Basic and Clinical Pharmacology 1102-1134

Case Study Overview

  • Patient: 21-year-old woman with Crohn’s disease.

  • Diagnosis: Crohn's disease affecting the terminal ileum and proximal colon (confirmed by colonoscopy/small bowel radiography).

  • Treatment history: Initially treated with mesalamine and budesonide with good response, but symptoms have relapsed in the past 2 months.

  • Current symptoms include:

    • Fatigue

    • Cramping

    • Abdominal pain

    • Nonbloody diarrhea (up to 10 times daily)

    • 15-lb weight loss

  • Laboratory findings: Notable for anemia and elevated C-reactive protein.

Introduction to Gastrointestinal Drug Treatment

  • Various drug classes are important for treating GI diseases, either affecting gastrointestinal organs or used almost exclusively for gut effects.

Drug Classes in Acid-Peptic Diseases

Definitions and Mechanisms:

  • Acid-Peptic Diseases

    • Includes conditions like gastroesophageal reflux, peptic ulcers (gastric/duodenal), and stress-related mucosal injury.

    • Caused by mucosal erosions/ulceration due to imbalance between aggressive factors (acid, pepsin, bile) and defensive factors (mucus, bicarbonate, prostaglandins).

    • 90% of peptic ulcers caused by H. pylori infection or NSAID use.

Treatment Options:

  • Agents that Reduce Intragastric Acidity

    • Proton Pump Inhibitors (PPIs): Block H+/K+ ATPase enzyme in parietal cells leading to decreased acid secretion.

    • H2-Receptor Antagonists: Decrease acid secretion by competitive inhibition at H2 receptors.

    • Antacids: Neutralize stomach acidity, providing symptomatic relief but not addressing underlying causes.

Physiology of Acid Secretion

  • Parietal cells secrete acid stimulated by gastrin, acetylcholine, and histamine through H2 and M3 receptors.

  • Interplay between gastric signaling pathways regulates stomach acidity and secretion.

Antacids

  • MOA: Weak bases neutralize gastric acid, forming salt and water, providing relief for dyspepsia and hyperacidity.

  • Types:

    • Sodium bicarbonate: Rapid reaction, may cause gas and belching.

    • Calcium carbonate: Less soluble, may cause metabolic alkalosis.

    • Aluminum/Magnesium salts: Slow reaction, minimize side effects on bowel function.

    • Consider drug interactions affecting absorption of other medications.

H2-Receptor Antagonists

  • Four drugs in clinical use: cimetidine, ranitidine, famotidine, nizatidine.

  • MOA: Competitive blockade of H2 receptors reduces acid secretion.

  • Clinical uses: GERD, peptic ulcer disease, nonulcer dyspepsia, prevention of stress-related bleeding.

Proton-Pump Inhibitors (PPIs)

  • Six PPIs in use: omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole.

  • MOA: Irreversible blockade of H+/K+ ATPase, prolonging acid inhibition.

  • Clinical Uses: Effective for healing peptic ulcers, gastroesophageal reflux disease, and stress gastritis.

Mucosal Protective Agents

  • Sucralfate: Forms a viscous paste protecting ulcers.

  • Prostaglandin Analog (Misoprostol): Increases mucus and bicarbonate production, reduces NSAID-induced ulcers.

Laxatives

Categories:

  1. Bulk-forming laxatives: Increase fiber to promote stool passage (e.g., psyllium).

  2. Stool surfactants: Moisten stool (e.g., docusate).

  3. Osmotic laxatives: Draw fluid into intestines to accelerate bowel movement (e.g., magnesium hydroxide).

  4. Stimulant laxatives: Increase gut motility (e.g., senna).

Antidiarrheal Agents

  • Opioid Agonists (e.g., Loperamide): Slow intestinal motility without CNS effects.

  • Bismuth Compounds: Used for treating diarrhea and gastrointestinal discomfort.

Drugs for Irritable Bowel Syndrome (IBS)

  • 5-HT3 Antagonists (Alosetron): Effective for severe diarrhea-predominant IBS in women; associated with serious side effects.

Anti-Inflammatory Drugs for IBD

  • Aminosalicylates: First-line treatment for mild to moderate ulcerative colitis and Crohn's disease; various formulations (e.g., mesalamine).

  • Glucocorticoids: Used for moderate to severe disease control; may cause significant side effects including immunosuppression.

  • Immunomodulators (e.g., Azathioprine, 6-MP): Long-term remission maintenance for inflammatory bowel conditions.

  • Anti-TNF Agents (Infliximab, Adalimumab): Given for moderate to severe cases unresponsive to standard therapies; associated with risks like infections and anti-body development.

Summary of Treatment Considerations

  • Assess disease severity and medication efficacy.

  • Employ a stepwise approach based on the response to previous therapies, starting with safer agents (like 5-aminosalicylates) before moving to immunosuppressants and biologics as needed.