Histamine and Anti-histamine Drugs

Medical Pharmacology Chapter 21: Histamine

Histamine Antagonists Introduction:
- Physiologic antagonists: example -- epinephrine, agents that produce opposing effects, acting and different receptors
- Release inhibitors: reduced mast cell degranulation: example: cromolyn and nedocromil
- Receptor antagonists: selective blockade of histamine receptors (H₁, H₂, H₃ types)
- Histamine Antagonist Pharmacodynamics:
  - Histamine H₁Receptor Blockade:
    - H₁ receptor blockers exhibit competitive antagonism for H₁ receptor sites whereas little effects at H₂ receptor sites and negligible effects of H₃ sites are observed.
    - H₁ receptor blockers prevent bronchiolar or gastrointestinal smooth muscle constriction
    - H₁ receptor blockers do not completely prevent cardiovascular effects (some of these effects are mediated by H₂ receptors)
    - H₁ receptor blockers cannot affect increases in gastric acid secretion or mast cell histamine release because these effects are H₂ receptor site-mediated.

H₁ receptor antagonists:
- General properties:
  - H₁ antagonists include both first-generation and second-generation compounds
    - Both categories of agents are orally active and are metabolized by the liver using the cytochrome P450 drug-metabolizing system
    - The average duration of pharmacological action is about 4-6 hours
      - Meclizine (Antivert) and several second-generation drugs far longer acting, with effects lasting 12-24 hours.
  - First-generation agents tend to be relatively more sedating and more likely than second-generation drugs to block autonomic receptors.
    - For example, antimuscarinic effects [blockade of cholinergic, muscarinic-type receptors]
  - Second-generation agents are relatively less sedating compared to the earlier first-generation agents and exhibit less CNS penetration, which accounts for reduced sedation.
    - Some of the second-generation agents are metabolized by a cytochrome P450 type that is inhibited by other drugs, such as the antifungal agent ketoconazole (Nizoral).
      - Therefore, plasma concentrations of certain second generation H1 antagonists may increase, even the toxic levels, if the patients also taking drugs such as ketoconazole (Nizoral) or erythromycin estolate (Ilosone).

**Receptor Type: Sites of Action**
H₁	endothelium, brain, smooth muscle
H₂	mast cells, gastric mucosa, cardiac muscle, brain

Some important histamine promoted effects occur not true histamine's interaction with histamine receptors but by histamine interaction with other receptors.
- Many of these interactions are responsible for "side effects" associated with antihistamines medications.
  - One prominent example is the side effect of sedation.
    - The side effect is the basis for antihistamine use as a sleep aid.

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.

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.