Prepared By:

Mr. Jalaram Thakkar

M. Pharm.

Pathophysiology of peptic ulcer

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Tuesday, April 11, 2023

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Ulcers are defined as a breach in the mucosa of the alimentary

tract that extends through the muscularis mucosa into the

submucosa or deeper.

Peptic ulcers are chronic, most often solitary, lesions that

occur in any portion of the gastrointestinal tract exposed to the

aggressive action of acid-peptic juices. At least 98% of peptic

ulcers are either in the first portion of the duodenum or in the

stomach, in a ratio of about 4:1.

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Epidemiology

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• In the American population, about 2.5% of males and 1.5% of females have peptic ulcers. For both men and women in the United States, the lifetime risk of developing peptic ulcer disease is about 10%.

The overall mortality from PUD has decreased, death rates have increased in patients older than 75 years of age, and that is due to increased consumption of NSAIDs and an aging population. Patients with gastric ulcer have a higher mortality rate than those with duodenal ulcer because gastric ulcer is more prevalent in older individuals.

H2-receptor antagonists (H2RAs), proton pump inhibitors (PPIs), and drugs that promote mucosal defense are used in PUD.

There are two key facts1.Mucosal exposure to gastric acid and pepsin.2.There is a very strong causal association with H. pylori infection.

Imbalance between defenses and aggressive factorsDefensive factors:-- Prevent the stomach and duodenum from self-digestion– Mucus: continually secreted, protective effect– Bicarbonate: secreted from endothelial cells– Blood flow: Good blood flow maintains mucosal integrity– Prostaglandins: Stimulate secretion of bicarbonate and mucus, promote blood flow, suppress secretion of gastric acid

ETIOLOGY AND RISK FACTORS

Aggressive factors: Helicobacter pylori: Gram negative bacteria, can live in

stomach and duodenum, may breakdown mucus layer => inflammatory response to presence of the bacteria also produces urease – forms CO2 and ammonia which are toxic to mucosa

Gastric Acid: needs to be present for ulcer to form => activates pepsin and injures mucosa

Decreased blood flow: causes decrease in mucus production and bicarbonate synthesis, promote gastric acid secretion

NSAIDS: inhibit the production of prostaglandins Smoking: nicotine stimulates gastric acid production

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Common causes Helicobacter pylori infection Nonsteroidal anti-inflammatory drugs Critical illness (stress-related mucosal damage)

Uncommon causes Hypersecretion of gastric acid (e.g., Zollinger-Ellison syndrome) Viral infections (e.g., cytomegalovirus) Vascular insufficiency (crack cocaine–associated) Rare genetic subtypes Idiopathic

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Acute Esophagitis & Gastritis

Gastric peptic ulcer:

Gastric peptic ulcer:

Gastric Ulcer

Duodenal Peptic Ulcer

Gastric Ulcer

Peptic ulcer - Endoscopy

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• Gastric and duodenal ulcers occur because of an imbalance between aggressive factors (gastric acid and pepsin) and mechanisms that maintain mucosal integrity (mucosal defense and repair).

•Alterations in mucosal defense that are induced by HP or NSAIDs are the most important cofactors in the formation of peptic ulcers.

Pathophysiology

GASTRIC ACID AND PEPSIN Produce mucosal damage Patients with ZES have gastric acid hypersecretion

resulting from a gastrin-producing tumor.

HELICOBACTER PYLORI Helicobacter pylori is a spiral-shaped, pH-sensitive,

gram-negative, microaerophilic bacterium that resides between the mucus layer and surface epithelial cells in the stomach.

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• Infection identified by hypochlorhydria • HP produces large amounts of urease, which hydrolyzes urea in the gastric juice and converts it to ammonia and carbon dioxide.• Ammonia creates a neutral microenvironment within and surrounding the bacterium, which protects it from the lethal effect of acid.• HP to cause gastroduodenal mucosal injury. Pathogenic mechanisms include: (a)Direct mucosal damage, (b)Alterations in the host immune/inflammatory response.

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(c) Hypergastrinemia leading to increased acid secretion.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS• Cause gastric mucosal damage by two important

mechanisms:

(a) Direct or topical irritation of the gastric epithelium

(b) Systemic inhibition of endogenous mucosal prostaglandin synthesis.

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Metabolism of arachidonic acid after its release from membranephospholipids. ASA, aspirin; HPETE, hydroperoxyeicosatetraenoic acid; NSAIDs, nonsteroidal antiinflammatory drugs; PG, prostaglandin.

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Tissue distribution and actions of cyclooxygenase (COX) isoenzymes. Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin (ASA) inhibit COX-1 and COX-2 to varying degrees; COX-2 inhibitors inhibit only COX-2.

Symptoms Abdominal pain 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) 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 obstruction22

Laboratory tests Gastric acid secretory studies The hematocrit and hemoglobin are low with bleeding, and

stool hemoccult tests are positive Tests for Helicobacter pylori

Other diagnostic tests Fiberoptic upper endoscopy (esophagogastroduodenoscopy)

detects more than 90% of peptic ulcers and permits direct inspection, biopsy, visualization of superficial erosions, and sites of active bleeding

Barium contrast techniques detect peptic ulcers.

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TREATMENT: Peptic Ulcer Disease

The treatment of chronic PUD varies depending on the etiology of the ulcer (HP or NSAID).

The goal of therapy in HP-positive patients is to eradicate HP,, heal the ulcer and cure the disease.

The goal of therapy in a patient with a NSAID-induced ulcer is to heal the ulcer as rapidly as possible. Patients at high risk of developing NSAID ulcers should be switched to a COX-2 inhibitor or receive prophylactic drug cotherapy to reduce ulcer risk and ulcerrelated complications.

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NONPHARMACOLOGIC THERAPY

Eliminate or reduce…..

Psychological stress, Cigarette smoking, and The use of selective NSAIDs

PHARMACOLOGIC THERAPY

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H2 receptor blockers:

- Cimetidine (Tagamet®)

First H2-blocker available

Inhibits P450 => Drug interaction

- Ranitidine (Zantac®)

Does not inhibit P450 => fewer side effects

- Nizatidine (Axid®)

- Famotidine (Pepcid®)

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Proton pump inhibitors:- Irreversibly inhibit the H+/K+ - ATPase in gastric parietal cells

- Drugs are inactive at neutral pH, but since they are weak bases, are activated in the acidic stomach milieu => restricted activity

– Acid production abliterated for 24-48 hours

• Omeprazole (Prilosec®)

• Lansoprazole (Prevacid®)

• Esomeprazole (Nexium®)

• Rabeprazole

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Mucosal protective agents: Misoprostol

– Prostaglandin E1 analog (PG stimulate mucus and bicarbonate production)

– Used when treatment with NSAIDs inhibits endogenous PG synthesis

Sucralfate

– Complex of aluminum hydroxide and sulfated sucrose

– Forms complex gels with mucus => mucus stabilized => diffusion of H+ impaired

– Not absorbed => essentially free of side effects

– Must be taken every 6 hours29

H. Pylory induced peptic ulcer

Combinations must be used:

• Bismuth (PeptoBismol®) – disrupts cell wall of H. pylori

• Clarithromycin – inhibits protein synthesis

• Amoxicillin – disrupts cell wall

• Tetracyclin – inhibits protein synthesis

• Metronidazole – used often due to bacterial resistance to amoxicillin and tetracyclin, or due to intolerance by the patient

Standard treatment regimen for peptic ulcer:

Omeprazole + amoxicillin + metronidazole30

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THANK YOU

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