Peptic Ulcer Disease

Peptic ulcer disease (PUD) refers to a defect in the gastric or duodenal mucosal

wall that extends through the muscularis mucosa into the deeper layers of the

submucosa. Ulcer formation is the net result of a lack of homeostasis between

factors within the GI tract responsible for the breakdown of food (e.g., gastric acid

and pepsin) and factors that promote mucosal defense and repair (e.g.,

bicarbonate, mucus secretion, and PGs). The mucus and bicarbonate barrier,

through its buffering action, is the primary source of defense against gastric acid.

It allows an acidic environment to be maintained on the epithelial lining. PGs

inhibit gastric acid secretion, stimulation of mucus and bicarbonate production,

increase mucosal blood flow and stimulate epithelial cell regeneration.

➢ There are many etiologies of PUD such as:

● H. Pylori infection

● Use of NSAIDs

● Stress-related mucosal damage (SRMD): occurs more frequently in critically

ill patients and is due to compromised mesenteric perfusion resulting in

mucosal defects.

● Zollinger-Ellison syndrome

● Others (cigarette smoking) …

The relatively high incidence of PUD in the elderly may be due to higher NSAID

use. H. pylori infection and NSAID use account for most cases of PUD. Ulcers

related to H. pylori infection more commonly affect the duodenum. Ulcers related

to NSAIDs more frequently affect the stomach. Gastric ulcer (GU) tends to occur

much later in life than duodenal ulcer (DU), with the peak incidence of GU

occurring in patients over 60 years of age. Malignancy is more commonly found

with GU than DU.

Complications of PUD include gastrointestinal (GI) bleeding, perforation, and

obstruction. Complications of untreated or undiagnosed H. pylori infection

include gastric cancer and PUD.

Patients typically present with early satiety after meals, nausea, vomiting, abdominal pain, and weight loss. Perforation requires emergent surgical intervention, and these patients should not undergo endoscopy.

PUD can be classified as uncomplicated or complicated. Uncomplicated disease is typically characterized by mild epigastric pain, whereas complicated disease involves acute upper GI complications such as GI bleeding, obstruction, or perforation. Bleeding may be occult or may present as melena or hematemesis.

➢ Diagnosis

Radiologic and/or endoscopic procedures are usually required to document the

presence of ulcers. Because endoscopic testing is invasive and expensive, it is only

indicated in patients 60 years of age or older with new-onset dyspepsia. Patients

with dyspepsia who are younger than 60 years may forego endoscopy but should

be tested for H. pylori using noninvasive testing and treated if positive. Those who

test negative for H. pylori should be offered a trial (4–8 weeks) of acid

suppression therapy or proceed to endoscopy. Persistent dyspepsia despite a trial

of acid suppressive therapy warrants upper endoscopy evaluation.

Routine laboratory tests are not helpful in establishing a diagnosis of PUD.

Hematocrit, hemoglobin, and stool guaiac tests are used to detect bleeding.

Diagnostic tests to detect H. pylori presence can be either endoscopic or

nonendoscopic.

Endoscopic diagnosis involves extraction of gastric tissue samples that are

subsequently tested for H. pylori.

Nonendoscopic testing methods for H. pylori include the urea breath test,

serologic testing, and stool antigen assay. These tests are less invasive and less

expensive than endoscopy.

The urea breath test is usually first line because of its high sensitivity and

specificity and short turnaround time. Concomitant acid suppressive or antibiotic

therapy may give false-negative results. The urea breath test can also be used to

confirm eradication of H. pylori infection.

Serologic testing provides a quick (within 15 minutes) office-based assessment of

exposure to H. pylori, but it cannot differentiate active infection from previously

treated infection; patients can remain seropositive for years after eradication.

Serologic testing is recommended in patients with recent or current antibiotic or

acid-suppressive therapy.

Stool antigen assays can be useful for initial diagnosis or to confirm H. pylori

eradication. They have high sensitivity and specificity and are affected less by

concomitant medication use.

NONPHARMACOLOGIC TREATMENT

Any Patients with PUD should eliminate or reduce psychological stress, cigarette

smoking, and use of NSAIDs.

Although there is no need for a special diet, patients should avoid foods and

beverages that cause dyspepsia or exacerbate ulcer symptoms (eg, spicy foods,

caffeine, and alcohol).

Emergency surgery may be required for bleeding, perforation, or obstruction.

PHARMACOLOGIC TREATMENT

INITIAL MANAGEMENT

Treat the underlying etiology.

Eradication of Helicobacter pylori (H. pylori) — Patients with peptic ulcers should

be tested for infection with H. pylori and treated accordingly. Eradication of H.

pylori in patients with peptic ulcer disease is associated with higher healing rates

in patients with duodenal and gastric ulcers. In addition, eradication of H. pylori

infection is associated with lower ulcer recurrence rates in patients with gastric

and duodenal ulcers who are not placed on maintenance anti-secretory therapy.

Discontinue nonsteroidal anti-inflammatory drugs (NSAIDs) — Patients with

peptic ulcers should be advised to avoid NSAIDs. NSAIDs, including aspirin,

increase the risk of peptic ulcer disease and are associated with an increased risk

of complications from a peptic ulcer.

Rare or unclear cause — Rare causes of ulcer disease (eg, infections, Crohn

disease, and ischemia) should be addressed and treated. In patients with peptic

ulcer disease of unclear etiology, additional evaluation is needed to exclude other

rare causes of peptic ulcer.

Initial anti-secretory therapy

Choice of therapy — All patients with peptic ulcers should receive anti-secretory

therapy with a proton pump inhibitor (PPI) (eg, omeprazole 20 to 40 mg daily or

equivalent) to facilitate ulcer healing. PPI use results in faster control of peptic

ulcer disease symptoms and higher ulcer healing rates as compared with H2RA as

a consequence of stronger acid suppression. PPIs also heal NSAID-related ulcers

more effectively as compared with H2RAs.

Duration

The duration of initial anti-secretory therapy varies based on the ulcer

characteristics, the underlying etiology (H. pylori, NSAID use) and the presence of

ulcer complications (eg, bleeding, perforation, penetration, or gastric outlet

obstruction).

a) Treatment of H. Pylori-Associated Ulcers

All patients with evidence of active infection with H. pylori should be offered

treatment. Goal of H. pylori therapy: complete eradication.

Anti-secretory therapy in H. pylori-positive ulcer

● Uncomplicated ulcer – In patients with uncomplicated ulcers, PPI (eg,

omeprazole 20 mg twice daily) given for 14 days, along with the antibiotic

regimen to treat H. pylori, is usually adequate to induce healing.

● Complicated ulcer – All patients with complicated peptic ulcers (ulcers with

bleeding, perforation, penetration, or gastric outlet obstruction) should

initially receive acid suppressive therapy with an intravenous PPI. Once

patients are tolerating oral medications, they should be switched to an oral

PPI at high-dose twice daily to enhance healing (eg, omeprazole 40 mg

twice daily). Dosing should generally be reduced to once daily after four

weeks. However, in patients with bleeding, the intravenous PPI can be

switched to a lower oral dose (eg, 20 mg omeprazole once daily) 72 hours

after endoscopy, provided there is no evidence of recurrent bleeding.

The duration of treatment depends on the location and cause of the ulcer, but is

typically between 4 and 12 weeks in total.

In patients with complicated duodenal ulcers, we suggest anti-secretory

treatment for four to eight weeks.

In patients with complicated gastric ulcers, we suggest anti-secretory therapy for

a total duration of 8 to 12 weeks.

The choice of initial antibiotic regimen to treat H. pylori should be guided by the

presence of risk factors for macrolide resistance and the presence of a penicillin

allergy.

Risk factors for macrolide resistance include:

● Prior exposure to macrolide therapy for any reason.

● High local clarithromycin resistance rates ≥15 percent or eradication rates

with clarithromycin-based triple therapy ≤85 percent.

For initial therapy in patients without risk factors for macrolide resistance, we

suggest triple therapy with a proton pump inhibitor (PPI), amoxicillin (1 g twice

daily), and clarithromycin (500 mg twice daily) for 14 days (Grade 2B). We suggest

substitution of amoxicillin with metronidazole only in penicillin-allergic individuals

since metronidazole resistance is common and can reduce the efficacy of

treatment.

We suggest bismuth quadruple therapy as initial treatment in patients with risk

factors for macrolide resistance. Quadruple therapy consists of a PPI, bismuth

subsalicylate, and two antibiotics (metronidazole and tetracycline) given four

times daily for 14 days.

Tests to confirm eradication should be performed in all patients treated for H.

pylori. Eradication may be confirmed by a urea breath test, fecal antigen test, or

upper endoscopy performed four weeks or more after completion of antibiotic

therapy. PPI therapy should be withheld for one to two weeks prior to testing.

In patients with persistent H. pylori infection, the choice of antibiotic therapy

should be guided by the patient’s initial treatment regimen and the presence of

relevant antibiotic allergies. For patients failing a course of H. pylori treatment,

we suggest an alternate regimen using a different combination of medications. In

general, clarithromycin and antibiotics used previously should be avoided if

possible. Culture with antibiotic sensitivity testing should be performed to guide

antibiotic treatment in patients who have failed two prior treatment regimens.

b) NSAID-related peptic ulcers

● Any Patients with PUD should eliminate or reduce use of NSAIDs (including

aspirin). If possible, alternative agents such as acetaminophen or a

nonacetylated salicylate (eg, salsalate) should be used for pain relief.

● Patients with NSAID-associated ulcers should be treated with a PPI (eg,

omeprazole 20 to 40 mg daily) for four to eight to weeks based on the size

of the ulcer. In patients with peptic ulcers who need to remain on NSAIDs

or aspirin, maintenance antisecretory therapy with a PPI (eg, omeprazole

20 mg daily) can reduce the risk of ulcer complications or recurrence

*Prophylactic regimens against PUD are often required in patients receiving

long-term NSAID or aspirin therapy for osteoarthritis, rheumatoid arthritis, or

cardio protection. Misoprostol, H2RAs, PPIs, and COX-2 selective inhibitors

have been evaluated in controlled trials to reduce the risk of NSAID-induced

PUD. In patients at risk for NSAID-induced ulcers, PPIs at standard doses

reduce the risk of both gastric and DUs as effectively as misoprostol and more

effectively than H2RAs. In addition, PPIs are generally better tolerated than

misoprostol.

1. Misoprostol: Synthetic PG E1 analog that exogenously replaces PG stores.

Limited use, because of high frequency of bothersome GI effects such as

abdominal pain, flatulence, and diarrhea.

Not Use in pregnancy; Abortifacient effects.

2. H2-Receptor Antagonists: Standard doses of H2RAs (e.g., famotidine 40

mg/day) are effective in preventing NSAID-related duodenal ulceration but not

gastric ulceration (the most frequent type of ulcer-associated with NSAIDs).

3. Proton Pump Inhibitors: is more effective than H2RAs in reducing the risk of

nonselective NSAID-related gastric and duodenal ulceration. PPIs are also as

effective as misoprostol but better tolerated. All PPIs are effective when used

in standard doses

4. COX-2 Selective Inhibitors: Selective COX-2 inhibitors are no more effective

than the combination of a PPI and a nonselective NSAID in reducing the

incidence of ulcers and are associated with a greater incidence of CV events

(e.g., ischemic stroke).

Celecoxib is the only agent in this class that remains on the market; its

postulated improved GI safety when compared to nonselective NSAIDs.

Longer-term studies evaluating the CV risks associated with the use of COX-2

inhibitors have found a higher incidence of CV mortality with these agents

compared to traditional NSAIDs

5. Sucralfate: Is a negative charged, nonabsorbable agent that forms a

complex by binding with positively-charged proteins in exudates, forming a

viscous, paste-like, adhesive substance.

Limited use, need for multiple daily dosing, large tablet size, and interaction

with a number of other medications (e.g., digoxin and fluoroquinolones).

Side effects: constipation, nausea, metallic taste, and the possibility for

aluminum toxicity in patients with renal failure.

3. Prevention of Stress-Related Mucosal Damage

Stress ulceration is defined as ulceration of the upper gastrointestinal (GI) tract

(esophagus, stomach, and duodenum) that occurs due to hospitalization.

Stress ulceration is common in critically ill patients. Prevention of stress ulcers

involves maintaining hemodynamic stability. Stress ulcer prophylaxis (SUP) is

only indicated in intensive care unit (ICU) patients with certain risk factors. The

clinician must weigh the risks and benefits of using acid suppression, especially

PPIs, in low-risk patients. PPIs and H2RAs are the drugs of choice for SUP;

however, antacids and sucralfate may be acceptable options in some patients.

Zollinger-Ellison Syndrome(ZES): is caused by a gastrin produced tumor

called a gastrinoma. This results in a state of gastric acid hypersecretion in

which patients develop diarrhea and malabsorption. High-dose oral PPI

therapy is the treatment of choice for ZES and may be used long term in

patients when the tumor cannot be identified or fully resected.

Treatment of Refractory Ulcers: Refractory ulcers are defined as ulcers that

fail to heal despite 8 to 12 weeks of acid suppressive therapy. The presence of

refractory ulcers requires a thorough assessment, including evaluation of

medication adherence, extensive counseling and questioning regarding recent

over-the-counter and prescription medication use, and testing for H. pylori

using a different method than previously done if testing was negative.

Changing from H2RA therapy to a PPI should be considered. Patients should be

advised to avoid NSAIDs and tobacco.

Surgical management is reserved for the gastric ulcers that fail to heal after

twice-daily anti-secretory therapy with a PPI for 24 weeks.

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.

* Patients with uncomplicated PUD are usually symptom free after treatment

with any of the recommended antiulcer regimens.

* Persistent or recurrent symptoms within 14 days after the end of treatment

suggests failure of ulcer healing or H. pylori eradication or presence of 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.

Reference

1. Chisholm-burns M, Schwinghammer T, Malone P, Kolesar J, Lee K,

Bookstaver B. Pharmacotherapy principles and practice 5th ed. Mc-Graw-

Hill; 2019. Chapter 18, peptic ulcer disease; p 305-314.

2. J Thomas Lamont. Treatment regimens for Helicobacter pylori. [updated

2020 September 16; cited 2020 October 31] Available

https://www.uptodate.com/contents/approach-to-refractory-peptic-ulcer-

disease?

3. Nimish B Vakil, MD, AGAF, FACP, FACG, FASGESection. Peptic ulcer disease:

Treatment and secondary prevention. [Updated 2020 April 01; cited 2020

October31].Available form: https://www.uptodate.com/contents/peptic-

ulcer-disease-treatment-and-secondary-prevention?

Done by Pharm D students: Nour Alomari and Mohammad Khear.

Supervised by clinical pharmacist: Eshraq Al-abweeny.