Peptic Ulcer Disease (PUD)Pharm.D Balsam Alhasan

DEFINITION:

• Peptic ulcer disease (PUD) refers to a group of ulcerative disorders of the upper GI tract that require acid and pepsin for their formation.

• Ulcers differ from gastritis and erosions in that they extend deeper into the muscularis mucosa.

• The three common forms of peptic ulcers include:1. Helicobacter pylori (HP)– associated ulcers, 2. Nonsteroidal antiinflammatory drug (NSAID)–induced ulcers,3. And stress-related mucosal damage (also called stress

ulcers).

PATHOPHYSIOLOGY

• The pathogenesis of duodenal ulcers (DU) and gastric ulcers (GU) is multifactorial and most likely reflects a combination of pathophysiologic abnormalities and environmental and genetic factors.

• Most peptic ulcers occur in the presence of acid and pepsin when HP, NSAIDs, or other factors disrupt normal mucosal defense and healing mechanisms.

• Acid is an independent factor that contributes to disruption of mucosal integrity. Increased acid secretion has been observed in patients with DU and may result from HP infection. Patients with GU usually have normal or reduced rates of acid secretion.

PATHOPHYSIOLOGY (Cont.)

• Alterations in mucosal defense induced by HP or NSAIDs are

the most important cofactors in peptic ulcer formation.

Mucosal defense and repair mechanisms include mucus and

bicarbonate secretion, intrinsic epithelial cell defense, and

mucosal blood flow. Maintenance of mucosal integrity and

repair is mediated by endogenous prostaglandin production.

PATHOPHYSIOLOGY (Cont.)

• HP infection causes gastritis in all infected individuals and is

causally linked to PUD. However, only about 20% of infected

persons develop symptomatic PUD. Most non-NSAID ulcers

are infected with HP, and HP eradication markedly decreases

ulcer recurrence. HP may cause ulcers by direct mucosal

damage, altering the immune/inflammatory response, and by

hypergastrinemia leading to increased acid secretion.

PATHOPHYSIOLOGY (Cont.)• Nonselective NSAIDs (including aspirin) cause gastric mucosal

damage by two mechanisms:

• (1) A direct or topical irritation of the gastric epithelium, and

• (2) Systemic inhibition of the cyclooxygenase-1 (COX-1)

enzyme, which results in decreased synthesis of protective

prostaglandins.

• Use of corticosteroids alone does not increase the risk of ulcer

or complications, but ulcer risk is doubled in corticosteroid

users taking NSAIDs concurrently.

Other Factors:• Epidemiologic evidence links cigarette smoking to PUD,

impaired ulcer healing, and ulcer-related GI complications.

• The risk is proportional to the amount smoked per day.

• Although clinical observation suggests that ulcer patients are

adversely affected by stressful life events, controlled studies

have failed to document a cause-and-effect relationship.

Other Factors:

• 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.

CLINICAL PRESENTATION

• Abdominal pain is the most frequent symptom of PUD. The

pain is often epigastric and described as burning but can

present as vague discomfort, abdominal fullness, or

cramping.

• A typical nocturnal pain may awaken patients from sleep,

especially between 12 AM and 3 AM.

• Pain from DU often occurs 1 to 3 hours after meals and is

usually relieved by food, whereas food may precipitate or

accentuate ulcer pain in GU.

CLINICAL PRESENTATION

• Antacids provide rapid pain relief in most ulcer patients.

• Heartburn, belching, and bloating often accompany the pain.

• Nausea, vomiting, and anorexia are more common in GU than

DU.

• The severity of symptoms varies from patient to patient and

may be seasonal, occurring more frequently in the spring or

fall.

CLINICAL PRESENTATION

• Pain does not always correlate with the presence of an ulcer.

• Asymptomatic patients may have an ulcer at endoscopy, and

patients may have persistent symptoms even with

endoscopically proven healed ulcers. Many patients

(especially older adults) with NSAID-induced, ulcer-related

complications have no prior abdominal symptoms.

Complications:

• Complications of ulcers caused by HP and NSAIDs include:

1. Upper GI bleeding,

2. Perforation into the peritoneal cavity,

3. Penetration into an adjacent structure (e.G., Pancreas,

biliary tract, or liver),

4. And gastric outlet obstruction.

• Bleeding may be occult or present as melena or hematemesis.

Complications:

• Perforation is associated with sudden, sharp, severe pain,

beginning first in the epigastrium but quickly spreading over

the entire abdomen.

• Symptoms of gastric outlet obstruction typically occur over

several months and include early satiety, bloating, anorexia,

nausea, vomiting, and weight loss.

DIAGNOSIS

• The physical examination may reveal epigastric tenderness

between the umbilicus and the xiphoid process that less

commonly radiates to the back.

• Routine laboratory tests are not helpful in establishing a

diagnosis of uncomplicated PUD. The hematocrit, hemoglobin,

and stool hemoccult tests are used to detect bleeding.

Diagnostic Procedures:

• The diagnosis of HP infection can be made using endoscopic

or nonendoscopic tests. The tests that require upper

endoscopy are invasive, more expensive, uncomfortable, and

usually require a mucosal biopsy for histology, culture, or

detection of urease activity.

• The nonendoscopic tests include serologic antibody detection

tests, the urea breath test (UBT), and the stool antigen test.

Diagnostic Procedures:

• Serologic tests detect circulating immunoglobulin G directed

against HP but are of limited value in evaluating post-

treatment eradication.

• The UBT is based on urease production by HP.

• Testing for HP is only recommended if eradication therapy is

considered.

Diagnostic Procedures:

• If endoscopy is not planned, serologic antibody testing is

reasonable to determine HP status. The UBT is the preferred

nonendoscopic method to verify HP eradication after

treatment.

• The diagnosis of PUD depends on visualizing the ulcer crater

either by upper GI radiography or endoscopy. Radiography

may be the preferred initial diagnostic procedure in patients

with suspected uncomplicated PUD.

Diagnostic Procedures:

• Upper endoscopy should be performed if complications

are thought to exist or if an accurate diagnosis is

warranted. If a GU is found on radiography, malignancy

should be excluded by direct endoscopic visualization

and histology.

DESIRED OUTCOME

• The goals of treatment are relieving ulcer pain, healing

the ulcer, preventing ulcer recurrence, and reducing

ulcer-related complications.

• In HP positive patients with an active ulcer, a previously

documented ulcer, or a history of an ulcer-related

complication, the goals are to eradicate the organism,

heal the ulcer, and cure the disease with a cost-effective

drug regimen.

TREATMENT

NONPHARMACOLOGIC TREATMENT• Patients with PUD should eliminate or reduce psychological

stress, cigarette smoking, and the use of nonselective NSAIDs

(including aspirin). If possible, alternative agents such as

acetaminophen, a nonacetylated salicylate (e.g., salsalate), or

a COX-2 selective inhibitor should be used for pain relief.

• Although there is no need for a special diet, patients should

avoid foods and beverages that cause dyspepsia or

exacerbate ulcer symptoms (e.g., spicy foods, caffeine,

alcohol).

PHARMACOLOGIC TREATMENT

• Eradication of HP is recommended for HP-infected

patients with GU, DU, ulcer-related complications, and in

some other situations. Treatment should be effective,

well tolerated, easy to comply with, and cost-effective

(Table 29-1).

Therapeutic Options:

• First-line eradication therapy is a proton pump inhibitor (PPI)–

based, three-drug regimen containing two antibiotics, usually

clarithromycin and amoxicillin, reserving metronidazole for

back-up therapy (e.g., clarithromycin– metronidazole in

penicillin-allergic patients). The PPI should be taken 30 to 60

minutes before a meal along with the two antibiotics.

Therapeutic Options:

• Although an initial 7-day course provides minimally

acceptable eradication rates, longer treatment periods (10 to

14 days) are associated with higher eradication rates and less

antimicrobial resistance.

• First-line treatment with quadruple therapy using a PPI (with

bismuth, metronidazole, and tetracycline) achieves similar

eradication rates as PPIbased triple therapy and permits a

shorter treatment duration (7 days).

• However, this regimen is often recommended as second-

line treatment when a clarithromycin–amoxicillin

regimen is used initially. All medications except the PPI

should be taken with meals and at bedtime.

Failed Eradication :• If the initial treatment fails to eradicate HP, second-line

empiric treatment should: • (1) use antibiotics that were not included in the initial

regimen; • (2) include antibiotics that do not have resistance problems; • (3) use a drug that has a topical effect (e.g., bismuth); and • (4) be extended to 14 days. • Thus, if a PPI–amoxicillin–clarithromycin regimen fails, therapy

should be instituted with a PPI, bismuth subsalicylate, metronidazole, and tetracycline for 14 days.

Conventional Protocols:

• Treatment with a conventional antiulcer drug (e.g., PPI,

histamine-2 receptor antagonist [H2RA], or sucralfate alone is

an alternative to HP eradication but is discouraged because of

the high rate of ulcer recurrence and ulcer-related

complications.

• Dual therapy (e.g., H 2RA plus sucralfate, H2RA plus PPI) is not

recommended because it increases cost without enhancing

efficacy.

Maintenance therapy:

• Maintenance therapy with a PPI or H2RA (Table 29-2) is

recommended for high-risk patients with ulcer complications,

patients who fail HP eradication, and those with HP-negative

ulcers.

• For treatment of NSAID-induced ulcers, nonselective NSAIDs

should be discontinued (when possible) if an active ulcer is

confirmed.

• Most uncomplicated NSAID-induced ulcers heal with standard

regimens of an H2RA, PPI, or sucralfate (see Table 29-2) if the

NSAID is discontinued.

Patients on NSAIDs:

• If the NSAID must be continued, consideration should be given

to reducing the NSAID dose or switching to acetaminophen, a

nonacetylated salicylate, a partially selective COX-2 inhibitor,

or a selective COX-2 inhibitor.

• PPIs are the drugs of choice when NSAIDs must be continued

because potent acid suppression is required to accelerate

ulcer healing. If HP is present, treatment should be initiated

with an eradication regimen that contains a PPI.

Special Cases:• Patients at risk of developing serious ulcer-related

complications while on NSAIDs should receive prophylactic

therapy with misoprostol or a PPI.

• 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 HP

negative patients, higher PPI doses (e.g., omeprazole 40

mg/day) heal the majority of ulcers. Continuous PPI treatment

is often necessary to maintain healing.

Evaluation Of Therapeutic Outcomes:• Patients should be monitored for symptomatic relief of ulcer

pain as well as potential adverse effects and drug interactions

related to drug therapy.

• 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 one of the recommended antiulcer

regimens.

Evaluation Of Therapeutic Outcomes:• The 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.

Evaluation Of Therapeutic Outcomes:• High-risk patients on NSAIDs should be closely

monitored 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.

Questions?