Pharmacology of Drugs Acting on the Gastrointestinal System

Introduction

• Overview of the gastrointestinal (GI) tract and its components:
  • Mouth, esophagus, stomach, intestines, salivary glands, pancreas, liver, gallbladder
• Interaction of the nervous and endocrine systems in regulating gastric secretions and motility.

Gastric Secretion Physiology

• Digestion begins with sensory cues (sight, thought, smell).
• Vagus nerve stimulation leads to gastric secretion.
• Gastric Glands Cells:
  • Surface and Neck Mucous Cells: Produce mucous to protect the stomach lining.
  • Parietal Cells: Produce hydrochloric acid (HCl) for low pH environment.
  • Chief Cells: Produce pepsinogen and gastric lipase for protein and fat digestion.
  • ECL Cells: Produce histamine, inducing acid production.
  • G Cells: Produce gastrin, regulating gastric activity.

Mechanism of Gastric Acid Secretion

• Neural Activation:
  • Vagus nerve releases acetylcholine (ACh), activating muscarinic M3 receptors on parietal cells.
  • ACh also stimulates ECL cells (M1 receptors) and G cells (M3 receptors) for histamine and gastrin release.
• Histamine Function:
  • Histamine activates H2 receptors on parietal cells, increasing cAMP and promoting acid secretion.
• Gastrin Function:
  • Gastrin stimulates further histamine release and directly affects parietal cells.
• Proton Pump Activation:
  • H+/K+ ATPase (proton pump) actively transports H+ ions into the lumen, producing HCl with Cl- ions.

Pharmacological Approaches to Acid Exposure

H2-Receptor Antagonists

• Mechanism: Competitively inhibit histamine at H2 receptors, reducing acid secretion.
• Examples:
  • Cimetidine, Famotidine, Nizatidine, Ranitidine.

Proton-Pump Inhibitors (PPIs)

• Mechanism: Bind to H+/K+ ATPase, suppressing hydrogen ion secretion.
• Examples:
  • Dexlansoprazole, Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole.

Non-Systemic Antacids

• Mechanism: Neutralize hydrochloric acid; do not decrease acid secretion.
• Examples:
  • Aluminum hydroxide, Magnesium hydroxide, Calcium carbonate.

Mucosal Protective Agents

• Misoprostol:
  • Prostaglandin E1 analog, decreases cAMP levels, increases gastric mucus and blood flow to mucosa.
• Sucralfate:
  • Forms a barrier on ulcer base, protecting and promoting healing.

Management of Nausea and Vomiting

• Vomiting Center Mechanism:
  • Stimulated by various neural pathways, leading to smooth muscle contractions.
• Key Pathways:
  • Chemoreceptor trigger zone (dopamine D2, 5-HT3, NK-1 receptors)
  • Vagal afferent fibers (5-HT3, NK-1 receptors)
  • Central vestibular nuclei (muscarinic, histamine H1 receptors).

Antiemetic Medications

• Dopamine D2 Receptor Blockers:
  • Chlorpromazine, Prochlorperazine, Metoclopramide.
• Serotonin 5-HT3 Receptor Blockers:
  • Ondansetron (often combined with Aprepitant/Rolapitant for enhanced effect).
• Vestibular System Agents:
  • Scopolamine (muscarinic antagonist), Antihistamines (Diphenhydramine, Dimenhydrinate, Meclizine, Promethazine).

Management of Constipation

• Laxatives Overview:
  • Types include bulk laxatives, osmotic laxatives, irritants, and stimulants.

Types of Laxatives

1. Bulk Laxatives:
   • Insoluble fibers, e.g., Psyllium, Methylcellulose, Calcium Polycarbophil.
   • Expand in water, triggering contractions.
2. Osmotic Laxatives:
   • Nonabsorbable soluble compounds, e.g., Magnesium Citrate, Lactulose.
   • Pull water into the colon, increasing stool volume.
3. Irritant/Stimulant Laxatives:
   • Directly prevent water reabsorption or irritate intestinal mucosa.
   • Examples: Bisacodyl, Castor Oil, Senna.

Management of Diarrhea

• Types of Diarrhea:
  • Secretory, osmotic, inflammatory.

Treatment Options for Diarrhea

1. Adsorbents:
   • Methylcellulose absorbs toxins, reducing motility.
2. Antimotility Agents:
   • Diphenoxylate, Loperamide (low abuse potential).
   • Act on opiate receptors to reduce motility.
3. Bismuth Subsalicylate:
   • Inhibits replication of bacteria/viruses, reduces inflammation.

Conclusion

• Summary of drugs and mechanisms in the management of GI disorders.
• Importance of understanding pharmacology for effective treatment.