Medical Pharmacology Chapter 27:  Gastrointestinal Drugs

• Drug Treatment

  • Patients with documented duodenal ulcers (upper GI contrast radiography or endoscopy):  treat for H. pylori

  • Many drugs, usually in combination, are used in management and eradication of H. pylori infection.

    • Drugs include:

      • Bismuth compounds

      • Amoxicillin

      • Tetracycline (Achromycin)

      • Clarithromycin (Biaxin)

      • Metronidazole (Flagyl)

      • Omeprazole (Prilosec), Lansoprazole (Prevacid)

      • H₂ antagonists

  • Bismuth compounds

    • Mechanism of Action

      • Cytoprotective effects

      • Compounds bind to the ulcer base, stimulating mucus and prostaglandin production

      • Antibacterial effect: inhibition of proteolytic, lipolytic, and urease activities

    •  In monotherapy: bismuth compounds eradicate H. pylori in about 20% of patients

    • Bismuth compounds in combination with antibiotics eradicate H. pylori in up to 95% of patients.

  • Most successful protocol: triple therapy

    • Bismuth compounds

    • Metronidazole (Flagyl)

    • Amoxicillin or tetracycline (Achromycin)

      • Triple therapy (two weeks) plus H₂ blocker therapy (six weeks) is also a recommended protocol

      • Further increase in the rate of H. pylori eradication may be accomplished by the addition of omeprazole (Prilosec) to the regimen.

  •   Drawbacks of triple therapy

    • Patient compliance (two-week treatment: 200 tablets)

    • Side effects

•  Some Specifc Drug Classes

  • Antacids

    • Most widely used: mixture of aluminum hydroxide and magnesium hydroxide (neutralizes HCl)

    •   Aluminum hydroxide: side effects

      • Constipation

      • Systemic phosphate depletion (weakness, malaise, anorexia)

    •   Magnesium hydroxide: side effects

      • Loose stools

      • Ionic magnesium stimulates gastric release ("acid rebound")

      • Magnesium trisilicate-- slow-acting antacid

    • Calcium carbonate (converted a calcium chloride in the stomach)

      • Associated with "acid rebound"

      • With excessive, chronic use, calcium carbonate may cause:

        •  Milk-alkali syndrome with elevation of:

          • Serum calcium

          • Phosphate

          • Urea nitrogen

          • Creatinine

          • Bicarbonate levels

        • May result in renal calcinosis; possibly progressive renal insufficiency

    • Sodium bicarbonate: effective antacid, but systemic alkalosis may occur

  •  H₂ Receptor Antagonists

    • Effective inhibitor of stimulated and non-stimulated gastric acid secretion

      • Healing rates: similar between antacids and H₂ receptor antagonists (compliance better with receptor blockers)

    • Specific Agents

      1. Cimetidine (Tagamet) reduces acid secretion responses to:histamine, caffeine, hypoglycemia, gastrin

         • Few side effects; interaction with cytochrome P450 drug metabolizing system

         • Tender gynecomastia: the two-week antiandrogenic effects (seen typically in Zollinger-Ellison disease patients following prolonged space ortreatment with large doses

      2. Ranitidine (Zantac) is ix times as potent as cimetadine in inhibiting gastric acid secretion

         • No antiandrogenic properties

         • Smaller inhibitory effect on cytochrome P450 system then cimetidine (Tagamet)

      3.  Famotidine (Pepcid) and nizatidine (Axid) are potent H₂ receptor blockers

         • Rare blood dyscrasias and rare hepatotoxicity (similarto that seen with cimetadine and ranitidine)

  • Anticholinergic drugs

    • Atropine is not as effective as H₂ receptor blockers

      • Side effects

        1. Dryness of mouth

        2. Blurred vision

        3. Urinary retention

        4. Cardiac arrhythmias

  • Coating Agents

    • Sucralfate (Carafate) is a complex polyaluminum hydroxide salt of sucrose sulfate

      • Highly polar antacid pH: binds to ulcer bed (granulation tissue, not to gastric or duodenal mucosa)

        • Decreases proton diffusion to the ulcer base

      • May increase endogenous tissue prostaglandins and may bind epidermal growth factors and other growth factors-- improving mucosal defense

    • Colloidal bismuth: is a bismuth-protein coagulant

      • May protect also from pepsin and acid digestion

      • May inhibit pepsin activity

      • Prevents proton diffusion into the ulcer

      • Stimulates gastric mucosal secretion of protective agents:

      • Colloidal bismuth only class of antiulcer drugs that can eradicate H. pylori and cure associated gastritis

  • Prostaglandins

    • Reduction in basal and stimulated gastric acid secretion is associated with enhanced mucosa resistance to injury (PGE₁/PGE₂).

  • Proton Pump Inhibitors

    • Parietal cells H⁺ ion secretion depends on a H⁺,K⁺-ATPase pump that promotes H⁺ / K⁺ exchange.

      • H⁺,K⁺-ATPase located in apical membrane and tubulovesicular apparatus of parietal cells

      • Luminal surface of the membrane enzyme is exposed to gastric luminal acid

    • Omeprazole (Prilosec) and lansoprazole (Prevacid) inhibit the proton pump, effectively irreversibly, requiring synthesis of new enzyme protein to overcome drug-induced inhibition.

    • Omeprazole and lansoprazole approved for treatment of:

      • Duodenal ulcer

        •  May be used in conjunction with triple therapy

      • Erosive esophagitis

      • Gastric acid hypersecretory states, including Zollinger-Ellison syndrome.

  •  

    Parietal Cell:  HCl secretion

    "Parietal Cell-HCl secretion" courtesy of Robert H. Parsons, Ph.D., Rensselaer Polytechnic Institute, used with permission

Friedman, L. S. and Peterson, W.L. Peptic Ulcer and Related Disorders In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., and Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp. 1597-1616.

• Important Drugs for Gastrointestinal Disorders

  • H₂ Histamine receptor blockers

    • Cimetidine (Tagamet)

    • Ranitidine (Zantac)

    • Famotidine (Pepcid)

    • Nizatidine (Axid)

  • Antimuscarinic drugs

    • Atropine

    • Propantheline

    • Pirenzepine

  • Proton pump inhibitor

    • Omeprazole (Prilosec)

    • Lansoprazole (Prevacid)

    • Dexlanoprazole (Kapidex)

    • Esomeprazole (Nexium)

    • Pantoprazole (Protonix)

    • Rabeprazole (AcipHex) and in combination with domperidone, Dorafem

    • Ilaprazole (Noltec)

  • Mucosal protective agents

    • sucralfate (Carafate)

    • misoprostol (Cytotec)

  • Antidiarrheal drugs

    • Diphenoxylate

    • Kaopectate

    • Bismuth Subsalicylate

    • Loperamide

    • Paragoric

  • Laxative Drugs

    • Bisacodyl

    • Magnesium Hydroxide

    • Mineral Oil

    • Docusate

    • Lactulose

    • Methyl Cellulose

    • Psyllium

  • Antacids

    • Magnesium hydroxide

    • Aluminum hydroxide

    • Calcium carbonate

  • Drugs that dissolve gallstones

    • Chenodiol

    • Monoctanoin

  • Drugs acting on G.I. motility

    • Bethanechol

    • Metoclopramide

Friedman, L. S. and Peterson, W.L. Peptic Ulcer and Related Disorders In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., and Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp. 1597-1616.