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Peptic Ulcer Disease

Elizabeth Yu Tan, RPh MS Pharm


Faculty, Department of Pharmacy
School of Health Care Professions
University of San Carlos, Cebu City, Philippines

Peptic Ulcer Disease (PUD)


Refers to a group of ulcerative disorders of the upper
gastrointestinal (GI) tract that require acid and pepsin for their
formation.
Ulcers typically extend deeper into the muscularis mucosa as
compared to gastritis andDevelop
erosions.
most often in the stomach and
duodenum of ambulatory px

3 common forms of PUD:


H. pylori-associated
NSAID-induced
Stress ulcers occur primarily in the stomach
Approximately 60-100 % of ulcers recur within 1 year of initial
ulcer healing with conventional therapy.

Pathophysiology
Mucosal defense and repair mechanisms (mucus and
bicarbonate secretion, intrinsic epithelial cell defense,
and mucosal blood flow) protect the gastroduodenal
mucosa from noxious endogenous and exogenous
substance
The viscous nature and near-neutral pH of the
mucus-bicarbonate barrier protect the stomach from
the acidic contents in the gastric lumen.
Alterations in mucosal defense that are induced by H.
pylori or NSAIDs are the most important cofactors in
the formation of peptic ulcers.

Pathophysiology
Bacterial and host factors contribute to the ability of H. pylori
to cause gastroduodenal mucosal injury. Pathogenic
mechanisms include (a) direct mucosal damage, (b) alterations
in the host immune/inflammatory response, and (c)
hypergastrinemia leading to increased acid secretion.
NSAIDs cause gastric mucosal damage by two important
mechanisms: (a) direct or topical irritation of the gastric
epithelium and (b) systemic inhibition of endogenous mucosal
prostaglandin synthesis
Although the initial injury is initiated topically by the acidic
properties of many of the NSAIDs, systemic inhibition of the
protective prostaglandins plays the predominant role in the
development of gastric ulcer.

Pathophysiology
Epidemiologic evidence links cigarette smoking to PUD,
impaired ulcer healing, and ulcer-related GI complications.
Risk is proportional to amount smoked per day.
Although clinical observation suggests that ulcer patients
are adversely affected by stressful life events, controlled
studies have not documented a cause-and-effect
relationship.
Coffee, tea, cola beverages, beer, milk, and spices may
cause dyspepsia but do not increase PUD risk. Ethanol
ingestion in high concentrations is associated with acute
gastric mucosal damage and upper GI bleeding but is not
clearly the cause of ulcers.

Presentation of PUD
General
Mild epigastric pain or acute life-threatening upper gastrointestinal complications
Symptoms
Abdominal pain that is often epigastric and described as burning, but may
present as vague discomfort, abdominal fullness, or cramping.
A typical nocturnal pain that awakens the patient from sleep (especially
between 12 AM and 3 AM).
The severity of ulcer pain varies from patient to patient, and may be seasonal,
occurring more frequently in the spring or fall; episodes of discomfort usually
occur in clusters, lasting up to a few weeks and followed by a pain-free period
or remission lasting from weeks to years.
Changes in the character of the pain may suggest the presence of
complications.
Heartburn, belching, and bloating often accompany the pain.
Nausea, vomiting, and anorexia, are more common in patients with gastric
ulcer than with duodenal ulcer, but may also be signs of an ulcer-related
complication
Signs
Weight loss associated with nausea, vomiting, and anorexia
Complications, including ulcer bleeding, perforation, penetration, or obstruction

Signs and Symptoms


Ulcer-related pain in duodenal ulcer often occurs 1 to 3 hours
after meals and is usually relieved by food, but this is variable
In gastric ulcer, food may precipitate or accentuate ulcer
pain.
Patients taking NSAIDs often report dyspepsia, but dyspeptic
symptoms do not directly correlate with an ulcer.
If an ulcer is not confirmed in a patient with ulcer-like
symptoms at the time of endoscopy, the disorder is referred to
as nonulcer dyspepsia.
Ulcer-like symptoms may occur in the absence of peptic
ulceration in association with H. pylori gastritis or duodenitis.
There is no one sign or symptom that differentiates between
H. pylori-associated and NSAID-induced ulcer.

Potential Causes of PUD


Common causes
Helicobacter pylori infection
Nonsteroidal antiinflammatory drugs
Critical illness (stress-related mucosal damage)
Uncommon causes
Hypersecretion of gastric acid (e.g., Zollinger-Ellisons
syndrome)
Viral infections (e.g., cytomegalovirus)
Vascular insufficiency (crack cocaine associated)
Radiation
Chemotherapy (e.g., hepatic artery infusions)
Rare genetic subtypes
Idiopathic

Etiology and Risk Factors


Most peptic ulcers
occur in the presence
of acid and pepsin
when H. pylori,
NSAIDs, or other
factors disrupt normal
mucosal defense and
healing mechanisms.
Benign gastric ulcers
can occur anywhere
in the stomach,
although most are
located on the lesser
curvature.
Most duodenal ulcers
occur in the first part
of the duodenum
(duodenal bulb).

Risk Factors for NSAID-Induced Ulcers


and Upper GI Complications
Established risk factors
Older than 60 years of age
Previous peptic ulcer
Previous ulcer-related upper GI
complication
Concomitant use of corticosteroid
High-dose NSAIDs
Multiple NSAID use or NSAID plus
aspirin use
Choice of NSAID
Aspirin (including cardioprotective dosages)
Concomitant use of anticoagulant or
coagulopathy
Concomitant use of antiplatelet drug such
as clopidogrel
Concomitant use of oral bisphosphonates
Concomitant use of selective serotonin
reuptake inhibitor
Chronic illness (e.g., cardiovascular disease)

Possible risk factors


NSAID-related dyspepsia
Helicobacter pylori infection
Rheumatoid arthritis (extent of
disability)
Alcohol consumption

GI Risk Factor Stratification for Chronic


NSAID Use
Category

Risk Factors

High Risk History of previous complicated ulcer.


Multiple (>2) risk factors.
Moderate
Risk (1-2
risk
factors)

Age>65 years
High dose NSAID therapy
Previous history of uncomplicated ulcer
Concurrent use of aspirin (including low
dose), corticosteroids, or anticoagulants
Low Risk No risk factors

Prevention of NSAID-induced PUD


If low CV risk and:
Low GI risk - NSAID (lowest dose of the least
ulcerogenic agent)
Moderate GI risk - NSAID + PPI or misoprostol
High GI risk - COX-2 inhibitor + PPI or
misoprostol
If high CV risk (requirement for low-dose aspirin) and:
Low GI risk - Naproxen + PPI or misoprostol
Moderate GI risk - Naproxen + PPI or misoprostol
High GI risk - avoid NSAID or COX-2 inhibitors

Management of NSAID-Associated PUD


1.Remove and re-evaluate need for
NSAID and/or aspirin. Test for H. pylori
and treat if positive.
2.Suppress stomach acid. Use PPI for
8-12 weeks.
3.Use Misoprostol if PPI is
contraindicated.
4.Use COX-2 inhibitors.

Helicobacter pylori
Approximately 20% of infected individuals will develop symptomatic
PUD
In developing countries, H. pylori prevalence exceeds 80% in adults and
correlates with lower socioeconomic conditions.
In industrialized countries, the prevalence of H. pylori in adults is
between 20% and 50%
H. pylori is transmitted person-to-person by three possible pathways;
fecaloral, oraloral, and gastrooral.
Transmission of the organism most likely is by the fecaloral route,
either directly from an infected person, or indirectly from fecalcontaminated water or food.

DIAGNOSIS OF PUD
The diagnosis of H. pylori infection can be made using
endoscopic or nonendoscopic tests. The tests that require
upper endoscopy are invasive, more expensive, and usually
require a mucosal biopsy for histology, culture, or detection
of urease activity.
At least three tissue samples are taken from specific areas of
the stomach, as patchy distribution of H. pylori infection can
lead to false-negative results.
Two types of nonendoscopic tests are available: tests that
identify active infection and tests that detect antibodies.
Antibody tests do not differentiate between active infection
and previously eradicated H. pylori.

Diagnosis of PUD
The nonendoscopic tests are noninvasive, more convenient,
and less expensive than the endoscopic tests.
The urea breath test is the most accurate noninvasive test
and is based on H. pylori urease activity.
The diagnosis of PUD depends on visualizing the ulcer
crater either by upper GI radiography or upper endoscopy.
Because of its lower cost, greater availability, and greater
safety, radiography is often the initial diagnostic procedure
in patients with suspected uncomplicated PUD.
If complications are thought to exist, or if an accurate
diagnosis is warranted, upper endoscopy is the diagnostic
procedure of choice.

TREATMENT

Pharmacologic Therapy
Indications for treatment of HP include gastric or
duodenal ulcer, mucosa-associated lymphoid tissue
(MALT) lymphoma, postendoscopic resection of gastric
cancer, and uninvestigated dyspepsia. Treatment should
be effective, well tolerated, convenient, and cost-effective.
First-line therapy to eradicate HP infection is usually
initiated with a proton pump inhibitor (PPI)based,
three-drug regimen for 10 to 14 days. If a second
treatment course is required, the regimen should contain
different antibiotics, or a four-drug regimen with a
bismuth salt, metronidazole, tetracycline, and a PPI
should be used.

Drug Regimens to Eradicate


Helicobacter pylori

Pharmacologic Therapy
Bismuth-based quadruple therapy is recommended as
an alternative for patients allergic to penicillin. All
medications except the PPI should be taken with
meals and at bedtime.
In sequential therapy, the antibiotics are administered
in a sequence rather than all together. The rationale is
to treat initially with antibiotics that rarely promote
resistance (eg, amoxicillin) to reduce bacterial load
and preexisting resistant organisms and then to follow
with different antibiotics (eg, clarithromycin and
metronidazole) to kill the remaining organisms.

Pharmacologic Therapy
If initial treatment fails to eradicate HP, second-line (salvage) treatment should:
(1) use antibiotics that were not included in the initial regimen, (2) use
antibiotics that are not associated with resistance, (3) use a drug that has a
topical effect (eg,bismuth), and (4) extend the treatment duration to 14 days. A
14-day course of the PPI-based quadruple regimen is the most commonly used
second-line therapy after failure of a PPIamoxicillinclarithromycin regimen.
Patients with NSAID-induced ulcers should be tested to determine HP status.
If HP positive, start treatment with a PPI-based three-drug regimen. If HP
negative, discontinue the NSAID and treat with either a PPI, H2RA, or
sucralfate
If the NSAID must be continued despite ulceration, initiate treatment with a
PPI (if HP negative) or a PPI-based three-drug regimen (if HP positive).
Cotherapy with a PPI or misoprostol or switching to a selective
cyclooxygenase-2 (COX-2) inhibitor is recommended for patients at risk of
developing an ulcer-related complication.

Pharmacologic Treatment
Limit maintenance therapy with a PPI or H2RA to highrisk patients with ulcer complications, patients who fail
HP eradication, and those with HP-negative ulcers.
Patients with ulcers refractory to treatment should
undergo upper endoscopy to confirm a nonhealing ulcer,
exclude malignancy, and assess HP status. HP-positive
patients should receive eradication therapy. In HPnegative patients, higher PPI doses (eg, omeprazole 40
mg/day) heal the majority of ulcers.
Continuous PPI treatment is often necessary to maintain
healing. Patients with refractory gastric ulcer may require
surgery because of the possibility of malignancy.

Oral Drug Regimens Used to Heal Peptic


Ulcers and Maintain Ulcer Healing

Nonpharmacologic Therapy
Patients with PUD should eliminate or reduce psychological
stress, cigarette smoking, and the use of nonselective NSAIDs
(including aspirin).
The patient should avoid foods and beverages (e.g., spicy foods,
caffeine, and alcohol) that cause dyspepsia or that exacerbate
ulcer symptoms.
If possible, alternative agents such as acetaminophen,
nonacetylated salicylate (e.g., salsalate), or COX-2 inhibitors
should be used for relief of pain.
Elective surgery is rarely performed because of highly effective
medical management.
Emergency surgery may be required for bleeding, perforation,
or obstruction.

Evaluation of Therapeutic Outcomes


Monitor patients for symptomatic relief of
ulcer pain, potential adverse drug effects, and
drug interactions.
Ulcer pain typically resolves in a few days
when NSAIDs are discontinued and within 7
days upon initiation of antiulcer therapy.
Most patients with uncomplicated PUD will
be symptom free after treatment with any of
the recommended antiulcer regimens.

Evaluation of Therapeutic Outcome


Persistence or recurrence of symptoms within 14 days after
the end of treatment suggests failure of ulcer healing or HP
eradication, or an alternative diagnosis such as
gastroesophageal reflux disease.
Most patients with uncomplicated HP-positive ulcers do not
require confirmation of ulcer healing or HP eradication.
Monitor patients taking NSAIDs closely for signs and
symptoms of bleeding, obstruction, penetration, and
perforation.
Follow-up endoscopy is justified in patients with frequent
symptomatic recurrence, refractory disease, complications,
or suspected hypersecretory states.

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