Peptic Ulcer Page 3

Drug Treatment

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

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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

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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.

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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

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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
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- 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)-- six 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): potent H₂ receptor blockers
      - rare blood dyscrasias and rare hepatotoxicity (similarto that seen with cimetadine and ranitidine)
- Anticholinergic drugs:
  - atropine: not as effective as H₂ receptor blockers
    - Side effects:
      1. dryness of mouth
      2. blurred vision
      3. urinary retention
      4. cardiac arrhythmias
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- Coating Agents:
  - Sucralfate (Carafate)-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: -- 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; enhanced mucosa resistance to injury (PGE₁/PGE₂).
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- Proton Pump Inhibitors:
  - Parietal cells H⁺ ion secretion depends on a H⁺,K⁺-ATPase pump-- promoting H K exchange
    - H⁺,K⁺-ATPase located in apical membraneto and tubulovesicular apparatus of parietal cells
    - Luminal surface of the membrane enzyme: exposed to gastric luminal acid
  - Omeprazole (Prilosec)and lansoprazole (Prevacid)inhibit the proton pump, effectively irreversibly -- requiring synthesis of new enzyme protein
  - 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
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