PCL 413 Pharmacotherapeutics 2

Peptic Ulcer

Peptic ulcer disease (PUD) refers to a group of disorders characterized by circumscribed lesions

of the mucosa of the upper gastrointestinal (GI) tract (particularly the stomach and duodenum).

The lesions occur in regions exposed to gastric juices

Pathophysiology. Ulcers develop when an imbalance exists between factors that protect gastric

mucosa and factors that promote mucosal corrosion.

1. Protective factors

a. Normally, the mucosa secretes a thick mucus that serves as a barrier between luminal acid and

Epithelial cells. This barrier slows the inward movement of hydrogen ions, and allows their

neutralization by bicarbonate ions in fluids secreted by the stomach and duodenum.

b. Alkaline and neutral pancreatic biliary juices also help buffer acid entering the duodenum

from the stomach.

c. An intact mucosal barrier prevents back-diffusion of gastric acids into mucosal cells. It also

has the capacity to stimulate local blood flow, which brings nutrients and other substances to the area and
removes toxic substances (e.g., hydrogen ions). Mucosal integrity also promotes cell growth and repair
after local trauma.

2. Corrosive factors. Peptic ulcer disease reflects the inability of the gastric mucosa to resist corrosion by
irritants, such as pepsin, HCl, and other gastric secretions.

a. Exposure to gastric acid and pepsin is necessary for ulcer development.

b. Disrupted mucosal barrier integrity allows gastric acids to diffuse from the lumen back into

mucosal cells, where they cause injury.

Clinical presentation. Signs and symptoms of PUD vary with the patient’s age and the location of

the lesion. Only about 50% of patients experience classic ulcer symptoms. The remainder are
asymptomatic or report vague or atypical symptoms.

1. Pain. Patients typically describe heartburn or a gnawing, burning, aching, or cramp-like pain.

Some patients report abdominal soreness or hunger sensations. It is unclear whether peptic ulcer

pain results from chemical stimulation or from spasm.

b. Gastric ulcer pain is less localized. It may be referred to the left subcostal region. Gastric ulcer

rarely produces nocturnal pain.

c. GERD patients most commonly present with heartburn, belching, regurgitation, or water

brash; atypical presentations include chest pain, hoarseness/laryngitis, loss of dental enamel,

asthma, chronic cough, or dyspepsia. Complications of GERD include oesophageal ulceration.

d. Dyspepsia applies broadly to a range of symptoms, including abdominal or retrosternal pain

and discomfort, heartburn, nausea, vomiting, and other symptoms referable to the proximal

GI tract.

e. Food usually relieves duodenal ulcer pain but may cause gastric ulcer pain. This finding may

explain why duodenal ulcer patients tend to gain weight, whereas gastric ulcer patients may

lose weight. Pain characteristically occurs 90 mins to 3 hrs after meals in duodenal ulcer

patients, whereas pain in gastric ulcer patients is usually present 45 to 60 mins after a meal.

Food aggravates reflux disease.

2. Nausea and vomiting may occur with either ulcer type.

3. Disease course. Both duodenal and gastric ulcers tend to be chronic, with spontaneous remissions and
exacerbations. Within a year of the initial symptoms, most patients experience a relapse.

a. In many cases, relapse is seasonal, occurring more often in the spring and autumn.

b. All patients with a confirmed duodenal or gastric ulcer should be tested for H. pylori infection.

If the patient is H. pylori–positive, eradication therapy will reduce the recurrence rate significantly and
preclude the need for maintenance medication.

Clinical evaluation

1. Physical findings. Patients with peptic ulcer disease may exhibit superficial and deep epigastric

tenderness and voluntary muscle guarding. With duodenal ulcer, patients also may show unilateral spasm
over the duodenal bulb. Gastric ulcer patients may have weight loss.

2. Diagnostic test results

a. Blood tests may show hypochromic anemia.

c. Gastric secretion tests may reveal hypersecretion of HCl in duodenal ulcer patients and normal or
subnormal HCl secretion in gastric ulcer patients.

d. Upper GI series (barium x-ray) reveals the ulcer crater in up to 80% of cases. Duodenal bulb

deformity suggests a duodenal ulcer.

e. Upper GI endoscopy, this is the most specific test, may be done if barium x-ray yields inconclusive

results. This procedure confirms an ulcer in at least 95% of cases and may detect ulcers not

demonstrable by radiography.

f. Biopsy might be necessary to determine whether a gastric ulcer is malignant.

g. H. pylori status is determined by non-invasive tests (not requiring endoscopy) or invasive

methods (requiring endoscopy).

(1) Non-invasive. Serology, the test of choice when endoscopy is not indicated, is inexpensive and used to
detect antibodies.

Breath tests can also be used to detect the organism, and are uniquely suited as non-invasive means of
confirming eradication of H. pylori after therapy. False-negative breath tests may occur in patients
receiving proton pump inhibitors, antibiotics, or bismuth compounds.

(2) Invasive. These methods include histological visualization of H. pylori or measurement of

urease activity, which require biopsy.

I. Treatment objectives

1. Relieve pain and other symptoms and promote healing

2. Prevent complications

3. Minimize recurrence (eradicate H. pylori in PUD)

4. Maintain adequate nutrition

5. Teach the patient about the disease to improve therapeutic compliance

6. Maintain the patient symptom-free

Diseases associated with peptic ulcer (differential diagnosis) include:

Chronic Pulmonary disease, Cirrhosis of liver, Chronic Renal failure and Pancreatic insufficiency.
Potential risk factors are:

1. Cigarette smoking, Smokers have an increased risk of developing peptic ulcer disease. In addition,
cigarette smoking delays ulcer healing and increases the risk and rapidity of relapse after the ulcer heals.
Nicotine decreases biliary and pancreatic bicarbonate secretion. Smoking also accelerates the emptying of
stomach acid into the duodenum.

2. Psychological stress 3. Genetic factors 4.diet 5. H.pylori infection.

Pathogenesis

1. H. pylori infection in the GIT which is responsible for 95% of duodenal ulcers and 80–85% of gastric
ulcers occurrence. H. pylori (formerly Campylobacter pylori) is a gram-negative microaerophilic, spiral
bacterium with multiple flagella that lives and infects the gastric mucosa. The bacterium is able to survive
in the acidic gastric environment by its ability to produce urease, which hydrolyzes urea into ammonia.
Ammonia neutralizes gastric hydrochloric acid (HCl), creating a neutral cloud surrounding the organism. H.
pylori eradication can cure peptic ulcers and reduce ulcer recurrence; it can eliminate the need for
maintenance therapy in many ulcer patients.

2. The use of NSAIDs may cause: superficial erosions and haemorrhages, silent ulcers, ulcers causing
clinical symptoms and complications.

Clinical manifestations

Upper abdominal pain, Anorexia, Weight loss, Nausea and vomiting, Heartburn and eructation

Haemorrhage, chronic iron deficiency anaemia, perforation

Goals of therapy in uncomplicated peptic ulcer disease

• To provide relief from pain and other ulcer symptoms

• To promote healing

• To prevent complications of peptic ulcer disease

• To maintain adequate nutrition

• To prevent recurrence.

The European Helicobacter pylori Study Group (1997) recommended that when patients are diagnosed
with H. pylori infection, the triple therapy eradication technique should be adopted.

One week of triple therapy using a proton pump inhibitor e.g. omeprazole 20 mg twice daily plus:

amoxicillin 1 g twice daily and clarithromycin 500 mg twice daily.

amoxicillin 500 mg three times daily plus metronidazole 400 mg three times daily
metronidazole 400 mg twice daily plus clarithromycin 250 mg twice daily.

Drugs used for prophylaxis of NSAID induced ulceration

In patients at risk of developing an ulcer such as elderly patients, patients who are taking drugs that

may increase risk or patients with a past history of gastrointestinal haemorrhage, prophylaxis may be
considered using:

misoprostol 200 micrograms twice to four times daily

ranitidine 150 mg twice daily

omeprazole 20 mg every day.

Drugs used in the treatment of peptic ulcer

i. Antacids: to counteract symptoms

ii. Drugs that inhibit acid secretion including H2-receptor antagonists, proton pump inhibitors,
prostaglandin analogues

iii. Drugs that do not inhibit acid secretion, but have a cytoprotective effect: chelated bismuth salts,
sucralfate.

Antacids

• These products are weak alkalis that bring about neutralisation of the acidic pH in the stomach.

• They provide symptomatic relief in dyspepsia, peptic ulceration and gastro-oesophageal reflux.

• Antacids may be used when symptoms occur and provide relief generally within 5–15 minutes of

administration.

• They should be administered between meals and at bedtime (relief duration ranges from 1

hour to 3 hours).

Systemic antacids : sodium bicarbonate

• After oral administration it is absorbed and may cause alkalosis.

• It is usually present in compound indigestion remedies.

• It should be used with care in patients on salt restricted intake (e.g. patients with hypertension).

• To be used for short-term periods.

Systemic antacids : calcium-containing salts

• These can induce rebound acid secretion and so should not be used for prolonged periods.
• Prolonged high doses may cause hypercalcaemia and alkalosis.

Non-systemic antacids

These are antacids that are not absorbed. They include aluminium salts, magnesium salts and aluminium–
magnesium compound preparations (mixture).

Side-effects

• Aluminium: constipation, phosphate depletion

• Magnesium: diarrhoea, hypermagnesaemia

Calcium carbonate: acid rebound, hypercalcaemia, renal calculi

• Sodium bicarbonate: hypernatraemia, bicarbonate alkalosis.

Factors to consider when choosing an antacid

• Mechanism of action: systemic or non-systemic

• Dosage form: liquid preparations more effective than solid formulations

• Administration and dosage regimen

• Side-effects

• Taste: flavour of liquid formulation or chewable tablets

• Packaging: convenience to carry around

• Price.

Other active ingredients in combination with antacids

• Antiflatulents: simeticone (used also in infantcolic) , activated charcoal

• Alginates: protectants against gastro-oesophageal reflux (e.g. aliginic acid).

H2 -receptor antagonists

These products are structural analogues of histamine.

They act as antagonists to the histamine type 2 receptors which are predominantly found in the gastric
parietal cells. Examples include cimetidine, ranitidine, famotidine and nizatidine. All have similar
effectiveness and all have rapid absorption after oral administration. Cimetidine and ranitidine are
primarily metabolised in the liver while famotidine and nizatidine are primarily excreted from the kidneys.
Side-effects

• Common: dizziness, fatigue, rash

• Rare: headache, liver dysfunction, blood disorders, bradycardia, confusion, gynaecomastia

(cimetidine).

Drugs interacting with cimetidine

Cimetidine binds to the cytochrome P450 enzymes and it may cause clinically significant drug interactions
particularly for drugs with a narrow therapeutic index.

Examples include: benzodiazepines, beta blockers, calcium channel blockers, imipramine, phenytoin,
theophylline, warfarin.

Proton pump inhibitors

Proton pump inhibitors act by irreversibly binding to K/HATPase. They have a prolonged duration of action.
Examples include omeprazole, esomperazol, lansoprazole, pantoprazole and rabeprazole. They are used in
gastro-oesophageal reflux disease, H.pylori triple therapy eradication programme and acid-NSAID peptic
ulcer disease.

They are rapidly absorbed after oral administration and are eliminated by hepatic metabolism. Side effects
include diarrhoea, nausea and vomiting, and headache. Dosage frequency: once daily.

Gastro-oesophageal reflux disease and peptic ulcer disease

Antacids may be used in addition to H2-receptor antagonists or proton pump inhibitors to manage
occurrence of symptoms.

Interactions for proton pump inhibitors

Proton pump inhibitors bind to P450 enzymes. Clinically significant drug interactions may occur

with the following:

• Antiepileptics – omeprazole and esomeprazole: effects of phenytoin may be enhanced

• Warfarin: possibly enhanced anticoagulant effect.

Prostaglandin analogues

Synthetic prostaglandin analogues, such as misoprostol, exhibit antisecretory and protective properties.
They promote healing of ulcers and are used to prevent NSAID-associated ulcers.

• Side-effects: crampy abdominal pain, diarrhoea

• Contraindication: pregnancy since it may cause miscarriage.

Bedtime ranitidine is more effective than bedtime omeprazole on residual nocturnal acid secretion. This is
clinically significant for patients taking a proton pump inhibitor twice daily who remain symptomatic during
the night.

H2-receptor antagonists are contraindicated in Hepatic and renal impairment, pregnancy, breast- feeding.

Side effects are gastrointestinal disturbances, headache, dizziness, rash, tiredness

PPIs contraindicated in Hepatic impairment, pregnancy, breast-feeding

Side effects are Gastrointestinal disturbances, headache, vomiting.

Pharmaceutical care Plan.

Advise patients on use of ulcer-healing agents prescribed, dose, duration of treatment and

response to therapy; advise on triple therapy where appropriate.

• Monitor frequency of medicine requests to identify worsening of the symptoms.

• Advise patient on use of adjunct therapy: antacids.

• Gastrointestinal investigations are based on H.pylori tests and endoscopy.

• Abnormal biochemical and haematological test results may occur in perforation or bleeding

ulceration.

• Assess concurrent drug therapy and other diseases.