Gastrointestinal Drugs Overview

Gastrointestinal Drugs

• Gastroesophageal Reflux Disease (GERD): Acid and pepsin from the stomach flow backward into the esophagus, often called heartburn.
• Causes of GERD:
  • Overproduction of acid/pepsin
  • Over relaxation of the Lower Esophageal Sphincter (LES)
• Peptic Ulcer Disease: A benign lesion of gastric or duodenal mucosa.
• Causes of Peptic Ulcer Disease:
  • Excess acid production
  • Intrinsic defect in the mucosal defense barrier
  • Helicobacter Pylori (H. pylori) infection (most ulcers)
  • Medication use (nonsteroidal anti-inflammatory drugs (NSAIDs))
  • Gastrinoma (Zollinger-Ellison Syndrome)
  • Stress ulcers
• Strategies for Protecting the Gastric Mucosa:
  • Mechanisms: Inhibit acid secretion, prevent contact, neutralize acid
  • Examples:
    • Cimetidine
    • Omeprazole
    • Prostaglandins
    • Muscarinic antagonists
    • Sucralfate
    • Antacids
• Multiple Mechanisms Regulate Gastric Acid:
  • Hormonal factors: Gastrin, Histamine, Acetylcholine
  • Paracrine factors: Histamine
  • Neural factors: Acetylcholine
• Strategies for Inhibiting Parietal Cell Acid Secretion: Gastrin antagonists, Histamine antagonists, Muscarinic antagonists
• H+, K+-ATPase (proton pump): Final transport pathway for parietal cell hydrogen ion secretion.
  • Located in the apical membrane.
  • Requires intracellular ATP
  • Inhibition blocks both basal and stimulated acid secretion.
• Omeprazole (Prilosec): Prototype H+, K+-ATPase inhibitor, prodrug needing low pH to be active. Irreversible inhibition of acid production.
  • Profound reduction of gastric acid with significant pH elevation (20mg/day for 7 days can reduce acid by 95%)
  • Highly protein-bound, metabolized by CYP2C & CYP3A. Short half-life (1-2hours), but long duration of action. Taken just prior to a meal and not with other acid-suppressant medications.
• Esomeprazole, Rabeprazole, Lansoprazole, Pantoprazole: H+, K+-ATPase inhibitors. Esomeprazole is an isomer of omeprazole. Pantoprazole is acid stable and given intravenously.
• Proton Pump Inhibitors (PPI) Side effects: Well tolerated, but hypergastrinemia (can lead to tumor growth), nausea, headaches, and skin rashes.
• Histamine H₂ Antagonists: Cimetidine, Ranitidine, Famotidine, Nizatidine.
• Cimetidine: Competitive H₂ receptor antagonist. Markedly inhibits basal acid secretion, including nocturnal secretion. Readily absorbed, relatively brief duration of action. Given multiple times daily.
• Ranitidine, Famotidine, Nizatidine: Similar mechanisms to Cimetidine but longer duration of action (8-12 hours). Can be administered less frequently.
• Anticholinergics: Pirenzepine, Telenzepine. Block acetylcholine at muscarinic (M3) receptors; effectively block acid secretion (30-40%). But limited by side effects.
• Prostaglandins (PGE2 & PGI2): Act on prostaglandin EP3 receptors on parietal cells and epithelial cells. Inhibit acid secretion and gastrin release. Stimulate mucus, bicarbonate secretion, and mucosal blood flow. Cytoprotective.
• Misoprostol (Cytotec): Synthetic analog of prostaglandin E_1. Anti-acid secretory. 0.1 to 0.2 mg results in 85% to 95% reduction in acid secretion to prevent NSAID gastric ulcers
  • Side effects: Diarrhea, abortion.
• Antacids: Weak bases neutralizing HCl in the stomach, raising gastric pH.
  • Magnesium hydroxide
  • Magnesium trisilicate
  • Magnesium-aluminum mixtures
  • Calcium carbonate
  • Sodium bicarbonate
• Sucralfate: Basic aluminum salt of sucrose octasulfate. Forms viscous paste adheres strongly to gastric and duodenal mucosa, especially to partially denatured proteins.
• Role of H. Pylori in Peptic Ulcer Disease: Eradication of the bacteria, along with inhibition of acid, is the treatment. Combination therapy with Omeprazole and Amoxycillin is common.
• Functional Disorders of the GI (loss of normal bowel movement patterns): Primary: infections, inflammation, congenital defects. Secondary: metabolic disorders, neurological disorders (diabetes mellitus).
• Prokinetic Drugs: Enhance transit of materials through the GI tract (enhance GI motility). Increase neuromuscular transmission.
  • Used for: Gastroesophageal reflux disease (GERD), Gastroparesis, Nighttime heartburn, Severe refractory constipation (sometimes caused by irritable bowel syndrome (IBS)). Increase action of other GI drugs.
  • Metoclopramide (Reglan): Antiemetic, improves gastric emptying by indirectly releasing acetylcholine, dopamine receptor antagonist.
    • Side effects: Sedation, dystonic reactions, anxiety, gynecomastia, galactorrhea.
  • Domperidone (Motilium): Antiemetic, improves gastric emptying, dopamine receptor antagonist, ganglionic stimulant
    • Side effects: Headaches, gynecomastia
• Anti-emetics: Metoclopramide, Domperidone, ondansetron, granisetron, hyoscine, atropine, cyclazine, promethazine, chlorpromazine, haloperidol
• Diarrhea: A condition of having at least three loose stools or liquid bowel movements each day, often due to viral, bacterial, or parasitic infection.
• Treatment of Diarrhea: Replacement of fluid and electrolytes (ORS - oral rehydration salts). Treatment of the cause (like an antibiotic if needed). Antidiarrheal agents (adsorbents like kaolin, pectin). Anti motility drugs (codeine).
• Laxatives: Drugs that promote defecation or passage of stools. Mild action (laxatives), stronger action (cathartics and purgatives).
• Types of Laxatives: Luminally active agents (Hydrophilic colloids, osmotic agents), Nonspecific stimulants or irritants, Prokinetic agents.