Medical Pharmacology Chapter 21:  Histamine

H₂ Receptor Antagonists

• 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.

• Pharmacology of H₂ receptor blockers:

  • H2 receptor blocker	Mechanism of Elimination
    Cimetidine (Tagamet)	Mainly renal
    Ranitidine (Zantac)	Mainly renal
    Famotidine (Pepcid)	Mainly renal
    Nizatidine (Axid)	Mainly renal

     

Pharmacodynamics: H₂ Receptor Antagonists

• Mechanism of action: H₂ Receptor Antagonists involves selective competitive antagonism at H₂ receptor sites.

• Effects on organ systems

  • Acid secretion and gastric motility

    • The most important action is a reduction in gastric acid secretion due to H₂ receptor blockade.

    • Blockade of gastric acid secretion in the presence of H₂ receptor blockade following histamine, gastrin, cholinomimetics (acetylcholine-like drugs such as bethanechol (Urecholine)) and  vagal stimulation.

    • Reduced gastric acid volume

    • Decreased pepsin concentration

  • 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 reduce gastric acid include:

      1. Antimuscarinic drugs (at high dosages required, side effects are significant)

      2. Antacids which require frequent dosing and may be associated therefore with  poor patient compliance

      3. Omeprazole (Prilosec) and lansoprazole (Prevacid) (proton pump blockers and) are very effective in reducing gastric acid by directly inhibiting an enzyme-pump which produce hydrogen ions (protons) in the stomach thus decreasing pH

    •  Sucralfate (Carafate) (a coating agent)  promotes healing

    •  Antibiotics are prominent in current therapy because of the importance of H. pylori in gastric ulcer disease.  

• Gastric Ulcer

  • H₂ receptor antagonists reduce symptoms and promote healing for benign gastric ulcers

•  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 also administered.

• Hypersecretory Disease

  •  Zollinger-Ellison syndrome is associated with acid hypersecretion which is caused by gastrin-secreting tumor.  This disorder is often fatal; however, H₂ receptor antagonists often control symptoms.

  •  Systemic mastocytosis and multiple endocrine adenomas are hypersecretory conditions in which H₂ receptor antagonists often control symptoms.

• Toxicity:  H₂ receptor antagonists

  • Overview: these agents are generally well tolerated.  The most common side effects include diarrhea, dizziness, somnolence, headache and rash.

    • Cimetidine (Tagamet) has the most adverse effects whereas, nizatidine (Axid) has the fewest adverse effects.

  • CNS effects are uncommon.  However, in the elderly confusional of states, delirium, and slurred speech may occur.  These effects are often associate with cimetidine (Tagamet) and are unusual with ranitidine (Zantac).

  • Endocrine effects are also relatively uncommon.  However cimetidine (Tagamet) does exhibit antiantherogenic effects because the drug blinds to androgen receptors and therefore can cause gynecomastia (men) and galactorrhea (women).

    •  Endocrine effects not associated with famotidine, ranitidine, nizatidine

  • Other uncommon side effects include blood dyscrasias [cimetidine (Tagamet): granulocytopenia, thrombocytopenia, neutropenia, aplastic anemia which is extremely rare], hepatotoxicity  with reversible cholestatic effects, reversible hepatitis, liver enzyme test abnormalities.

  • Use in pregnancy:

    • Harmful effects on the fetus have not been observed when H₂ blockers are prescribed to pregnant women even though  H₂ blockers are secreted into breast milk and may affect nursing infants.

      • The general rule, however is that since these drugs across the placenta, they should only be prescribed when absolutely required.

      • Since these drugs to cross the placenta, the drugs should only be prescribed when absolutely required. 

• Drug-drug Interactions

  • Cimetidine (Tagamet) is the prominent agent in this category for drug-drug interactions.  This observation occurs because cimetidine (Tagamet) is particularly effective in inhibiting the cytochrome P450 drug metabolizing system therefore influencing the metabolism of other drugs.  Additionally, cimetidine (Tagamet) reduces liver blood flow and the combination of effects on blood flow and metabolism tend to decrease the clearance (removal from the body) of certain drugs.

1. Burkhalter, A, Julius, D.J. and Katzung, B. Histamine, Serotonin and the Ergot Alkaloids (Section IV. Drugs with Important Actions on Smooth Muscle), in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 261-286.

2. 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.