•  Introduction-- overview
  • H₂ receptor antagonists inhibit histamine-induced stomach acid secretion
  • Interest in these drugs: based on the high incidence of peptic ulcer disease (and related gastrointestinal disease)
  • H₂ receptor antagonists: frequently prescribed, available as over-the-counter preparations in some dosage forms.

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• Pharmacology of H₂ receptor blockers:

Pharmacodynamics:H₂ Receptor Antagonists

• Mechanism of action: H₂ Receptor Antagonists
  • Selective competitive antagonism at H₂ receptor sites

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• Effects on organ systems
  • Acid secretion and gastric motility
    • Most important action: reduction in gastric acid secretion
    • Blockade of gastric acid secretion following:
      1. histamine
      2. gastrin
      3. cholinomimetics
      4. they do stimulation
    • gastric acid volume
    • pepsin concentration
    • Cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid): minimal effect on gastric smooth muscle function or on lower esophageal sphincter pressure (other GI secretions: not significantly reduced)
    • In addition to its effects on acid secretion, nizatidine decreases stomach emptying time (stimulates contractility)
  • Other effects: unrelated to H₂ receptor blockade
    •  Cimetadine (to lesser degree ranitidine; not famotidine or nizatidine): inhibits cytochrome P450 microsomal drug metabolizing system
    •  Cimetadine and ranitidine: inhibit renal clearance of basic drugs that use renal secretory transport systems
    •  Cimetadine, by binding to androgen receptors, produce antiandrogen effects

Clinical Uses:H₂ Receptor Antagonists

•  Peptic Ulcer Duodenal Disease:
  • H₂ receptor antagonists (low toxicity) by reducing gastric acidity has significantly advanced treatment of peptic ulcer disease
    •  Other agents that reduced gastric acid:
      1. antimuscarinic drugs (at high dosages required, side effects are significant)
      2. antacids:frequent dosing; often poor patient compliance
      3. Omeprazole (Prilosec) (proton pump blocker): very effective
    •  Sucralfate (Carafate) (a coating agent): promotes healing
    •  Antibiotics: prominent in current therapy-- due to the involvement in many instances of H. pylori.

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• Gastric Ulcer:
  • H₂ receptor antagonists: reduce symptoms; promote healing for benign gastric ulcers

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•  Gastroesophageal Reflux Disorder (erosive esophagitis)
  • H₂ receptor antagonists, at higher dosages than for management of peptic or gastric ulcer disease,are used as one component of treatment.
  • Proton pump blockers (e.g. omeprazole) are usually administered.

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• Hypersecretory Disease:
  •  Zollinger-Ellison syndrome:
    • acid hypersecretion -- caused by gastrin-secreting tumor
    • usually fatal
    • H₂ receptor antagonists often control symptoms
  •  Systemic mastocytosis and multiple endocrine adenomas:
    • hypersecretory conditions
    • H₂ receptor antagonists often control symptoms
•   Toxicity:H₂ receptor antagonists:
  • Overview
    • Generally well tolerated
      • Most common adverse effects:
        1. diarrhea
        2. dizziness
        3. somnolence
        4. headache
        5. rash
      • Cimetidine (Tagamet): most adverse effects
      • Nizatidine (Axid): fewest adverse effects
  • CNS effects (uncommon):
    • Elderly: confusion states, delirium, slurred speech {these side effects most associated with cimetadine; unusual with ranitidine}
  • Endocrine effects (uncommon):
    •  Cimetidine (Tagamet): antiandrogenic effects {cimetidine binds to androgen receptors}
      • gynecomastia (men)
      • galactorrhea (women)
    •  Cimetidine (Tagamet): reduced sperm count/reversible impotencefollowing high-dose administration, usually to treat hypersecretion {Zollinger-Ellison syndrome} --
      • endocrine effects not associated with famotidine, ranitidine, nizatidine
  • Blood Dyscrasias (uncommon):
    •  Cimetadine:
      • granulocytopenia
      • thrombocytopenia
      • neutropenia
      • aplastic anemia (extremely rare)
  • Hepatic Toxicity (uncommon):
    • reversible cholestatic effects
    • reversible hepatitis (with or without jaundice)
    • abnormalities in liver enzyme tests
  • Use in pregnancy:
    • Harmful effects on the fetus have not been observed when H₂ blockers are prescribed to pregnant women.
      •  H₂ blockers are secreted into breast milk and may affect nursing infants.
      •  Since these drugs to cross the placenta, the drugs should only be prescribed when absolutely required.

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• Drug-drug Interactions:
  • Cimetidine (Tagamet):
    • inhibition of cytochrome P450 drug metabolizing system:
    • reduces liver blood flow
    • both above factors decrease clearance of certain drugs
  • Ranitidine: does not appear to influence oxidative metabolism other drugs
  • All H₂ blockers (except famotidine) increase significantly ethanol bioavailability by inhibiting gastric first pass metabolism

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