Gastrointestinal Physiology and Pharmacology 1: The Digestive System (Peptic Ulcer Disease)

1. Gastric Anatomy

• The stomach is a J-shaped organ situated in the upper abdominal cavity, connecting to the esophagus above and the duodenum below.

• It is divided into three sections:

• Fundus: The broadest part, rich in gastric glands.

• Body: The main part of the stomach, also rich in gastric glands.

• Antrum: The narrowest part, connecting to the duodenum.

• Junctions:

• The junction between the stomach and esophagus is the cardia.

• The junction between the stomach and duodenum is the pylorus.

• The stomach wall comprises four layers:

• Serosa: The outermost layer, covering the stomach’s surface.

• Muscularis: Composed of three muscle layers: longitudinal, circular, and oblique, facilitating stomach contraction and food grinding.

• Submucosa: A layer of connective tissue, containing blood vessels, nerves, and glands.

• Mucosa: The innermost layer, in direct contact with food, containing gastric glands.

2. Role of the Central Nervous System and Cells in the Stomach

• Vagus Nerve (X): Releases acetylcholine, stimulating the secretion of acid, pepsinogen, and histamine by gastric cells.

• Parietal Cells (Oxyntic Cells): Secrete acid (HCl).

• Chief Cells (Zymogenic Cells): Secrete pepsinogen, which is converted to pepsin in an acidic environment.

• Enterochromaffin-like (ECL) Cells: Secrete histamine, stimulating parietal cells to secrete acid.

• G Cells: Secrete gastrin, stimulating ECL cells to release histamine and parietal cells to secrete acid.

• D Cells: Secrete somatostatin, inhibiting histamine and gastrin release, indirectly suppressing acid secretion.

3. Peptic Ulcer Disease (PUD)

• Definition: A condition characterized by sores ≥5mm in the stomach or duodenal mucosa, extending into the muscular layer of the mucous membrane.

• Classification:

• Location: Gastric ulcers (in the stomach), duodenal ulcers (in the duodenum).

• Etiology: Helicobacter pylori (Hp)-associated ulcers, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcers, stress ulcers.

• Cause: An imbalance between ulcerogenic factors and protective factors.

4. Protective and Ulcerogenic Factors

• Protective Factors:

• Mucus-Bicarbonate Barrier: A thick, viscous mucus layer with a near-neutral pH protects the mucosa from acid.

• Epithelial Cell Regeneration and Repair: Enables rapid mucosal recovery after injury.

• Prostaglandin E2 (PGE2): Promotes mucous and bicarbonate secretion by epithelial cells and increases blood flow to the mucosa.

• Ulcerogenic Factors:

• HCl: Gastric acid, causing mucosal damage.

• Helicobacter pylori: Bacteria residing in the stomach, causing inflammation and mucosal injury.

• Pepsin: A protein-digesting enzyme, active in an acidic environment, capable of damaging the mucosa.

• NSAIDs: Nonsteroidal anti-inflammatory drugs, inhibiting prostaglandin production, reducing mucosal protection.

• Bile Acids: Cause duodenal mucosal damage.

5. Helicobacter pylori (Hp)

• Description: A spiral-shaped bacterium capable of surviving in the acidic environment of the stomach.

• Mechanism of Disease:

• Urease Production: Converts urea into ammonia, neutralizing gastric acid and creating a favorable environment for bacterial growth.

• Catalase and Oxidase Production: Degrades mucus, enabling easier bacterial penetration of the mucosa.

• Direct Toxicity: Damages epithelial cells, causing degeneration and necrosis.

• Inflammatory Response: Activates the immune system, leading to inflammation, increasing the likelihood of mucosal injury.

• Gastric Damage:

• Alterations in Gastric Physiology: Decreased mucus production, increased acid production.

• Direct Toxicity: Causes epithelial cell necrosis.

• Inflammatory Response: Induces chronic gastritis, increasing the risk of ulceration.

6. Tests for H. pylori

• Invasive Methods:

• Histopathology: Analysis of biopsy tissue obtained from the stomach.

• Urease Test: Detects the presence of urease enzyme secreted by bacteria.

• Culture: Bacterial culture from a stomach biopsy specimen.

• Polymerase Chain Reaction (PCR): Analyzes bacterial DNA in a biopsy specimen.

• Non-invasive Methods:

• C14 or C13 Urea Breath Test: Measures the amount of C14 or C13 in expired air after ingesting a urea solution containing a radioactive isotope.

7. Clinical Manifestations of Peptic Ulcer Disease

• Pain:

• Epigastric pain, radiating to the back, especially with ulcers on the posterior stomach wall.

• Sharp, burning pain.

• Cyclical pain, often worse at night and after meals.

• Pain related to meals: More severe after eating, or when hungry.

• Heartburn, acid reflux, belching: Due to gastric acid refluxing into the esophagus.

• Bloating: Caused by gas buildup in the stomach.

• Vomiting, nausea: Due to gastric irritation or pyloric obstruction.

• Loss of appetite, weight loss: Due to pain, indigestion, or vomiting.

• Note: Atypical presentations without symptoms are possible (20% of cases).

8. Treatment of Peptic Ulcer Disease

• Non-pharmacological Treatment:

• Smoking and alcohol cessation: Protects the gastric mucosa and reduces ulcer risk.

• Stress reduction, relaxation: Stress can increase acid secretion and contribute to ulceration.

• Avoidance of over-the-counter medication: Avoid using drugs that pose a risk of ulceration, such as NSAIDs, corticosteroids, etc.

• Diet:

• Frequent meals, thorough chewing: Reduces the burden on the stomach and promotes digestion.

• During pain: Consume bland, easily digestible foods that do not irritate the stomach.

• Avoid acidic, spicy, and caffeinated foods: Irritate the mucosa and worsen ulcer symptoms.

• Pharmacological Treatment:

• Acid-Suppressive Medications:

• Proton Pump Inhibitors (PPIs): Transmembrane proteins in parietal cells of the stomach, using ATP to pump H+ out of the cell.

• Medications: Omeprazole, esomeprazole, lansoprazol, dexlansoprazol, rabeprazol, pantoprazol.

• Mechanism: Irreversibly inhibit proton pumps, reducing acid production.

• Dosage: Once daily, due to a long half-life (T1/2 from 0.5 to 2 hours).

• Pharmacokinetics: Absorbed into the bloodstream, transported to parietal cells, activated in an acidic environment, irreversibly bind to H+, K+-ATPase, disabling proton pump function.

• Enteric-coated capsules: To prevent degradation in the acidic environment of the stomach.

• Side effects with prolonged use (> 1 year): Osteoporosis, B12, iron, and magnesium deficiencies, Clostridium difficile infection, cognitive impairment, renal impairment, community-acquired pneumonia, gastric cancer,…

• H2 Receptor Antagonists (H2RAs): Block H2 receptors on parietal cells, inhibiting acid production.

• Medications: Cimetidine, ranitidine, famotidine, nizatidine.

• Mechanism: Prevent histamine from binding to H2 receptors, decreasing acid production.

• Highest bioavailability: Nizatidine, as other drugs undergo significant first-pass metabolism in the liver.

• Primarily excreted by the kidneys: Dosage should be reduced in patients with renal impairment.

• Indications: Gastroesophageal reflux disease (GERD), hypersecretion in Zollinger-Ellison syndrome, acute peptic ulcer disease, gastrointestinal bleeding, maintenance therapy after ulcer healing.

• Side effects: Diarrhea, constipation, nausea, vomiting, headache, dizziness, muscle pain, rash,… Cimetidine can have anti-androgen effects.

• Potassium-competitive inhibitors: Vonoprazan.

• Mechanism: Blocks the K+ exchange for H+ at the proton pump, inhibiting acid production.

• Advantages: Inhibits proton pump recovery, does not require activation in an acidic environment.

• T 1/2: 7.7 hours.

• Side effects: Similar to PPIs.

• Anticholinergic medications: Inhibit acid secretion by blocking cholinergic receptors on parietal cells of the stomach.

• Medications: Pirenzepine, telezepine (selective M1 antagonists).

• Side effects: Dry mouth, visual disturbances, constipation,…

• Anti-gastrin medications: Block gastrin receptors on parietal cells.

• Medication: Proglumid.

• Antacids: Neutralize gastric acid, reducing pain symptoms and promoting ulcer healing.

• Medications: Aluminum hydroxide, magnesium hydroxide, calcium carbonate, sodium bicarbonate, sodium citrate.

• Mechanism: Antacids are weakly alkaline, neutralizing gastric acid.

• Duration of action: Short.

• Effect: Rapid.

• Indications: Pain reduction, promotion of ulcer healing, reduction of GERD symptoms, prevention of stress ulcers or gastrointestinal bleeding.

• Dosage: 4-7 times daily, 1-2 hours after meals.

• Administration: Chew medication, administer at least 2 hours apart from other medications.

• Side effects: Diarrhea, constipation, sodium overload, hypercalcemia, alkalosis, osteoporosis,…

• Note:

• Caution in the elderly and those with renal impairment.

• Caution with NaHCO3 in patients with heart failure, hypertension (risk of sodium overload).

• Caution with CaCO3 in patients on a calcium-rich diet (risk of milk-alkali syndrome).

• Caution with Mg(OH)2 and NaHCO3 in patients with renal impairment.

• Avoid prolonged use of Al(OH)3.

• Be aware of interference with the absorption of other medications.

• Mucosal Protective Agents:

• Sucralfate:

• Mechanism: Forms an adherent, protective mucus layer over the mucosa, has a strong affinity for ulcer craters, stimulates mucosal secretion of prostaglandins, mucus, and cell proliferation.

• Characteristics: Activates in an acidic environment, administer 30 minutes after antacids, administer at least 2 hours before sucralfate, onset of action after 1 hour, prolonged action for 6 hours.

• Side effects: Constipation, nausea, metallic taste, indigestion, dry mouth.

• Misoprostol:

• Mechanism: Synthetic PGE1 analog, inhibits acid secretion, stimulates mucus and bicarbonate secretion, dose-dependent effect.

• Indication: Treatment of PUD (200mcg x 4 times daily or 400mcg x 2 times daily).

• Side effects: Diarrhea, flatulence, abdominal pain (take after or during meals).

• Contraindication: Not for use in pregnant women (causes uterine contractions, risk of miscarriage).

• Bismuth:

• Mechanism: Inhibits Hp activity, stimulates endogenous prostaglandin synthesis, used in combination with antibiotics to eradicate Hp.

• Side effects: Black stools, black tongue, black teeth.

• Note: Caution in the elderly and those at risk of drug accumulation.

• Contraindication: Do not use subsalicylate in patients with influenza (risk of Reye’s syndrome), those with sensitivity, bleeding disorders, pregnant women in the third trimester.

9. Note

• Peptic ulcer disease is a chronic condition that requires long-term treatment to prevent recurrence.

• Treatment should involve a combination of medication and lifestyle modifications.

• Consult a doctor for diagnosis and appropriate treatment.

10. References

• Pharmacology Textbook, Ho Chi Minh City University of Medicine and Pharmacy.

• Pathophysiology Textbook, Ho Chi Minh City University of Medicine and Pharmacy.

• Website of the Vietnamese Ministry of Health.

Note:

• This article is for informational purposes only and is not a substitute for professional medical advice.

• Consult with a doctor or pharmacist before using any medication.

• Self-medication can lead to serious side effects.