PEPTIC ULCER

DISEASE
Igboeli Nneka U
MPharm, FCPharm, PhD
DEPARTMENT OF CLINICAL PHARMACY &
PHARMACY MANAGEMENT,
FACULTY OF PHARMACEUTICAL SCIENCES,
UNIVERSITY OF NIGERIA, NSUKKA.
OVERVIEW
 Introduction

 Pathophysiology

 Peptic Ulcer
INTRODUCTION
 Peptic ulcers are lesions in the stomach or
duodenum that occur as a result of the activity of
acid and pepsin
 Chronic peptic ulcers differ from erosions and
gastritis in that the ulcer extends deeper into the
muscularis mucosa
 Stress ulcer is an acute form of peptic ulcer that
occurs primarily in critically ill patients and differs in
its underlying pathogenesis
ETIOLOGY AND RISK FACTORS
 Two common causes are NSAIDs and H pylori
 They also influence the chronicity of the disease

 Less common causes include hypersecretory states

like Zollinger-Ellison syndrome (ZES), viral
infections (e.g. cytomegalovirus), radiation and
chemotherapy (e.g. hepatic artery infusion)
 Factors that increase risk of PUD include alcohol,
ingestion, cigarette smoking, psychological stress,
corticorsteroids and chronic diseases such as renal
failure, cirrhosis, pacreatitis, obstructive
pulmonary disease, Crohn disease or organ
transplantation
ETIOLOGY AND RISK FACTORS CONT’D

 H. pylori infection is causally linked to chronic

gastritis, PUD, mucosa-associated lymphoid
tissue (MALT) lymphoma, and gastric cancer
 Differences in strain variability and host-
specific factors account for the variable
pathogenesis of the organism
 The association between H. pylori and PUD
bleeding remains unclear, but H. pylori
eradication decreases recurrent bleeding
 Prevalence of H. pylori varies by geographic
location, socioeconomic status, ethnicity,
and age, and is more common in developing
countries than in industrialized nations
ETIOLOGY AND RISK FACTORS CONT’D
 Transmission occurs usually during childhood from
the infected person by either the gastro–oral (vomitus)
or fecal–oral (diarrhea) route or from fecal-
contaminated water or food
 Individuals living in the same household with an H.
pylori–positive person, especially when there is
household crowding (intrafamilial clustering), are at
increased risk for acquiring the infection
 H. pylori can also be transmitted through the use of
inadequately sterilized endoscopes.
ETIOLOGY AND RISK FACTORS CONT’D – NSAID-
INDUCED ULCER

 There is a link between the chronic use of

NSAIDs and GI injury leading to gastric and
duodenal ulcers
 Gastric ulcer is most common and develops
primarily in the antrum
 Risk factors for NSAID-induced ulcer and
upper GI complications include:
ETIOLOGY AND RISK FACTORS CONT’D – NSAID-
INDUCED ULCER
 Established
 Confirmed prior ulcer or ulcer-related
complication
 Age >65 years
 Multiple or high-dose NSAID use
 Concomitant use of aspirin (including low
cardioprotective dosages,
e.g., 81 mg)
 Concomitant use of an anticoagulant,
corticosteroid, bisphosphonate,
 clopidogrel, or SSRI
 Selection of NSAID (selectivity of COX-1 vs.
COX-2)
 Controversial
 H. pylori
 Alcohol consumption
 Cigarette smoking
PATHOPHYSIOLOGY
 A physiological balance exists in healthy individuals
between gastric acid secretion and gastroduodenal
mucosal defense.
 Peptic ulcers occur when the balance between
aggressive factors (gastric acid, pepsin, bile
salts, H. pylori, and NSAIDs) and mucosal
defensive mechanisms (mucosal blood
flow,mucus,mucosal bicarbonate
secretion,mucosal cell restitution, and epithelial
cell renewal) are disrupted
 Increased acid secretion may occur in patients with
duodenal ulcer, but most patients with gastric ulcer
have normal or reduced rates of acid secretion
 Pepsin is an important cofactor that plays a role in the
proteolytic activity involved in ulcer formation
PATHOPHYSIOLOGY

 The viscous nature and near-neutral pH of the mucus-

bicarbonate barrier protect the stomach from the
acidic contents in the gastric lumen
 The maintenance of mucosal integrity and repair is
mediated by the production of endogenous
prostaglandins
 When aggressive factors alter mucosal defense
mechanisms, back diffusion of hydrogen ions occurs
with subsequent mucosal injury.
 H. pylori and NSAIDs cause alterations in mucosal
defense by different mechanisms and are important
factors in the formation of peptic ulcers
PATHOPHYSIOLOGY – H. PYLORI-RELATED ULCERS
 H. pylori is a gram-negative, spiral-shaped bacillus
that thrives in a microaerophilic environment
 The bacterium resides between the mucus layer and
surface epithelial cells in the stomach or any location
where gastric-type epithelium is found
 Flagella enable it to move from the lumen of the
stomach, where the pH is low, to the mucus layer,
where the pH is neutral
 Acute infection is accompanied by transient
hypochlorhydria, which enables the organism to
survive the acidic gastric juice
PATHOPHYSIOLOGY – H. PYLORI-RELATED ULCERS
 The method by which H. pylori induces
hypochlorhydria is hypothesized to be that its urease-
producing ability hydrolyze urea in the gastric juice
and converts it to ammonia and carbon dioxide, which
creates a neutral microenvironment that surrounds
the bacterium
 Adherence pedestals attach to gastric-type epithelium
and prevent the bacterium from being shed during cell
turnover and mucus secretion
 Colonization of the antrum and acid-secreting
body (corpus) of the stomach is associated with
gastric ulcer and gastric adenocarcinoma which
is typically accompanied by gastric atrophy and
decreased acid secretion.
PATHOPHYSIOLOGY – H. PYLORI-RELATED ULCERS
 Colonization of only the antrum increases the risk for
duodenal ulcer and gastric acid is normal or slightly
increased
 Direct mucosal damage is produced by virulence
factors (e.g., cytotoxin-associated gene, vacuolating
cytotoxin), elaborating bacterial enzymes (e.g.,
urease, lipases, proteases) and adherence
 H. pylori infection may also cause alterations in the
host immune response
PATHOPHYSIOLOGY - NSAID-INDUCED ULCERS
 Nonselective NSAIDs (Table 27-4), including aspirin,
cause peptic ulcers and upper GI complications by
systemically inhibiting protective prostaglandins in
the gastric mucosa
 There are two COX isoforms: cyclo-oxygenase-1 (COX-
1),which is found in the stomach, kidney, intestine,
and platelets, and cyclo-oxygenase-2 (COX-2), which is
induced with acute inflammation
 The inhibition of COX-1 is associated with upper GI
and renal toxicity, and the inhibition of COX-2 is
related to anti-inflammatory effects
 Nonselective NSAIDs, including aspirin, inhibit both
COX-1 and COX-2 to varying degrees and decrease
platelet aggregation, which may increase the risk for
upper GI bleeding
PATHOPHYSIOLOGY - NSAID-INDUCED ULCERS
 COX-2 inhibitors such as rofecoxib and valdecoxib do
not inhibit gastric mucosal prostaglandin synthesis or
serum thromboxane A2, which accounts for their
improved GI safety
 In contrast to the nonselective NSAIDs, the COX-2
inhibitors do not inhibit platelet aggregation and alter
bleeding time
 Unfortunately, both rofecoxib and valdecoxib were
withdrawn from the US market in 2004 because of
concerns about cardiovascular safety
 Celecoxib, a COX-2 inhibitor, currently remains
available in the United States despite similar
concerns about cardiovascular risk
 However, the benefit of celecoxib in reducing the risk
of gastric ulcer and upper GI complications may be
lower than
 PATHOPHYSIOLOGY - NSAID-INDUCED ULCERS
 Aspirin and nonaspirin NSAIDs also have a topical
(direct) irritating effect on the gastric mucosa, but the
resulting inflammation and erosions usually heal
within a few days
 Gastric damage is associated with the acidic
properties of aspirin and nonaspirin NSAIDs
and their ability to decrease the hydrophobicity of the
mucous gel layer in the gastric mucosa
 Thus, direct mucosal injury appears to correlate with
the pKa of a compound—suggesting the lower the
acidity of the drug, the less the short-term topical
damage
 Formulations such as enteric-coated aspirin,
buffered aspirin, NSAID prodrugs, and
parenteral or rectal preparations may spare
topical effects on the gastric mucosa
PATHOPHYSIOLOGY - NSAID-INDUCED ULCERS
 but all have the potential to cause a gastric ulcer
because of their systemic inhibition of endogenous
prostaglandins.81,98
 Clopidogrel does not cause ulcers, but may impair the
healing of gastric erosions
CLINICAL PRESENTATION

 Signs and symptoms

 mild epigastric pain to life-threatening upper GI
complications
 A change in the character of the pain may indicate
an ulcer-related complication
 The absence of epigastric pain, especially in older
adults who are taking NSAIDs, does not exclude
the presence of an ulcer or related complications
 Ulcerlike symptoms may occur in the absence of
peptic ulceration in association with H. pylori–
related gastritis or duodenitis
CLINICAL MANIFESTATIONS

 COMPLICATIONS
 Most serious life-threatening complications include upper
GI bleeding, perforation into the abdominal
cavity or penetration into an adjacent structure
(e.g., pancreas, liver, or biliary tract), and
obstruction
 The incidence of ulcer-related upper GI bleeding and
perforation is highest in individuals taking NSAIDs
who are older than 60 years of age
 The bleeding may be occult (hidden), present as
melena (black-colored stools), or hematemesis
(vomiting of blood)

COMPLICATIONS CONT’D
 Mortality is higher in patientswho continue to bleed or
who rebleed after the initial bleeding has stopped and
in patients with a perforated ulcer
 The pain associated with perforation is typically
sudden, sharp, and severe, beginning in the epigastric
area but quickly spreading throughout the upper
abdominal area
 Gastric outlet obstruction, the least frequent
complication, is caused by previous ulcer
healing and scarring or edema of the pylorus or
duodenal bulb and can lead to symptoms of
gastric retention, including early satiety,
bloating, anorexia, nausea, vomiting, and
weight loss.
CLINICAL ASSESSMENT AND DIAGNOSIS

 TESTS FOR DETECTING HELICOBACTER

PYLORI
 Detected using gastric mucosal biopsies in patients
undergoing upper endoscopy or by nonendoscopic tests
 The endoscopic tests require a mucosal biopsy for
the rapid urease test, histology, or culture
 For rapid urease test, in the presence of H. pylori
urease, urea is metabolized to ammonia and
bicarbonate resulting in an increase in pH, which
changes the color of a pH-sensitive indicator
 In rapid urease test, withhold H2RAs and PPIs 1 to 2
weeks before testing and antibiotics and bismuth salts
4 weeks before testing reduces the risk of false-
negatives
CLINICAL ASSESSMENT AND DIAGNOSIS
 Histology is the “Gold standard” for detection of
active H. pylori infection; >95% sensitive and specific
 Culture permits sensitivity testing to determine
antibiotic choice or resistance; 100% specific; tests for
active H. pylori infection and is usually limited to
patients who fail initial course of eradication therapy
 Nonendoscopic tests either identify active infection
or detect antibodies to H. pylori
 They are noninvasive, more convenient, and less
expensive than the endoscopic tests
 The urea breath test (UBT), the most accurate
noninvasive test, detects active H. pylori infection and
is also effective after eradiation treatment
CLINICAL ASSESSMENT AND DIAGNOSIS
 Radiolabeled urea with either C13 or C14 is given
orally; urease secreted by H. pylori in the stomach (if
present) hydrolyzes radiolabeled urea to produce
radiolabeled CO2, which is exhaled and then
quantified from the expired breath; radiation exposure
is minimal
 Antibody Detection (In-Office or Near Patient) is
a qualitative test; detects IgG antibodies to H. pylori
in whole blood or fingerstick
 Antibody Detection (Laboratory) is a quantitative
test; detects IgG antibodies to H. pylori in serum
using laboratory-based ELISA tests and latex
agglutination techniques
CLINICAL ASSESSMENT AND DIAGNOSIS
 The in-office and laboratory antibody tests are a cost-
effective method to initially diagnose H. pylori
infection, but because they do not differentiate
between active infection and previously eradicated H.
pylori, they should not be used to confirm eradication
 Fecal Antigen Test - an enzymatic immunoassay
test that identifies H. pylori antigen in stool;
sensitivity and specificity comparable to the UBT for
initial diagnosis. Considered an alterative to detecting
H. pylori before treatment and documenting
posttreatment eradication
LABORATORY TESTS, RADIOGRAPHY AND ENDOSCOPY
FOR PUD
 Laboratory tests are not helpful in the diagnosis of
PUD
 Serum hematocrit (Hct) and hemoglobin (Hgb) and
guaiac fecal occult blood tests assist in the evaluation
of ulcer-related bleeding
 Confirmation of a peptic ulcer requires visualizing the
ulcer either by GI radiography or upper endoscopy.
 Fiberoptic upper endoscopy
(esophagogastroduodenoscopy
 [EGD]) is the gold standard, as it detects

 greater than 90% of peptic ulcers and permits direct

inspection, biopsy, visualization of superficial
erosions, and sites of active bleeding.
TREATMENT

 THERAPEUTIC GOALS
 Depend on whether the ulcer is related to H.
pylori or associated with an NSAID or on
whether the ulcer is initial or recurrent and
whether complications have occurred
 They include:

 relieving ulcer symptoms,

 Healing the ulcer,

 preventing ulcer recurrence, and

 reducing ulcer-related complications

 When possible, the most cost-effective drug

regimen should be utilized.
NONPHARMACOLOGIC THERAPY
 Patients with PUD should discontinue NSAIDs
(including aspirin) if possible
 Patients unable to tolerate certain foods and
beverages (e.g., spicy foods, caffeine, and alcohol)
may benefit from dietary modifications.
 Lifestyle modifications including reducing stress
and decreasing or stopping cigarette smoking is
encouraged
NONPHARMACOLOGIC THERAPY
 Probiotics, especially strains of lactic acid–
producing bacteria such as Lactobacillus and
Bifidobacterium, lactoferrin, and foodstuffs (e.g.,
cranberry juice, ginger, chili, oregano, some milk
proteins) have been used to supplement H.pylori
eradication
 Patients with ulcer-related complications may
require surgery for bleeding, perforation, or
obstruction
PHARMACOTHERAPY
 Recommended first-line treatment in the United
States includes PPI-based three-drug regimens or
a bismuth-based four drug regimen
 If initial eradication fails, a second course of
therapy should be based on the selection of
antibiotics that have not been previously used
 Treatment of H. pylori–positive patients with a
conventional antiulcer drug or combining an
antisecretory drug with sucralfate is not
recommended because of high rates of ulcer
recurrence and complications
 Maintenance therapy with a PPI or H2RAshould
only be necessary in high-risk patients with a
history of ulcer complications, those with H.
pylori–negative ulcers, and patients with other
concomitant acid-related diseases (e.g., GERD)
PHARMACOTHERAPY
 Patients with NSAID-induced ulcers should be
tested to determine their H. pylori status
 H. pylori–positive patients should be initially
treated with a PPI based three-drug eradication
regimen
 If the patient is H. pylori–negative, the NSAID
should be discontinued and treatment should be
initiated with antiulcer medications
 The duration of treatment should be extended if
the NSAID is continued
 Prophylactic cotherapy with a PPI or misoprostol
or switching to an NSAID with greater COX-2
selectivity is recommended for
 patients at risk of exhibiting ulcer-related upper
GI complications
PHARMACOTHERAPY
 Antacids and antisecretory medications usually
provide relief of ulcer pain in most patients
 Treatment should be effective, well-
tolerated, easy to comply with, and cost-
effective
 Drug regimens should have an eradication rate
of at least 80% (intention-to-treat, ITT) or 90%
(per protocol analysis) and should minimize the
potential for antimicrobial resistance
 The PPI may be extended to 28 days if needed
for ulcer healing in the standard PPI-based
three-drug regimen
 Twice-daily dosing of the PPI appears to be
more effective than a single daily dose
PHARMACOTHERAPY
 Proton-Pump Inhibitor–Based Three-Drug
Regimens:
 PPI Standard dose BID X 14 days

 Clarithromycin 500 mg BID X14 days

 Amoxicillinc 1 g BID X14 days

 Or

 PPI Standard dose BID X 14 days

 Clarithromycin 500 mg BID X14 days

 Metronidazole 500 mg BID X14 days

 PPI Standard doses include: Omeprazole 20

mg BID; lansoprazole 30 mg BID; pantoprazole
40 mg BID; rabeprazole 20 mg daily or BID;
esomeprazole 20 mg BID or 40 mg daily
PHARMACOTHERAPY

 Bismuth-Based Four-Drug Regimens

 Bismuth subsalicylated 525 mg QID X10–14 days
 Metronidazole 250–500 mg QID X 10–14 days

 Tetracycline plus 500 mg QID X10–14 days

 PPI Standard dose Daily or BID X 10–14 days

 Or

 H2RA Standard dose BID X 4–6 weeks

PHARMACOTHERAPY

 Sequential Therapy :
 PPI Standard dosea BID for Days 1–10
 Amoxicillin 1 g BID for Days 1–5
 Clarithromycin 250–500 mg BID for
Days 6–10
 Metronidazole 250–500 mg BID for Days
6–10
PHARMACOTHERAPY
 Secondary or Rescue Therapy:
 Bismuth subsalicylated 525 mg QID
X10–14 days
 Metronidazole 500 mg QID X10–14 days
 Tetracycline 500 mg QID X10–14 days
 PPI Standard dose Daily or BID X10–14
days
 Or
 PPI Standard dose BID X 10–14 days
 Amoxicillin 1 g BID X10–14 days
 Levofloxacin 500 mg Daily X10–14 days
PHARMACOTHERAPY
 Increasing the duration of quadruple therapy
to 1 month does not substantially increas
eradication although the antisecretory drug
may be continued for an additional 2 weeks
(PPI) or 4 weeks (H2RA) in patients with
an active ulcer
 The rationale for sequential therapy is to
initially treat the patient with antibiotics
that rarely promote resistance (e.g.,
amoxicillin) in order to reduce the
bacterial load and pre-existing resistant
organisms and then to follow with
different antibiotics to kill the remaining
organisms
PATIENT EDUCATION
 Be informed of the importance of taking his
medications as prescribed to minimize
treatment failure and the development of
antibiotic resistance
 PPI should be taken twice daily 30 to 60
minutes before breakfast and dinner along
with amoxicillin and clarithromycin
 When placed on bismuth quadruple therapy
containing a PPI, he should take all
medications except the PPI four times a day,
with meals and at bedtime
PATIENT EDUCATION
 Be informed of the most common side effects
associated with his treatment regimen.
 All antibiotics included in the H. pylori
eradication regimens are usually associated
with mild side effects including nausea,
abdominal pain, and diarrhea
 C. difficile–associated diarrhea, a serious
antibiotic-related complication, occurs
occasionally
 Oral thrush and vaginal candidiasis (in
women) may also occur
 Clarithromycin and metronidazole may
cause taste disturbances
PATIENT EDUCATION
 Metronidazole-containing regimens increase
the frequency of side effects (especially when
the dose is >1 g/day) and may be associated
with a disulfiram-like reaction in patients who
consume alcohol
 Tetracycline may cause photosensitivity and
should not be used in children because it may
cause tooth discoloration
 Bismuth salts may cause darkening of the
tongue and stool
 Be advised of the risk for clinically important
drug–drug interactions that may occur with
the medications included in their eradication
regimen
ASSIGNMENTS

 Find out and document Strategies to Reduce the

Risk of Nonsteroidal Anti-Inflammatory Drug–
Induced Peptic Ulcers
 Document recent findings on adverse effects of
PPIs when used for a long time. Download
articles (2014 till date) on adverse effects of PPIs
THANK YOU