Histamine Page 3

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)

H₁ receptor antagonists:
- General properties:
  - H1 antagonists:
    - First-generation
    - Second-generation
    - Both groups: orally active, hepatic metabolism -- cytochrome P450 system
    - average duration of action: 4-6 hours
    - meclizine (Antivert) and several second-generation drugs: longer acting (12-24 hours)
  - First-generation agents:
    - relatively more sedating
    - more likely than second-generation agents to block autonomic receptors (i.e. antimuscarinic effects)
  - Second-generation agents:
    - relatively less sedating compared first-generation drugs
    - decreased CNS penetration (less lipid-soluble)
    - several second-generation drugs metabolized by CYP3A4 (cytochrome P450 microsomal system) and interact with other drugs (e.g. ketoconazole) that inhibits this cytochrome P450 form.
  - Metabolites:
    - Agents with active metabolites: astemizole (Hismanal), hydroxyzine (Vistaril), loratidine (Claritin), terfenadine (Seldane)
    - Cetirizine (Zyrtec) and fexofenadine (Allegra) (available drugs): metabolites of hydroxyzine (Atarax,Vistaril), terfenadine (Seldane)

Histamine Pharmacodynamics:
- Histamine H₁Receptor Blockade:
  - H₁ receptor blockers: competitive antagonism for H₁ receptor sites
  - Little effects at H₂ receptor sites and negligible effects of H₃ sites
  - 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 (H₂ receptor site-mediated)

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

Histamine Pharmacodynamics:
- Non-Histamine Receptor-Mediated Effects
  - First-generation H₁ receptor blockers cause effects mediated by many other receptor systems. These other effects in the mediated by activities at:
    1. muscarinic cholinergic receptors
    2. alpha adrenergic receptors
    3. serotonergic receptors
    4. local anesthetic receptor sites
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  - Sedation:
    - common side effect of first-generation H₁ antagonists
    - basis for use of first-generation H₁ antagonists as hypnotics
    - in children, first-generation H₁ antagonists may produce paradoxical excitement
    - toxicity ( first-generation H₁ antagonists): stimulation, agitation, ultimately coma
    - Newer H₁ antagonists cause little or no sedation
  - Anti-emetic/Antinausea:
    - some first-generation H₁ antagonists prevent motion sickness (should be used as prophylaxis)
  - Anti-Parkinsonism:
    - some first-generation H₁ antagonists our useful in suppressing Parkinsonism symptoms associated with some antipsychotic medications.
      - probably due to antimuscarinic effects
  - Anticholinergic effects:
    - Some first-generation H₁ antagonists have strong antimuscarinic actions (atropine-like effects). Some consequences:
      1. Urinary retention
      2. Blurred vision
  - Alpha adrenergic blocking effects:
    - Some first-generation H₁ antagonists block alpha adrenergic receptors. A consequence:
      - Orthostatic hypotension
  - Serotonergic blockade:
    - Some first-generation H₁ antagonists ( cyproheptadine (Periactin), usually categorized as an anti-serotoninergic drug) block serotonin receptors
  - Local Anesthetic effects:
    - Many first-generation H₁ antagonists are local anesthetics
      - sodium channel blockade (similar to procaine and lidocaine)
      - diphenhydramine (Benadryl) and promethazine (Pherergan): more potent and procaine as local anesthetic

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