Pharmacology Chapter: Peptic Ulcer

A peptic ulcer is a break in the inner lining of the esophagus, stomach, or duodenum
Types of peptic ulcers:
- Gastric ulcer (in the stomach)
- Duodenal ulcer (in the duodenum)
- Esophageal ulcer (in the esophagus)
Two main causes of peptic ulcers:
- Infection of the stomach by Helicobacter pylori (H. pylori)
- Chronic use of nonsteroidal anti-inflammatory medications (NSAIDs), e.g. aspirin

Esophageal defense: lower esophageal sphincter prevents reflux of acidic gastric contents into the esophagus
Stomach defense:
- Requires adequate mucosal blood flow due to high metabolic activity and oxygen requirements of the gastric mucosa
- Involves secretion of a mucus layer that protects gastric epithelial cells
- Mucus production is stimulated by prostaglandins E2 and I2, which also directly inhibit gastric acid secretion by parietal cells
- Drugs that inhibit prostaglandin formation (e.g. alcohol and NSAIDs) decrease mucus secretion and predispose to acid-peptic disease
- Secretion of bicarbonate ions by superficial gastric epithelial cells, which neutralizes HCl

Acetylcholine:
- Produced from nerve endings and stimulates M3 receptors on:
  - Parietal cells (produce HCl)
  - Enterochromaffin cells and mast cells (produce histamine)
  - G cells (produce gastrin)
Histamine:
- Produced by enterochromaffin cells and mast cells in response to stimulation of M3 receptors (by acetylcholine) and CCK3 receptors (by gastrin)
- Stimulates parietal cells to produce HCl
Gastrin:
- Produced by G cells in response to stimulation of M3 receptors (by acetylcholine) and stretch and chemical substances in food
- Stimulates parietal cells to produce HCl

Nocturnal (basal) acid secretion: dependent on histamine
Meal-stimulated acid secretion: stimulated by gastrin, acetylcholine, and histamine

Cephalic phase: stimulated by sight, smell, taste, or thought of food (via vagus nerve and histamine)
Gastric phase: stimulated by food in the stomach (via stretch and chemical substances in food)
Intestinal phase: inhibited by chyme in the duodenum

Most potent suppressors of gastric acid secretion
Irreversibly inactivate the proton pump in parietal cells, reducing both basal and stimulated acid secretion
Examples: omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole
Pharmacokinetics:
- Oral forms are acid-resistant and release the drug in the intestine
- Distributed by blood to parietal cells
- Irreversibly inactivate the proton pump molecule, providing 24-48 hour suppression of acid secretion despite shorter plasma half-lives
Adverse effects:
- Few and mild, including GI troubles, headache, and skin rashes
- Long-term use may lead to vitamin B12 deficiency and rebound hypersecretion of gastric acid
Drug interactions:
- May interfere with metabolism of drugs metabolized by cytochrome P450 enzymes
Therapeutic uses:
- Gastroesophageal reflux disease (GERD)
- Gastric and duodenal ulcers
- Prevention of NSAID-associated gastric ulcers

Examples: ranitidine, famotidine, nizatidine
Mechanism of action:
- Competitively inhibit H2 receptors on parietal cells, reducing gastric acid secretion
Pharmacokinetics:
- Small amounts metabolized by the liver (dose reduction not necessary in liver disease)
- Excreted by the kidney (dose reduction necessary in kidney disease)
Adverse effects:
- Few, including GI disturbances, headache, and fatigue
Therapeutic uses:
- Gastroesophageal reflux disease (GERD)
- Gastric and duodenal ulcers
- Prevention of stress ulcers

Examples: pirenzepine, telenzepine
Mechanism of action:
- Reversibly block muscarinic (M3) receptors on parietal cells, reducing meal-stimulated acid secretion
Adverse effects:
- Anticholinergic side effects, including dry mouth, blurred vision, and urinary retention
Therapeutic uses:
- Rarely used due to poor efficacy and side effects

Neutralize gastric acid, reducing pH and acid output
Examples: sodium bicarbonate, calcium carbonate, aluminum hydroxide, magnesium hydroxide
Mechanism of action:
- React with gastric HCl to form salt and water
- Stimulate mucosal prostaglandin production
Adverse effects:
- Systemic effects, including alkalosis, and GI effects, including diarrhea or constipation
Therapeutic uses:
- Heartburn and acid reflux
- Peptic ulcer disease

Examples: sucralfate, misoprostol, colloidal bismuth compounds
Mechanism of action:
- Form a protective barrier on the mucosal surface, preventing acid and pepsin damage
- Stimulate mucosal prostaglandin production
Adverse effects:
- Generally mild, including GI disturbances and diarrhea
Therapeutic uses:
- Peptic ulcer disease
- Gastroesophageal reflux disease (GERD)

Gastroesophageal reflux disease (GERD):
- Mild: H2 receptor antagonists
- Severe: proton pump inhibitors
Helicobacter pylori (H. pylori) infection:
- Triple therapy with proton pump inhibitors, clarithromycin, and amoxicillin or metronidazole
NSAID-related ulcers:
- Proton pump inhibitors
Peptic ulcer:
- Proton pump inhibitors### Motion Sickness Treatment
H1 Antihistaminics are the most effective drugs for motion sickness
Examples of H1 Antihistaminics include:
- Meclizine
- Cyclizine
- Dimenhydrinate
- Diphenydramine
- Promethazine, which is used in pregnancy and by NASA for space motion sickness

Anticholinergics, such as Scopolamine (hyoscine), are used to treat motion sickness and can be administered as a transdermal patch
Cannabinoids, such as Dronabinol and Nabilone, can be used to treat vomiting caused by cytotoxic anticancer drugs
Nabilone:
- Inhibits the chemoreceptor trigger zone (CTZ)
- Is orally well-absorbed with a half-life of 120 minutes
- Is metabolized and excreted in the urine and feces
- Can cause side effects such as drowsiness, dizziness, dry mouth, mood changes, and hallucinations

Ondansetron is not effective in treating motion sickness because it does not act on the vestibular nuclei, which only have muscarinic and H1 histaminic receptors