 14-day regimen as
outlined below.
• Omeprazole (Prilosec): 20 mg PO bid OR
Lansoprazole (Prevacid): 30 mg PO bid OR
Rabeprazole (Aciphex): 20 mg PO bid OR
Esomeprazole (Nexium): 40 mg PO qid
• PLUS Clarithromycin: 500 mg PO bid AND
Amoxicillin (Amoxil): 1 g PO bid.
ALTERNATIVE TRIPLE-THERAPY REGIMENS
• The alternative triple therapies, also administered for
14 days, are as follows:
• Omeprazole: 20 mg PO bid OR Lansoprazole: 30 mg
PO bid OR Rabeprazole: 20 mg PO bid OR
Esomeprazole: 40 mg PO qid PLUS Clarithromycin:
500 mg PO bid AND Metronidazole: 500 mg PO bid
QUADRUPLE THERAPY
• Therapies are generally reserved for patients in whom the
standard course of treatment has failed.
• Quadruple treatment includes the following drugs,
administered for 14 days:
• PPI, standard dose PLUS Bismuth 525 mg PO qid PLUS
Metronidazole 500 mg PO qid PLUS Tetracycline 500 mg PO
qid.
• Consider maintenance therapy with half of the standard doses
of H2-receptor antagonists at bedtime in patients with recurrent,
refractory, or complicated ulcers, particularly if cure of H
H2-receptor Antagonists
• H2 blocker antihistamine agents are used in the short-
term treatment of an active duodenal ulcer and as
prophylaxis in the long term.
• Cimetidine can be used as primary therapy to heal ulcers
not associated with H pylori infection.
• The duration of treatment is 6-8 weeks.
• A longer treatment course might be required for gastric
ulcers.
• Famotidine competitively inhibits histamine at H 2
receptor of gastric parietal cells, resulting in reduced
gastric acid secretion, gastric volume, and hydrogen
ion concentrations.
• Nizatidine competitively inhibits histamine at H 2
receptor of gastric parietal cells, resulting in reduced
gastric acid secretion, gastric volume, and hydrogen
ion concentrations.
• Ranitidine inhibits histamine stimulation of the H 2
receptor in gastric parietal cells, which, in turn,
reduces gastric acid secretion, gastric volume, and H+
concentrations.
• As of April 1, 2020, ranitidine was withdrawn from the
market due to an increasing number of products
containing the contaminant known as N-
nitrosodimethylamine (NDMA), a possible carcinogen.
 PHYSIOLOGY OF GASTRIC ACID SECRETION
• The H+-K+-ATPase acid-secreting (proton) pump is
located in the parietal cell.
• Gastric acid secretion by the parietal cell is regulated
mainly by three stimuli—acetylcholine (Ach), gastrin,
and histamine.
• Ach is the principal neurotransmitter modulating acid
secretion and is released from the vagus and
parasympathetic ganglionic cells; it mainly exerts
effects on M3 receptors.
• Vagal fibers not only have a direct effect on parietal cells,
but also modulate peptide release from G cells (antrum and
duodenum) and ECL cells, as well as inhibit somatostatin
secretion.
• Gastrin has direct hormonal effects on the parietal cell and
also stimulates histamine release.
• Histamine has paracrine-like effects on the parietal cell and
plays a central role in the regulation of acid secretion by the
parietal cell after its release from ECL cells.
• Somatostatin exerts inhibitory actions on gastric acid
secretion.
• Release of somatostatin from antral D cells is stimulated
in the presence of low intraluminal PH as well as
vasoactive intestinal peptide (VIP) and gastrin.
• After its release, somatostatin inhibits gastrin release
through paracrine effects and modifies histamine
release from ECL cells.
• Consequently, the precise state of acid secretion by the
parietal cell depends on the overall influence of the
positive and negative stimuli.
 ANTACIDS
• Antacids are a group of drugs that have been in use for
many years.
• They were initially first-line defense against peptic
ulcer disease; however, the discovery of proton pump
inhibitors (PPIs) revolutionized the treatment of peptic
ulcer disease.
• Currently, antacid use is restricted to relieve mild
intermittent gastroesophageal reflux disease (GERD)
with associated heartburn.
Indications
• Antacids are medications that do not require a
prescription; in other words, they are self-prescribed.
• They are a combination of various compounds with
various salts of calcium, magnesium, and aluminum as
active ingredients.
• They act by neutralizing the acid in the stomach and by
inhibiting pepsin, which is a proteolytic enzyme.
• Each of these cationic salts has a
characteristic pharmacological property that determines
• Antacids have therapeutic • Diarrhea caused by bile-
use for the following: acid

• Heartburn symptoms in • Biliary reflux

GERD • Constipation
• Duodenal and gastric • Osteoporosis
ulcers • Urinary alkalinization
• Stress gastritis • Phosphate binding in
• Pancreatic insufficiency chronic renal failure
• Non-ulcer dyspepsia
Mechanism of action
• The antacids reduce the acid reaching the duodenum by
neutralizing the acid present in the stomach.
• The main therapeutic objectives are:
oAlleviating pain
oRelieving pylorospasms
oAvoid digestion and corrosion by acid chyme
oThe salts' mechanism of neutralization of acid varies, and
each salt has a different mechanism with the ultimate goal
of acid neutralization.
Aluminum hydroxide
• The formulation of aluminum hydrochloride and water
results in the neutralization of the acid in the stomach.
• It is also known to inhibit pepsin activity.
• Aluminum hydroxide is complexed with a sulfated
polysaccharide sucrose octasulfate to form sucralfate.
• This complex does not have a significant buffering action
against the acid or has no effect on the pepsin secretion,
and does not alter the gastric acid production in any
way.
• Nevertheless, it is known to heal chronic ulcers and
prevent acute mucosal damage induced chemically by
reducing access to pepsin and acid.
• Sucralfate, like its aluminum hydroxide component, is
known to stimulate angiogenesis and granulation
tissue formation.
• Aluminum hydroxide is also useful in
hyperphosphatemia due to its ability to bind
phosphate in the gastrointestinal (GI) tract and
subsequently prevent the absorption of phosphate.
Calcium salts
• Calcium salts neutralize gastric acidity, resulting in
increased gastric and duodenal bulb PH; they also
inhibit pepsin's proteolytic activity if the PH is greater
than 4 and increase lower esophageal sphincter tone.
• The calcium released from calcium carbonate is known
to increase peristalsis in the esophagus, pushing the
acid into the stomach and providing relief from
heartburn symptoms.
• The calcium salts also form combined insoluble
compounds with dietary phosphate and prevent the
absorption of the latter.
• The acid-neutralizing mechanism of the antacids is
well understood, as mentioned above.
• In addition to this, other mechanisms add to the ulcer
healing properties of this class of drugs.
• The exact mechanism is still unclear, but it is believed
to be a combination of:
• Ability to promote angiogenesis
oBind to bile acids
oInhibit peptic activity
oSuppress helicobacter pylori growth
Pregnancy and Breastfeeding
• Antacids containing aluminum salts are safe to be used in
pregnant women as well as for women during labor for
aspiration prophylaxis.
• The information regarding the use of aluminum-containing
antacids in breastfeeding females has not been studied, but
aluminum is known to be endogenous to breast milk.
• In the case of calcium-containing antacids, excessive use is
to be avoided in pregnant women as calcium crosses the
placenta.
• The amount of calcium reaching the fetus is dependent
on the physiological changes in the mother.
• Maternal calcium intake also affects the amount of
calcium excreted in breast milk; the currently
prevailing opinion is that the use of calcium-
containing antacids is safe during breastfeeding.
 Adverse Effects
Adverse effects are prominent in the infant and the elderly populations.
The chronic use of antacids in this population is not a recommendation due to safety concerns.

Aluminum hydroxide o Microcytic anemia

• Aluminum use is associated Neurotoxicity
with an increased risk of o Osteomalacia Constipation
toxicity in individuals with o Fecal impaction Nausea
renal failure and infants. o Vomiting Abdominal cramps
o It presents as: o Hypomagnesemia
o Osteopenia o Hypophosphatemia
 Calcium Carbonate
The adverse reactions often seen with this group of antacids are:

oAbdominal pain oFlatulence

oAnorexia oXerostomia
oConstipation oHeadache
oAcid rebound oHypercalcemia
oNausea oHypophosphatemia
oVomiting oMilk-alkali syndrome
• Antacids can exhibit clinically significant
interactions with other medication a patient may
be taking.
• Some examples include:
oUsing antacids concomitantly with acidic drugs
(e.g., digoxin, chlorpromazine isoniazid) can result
in impaired absorption of these acidic
drugs, reducing the blood concentrations of the
drugs and impairing their therapeutic effects.
oConcurrent antacid use with some drugs (e.g.,
Pseudoephedrine, levodopa) can result in increased
absorption of the drugs, leading to potential toxicity
or adverse events from increased serum concentration
of these drugs.
oAntacids containing magnesium trisilicate and
magnesium hydroxide can bind to drugs like
tetracycline and fluoroquinolone antibiotics,
impeding their absorption and therapeutic effects.
• Sodium bicarbonate significantly affects urine acidity,
which can alter the renal elimination of some drugs by
the kidney; sodium bicarbonate inhibits the excretion of
basic drugs such as amphetamines and quinidine while
increasing the excretion of acidic drugs like aspirin.
Contraindications
The absolute contraindication is hypersensitivity
to any component of the formulation.
Also, antacid agents require caution in patients
with:
• Renal failure • Uremia
• Heart failure • GI hemorrhages
• Edema • Hyperparathyroidism
• Cirrhosis • Renal calculus
• Low-sodium diets • Achlorhydria