What is the mechanism of action for azelastine?

Mechanism of Action of Azelastine

Azelastine primarily works as a potent histamine H1-receptor antagonist, but also exhibits multiple additional anti-inflammatory and antiallergic properties that contribute to its clinical efficacy in treating allergic and non-allergic rhinitis.

Primary Mechanism: H1-Receptor Antagonism

• Azelastine hydrochloride is a phthalazinone derivative that exhibits histamine H1-receptor antagonist activity in isolated tissues, animal models, and humans 1
• It functions as a second-generation antihistamine with H1-receptor binding approximately tenfold greater than chlorpheniramine on a milligram-per-milligram basis 2
• The drug is administered as a racemic mixture with no difference in pharmacologic activity noted between the enantiomers in in vitro studies 1
• Its major metabolite, desmethylazelastine, also possesses H1-receptor antagonist activity 1

Additional Mechanisms of Action

Azelastine's therapeutic effects extend beyond simple H1-receptor blockade:

• Mast cell stabilization: Inhibits histamine release from mast cells following both antigen and non-antigen stimuli 3
• Leukotriene inhibition: Demonstrates effects on leukotrienes, which are important inflammatory mediators in allergic reactions 2
• Anti-inflammatory properties:
  • Downregulates intercellular adhesion molecule-1 (ICAM-1) expression 2
  • Reduces inflammatory cell migration in patients with rhinitis 2
  • Inhibits production or release of multiple chemical mediators including leukotrienes, free radicals, and cytokines 4
• Platelet activating factor inhibition: Shows effects on platelet activating factor in vitro and in vivo 2
• Kinin antagonism: Demonstrates effects against kinins, which are inflammatory mediators 2

Clinical Pharmacology

• Onset of action: Rapid onset with clinically significant effects as early as 15 minutes after intranasal administration 5, 6
• Duration of action: Prolonged activity lasting 12-24 hours 4
• Pharmacokinetics:
  • Systemic bioavailability after intranasal administration is approximately 40% 1
  • Maximum plasma concentrations achieved in 2-3 hours 1
  • Elimination half-life is approximately 22 hours 1
  • Primarily metabolized by the cytochrome P450 enzyme system 1

Clinical Implications of Mechanism

• The multiple mechanisms of action explain why azelastine can improve both early and late phase symptoms of allergic rhinitis 7
• Unlike many oral antihistamines, azelastine has demonstrated effects on nasal congestion in some studies, likely due to its multiple mechanisms beyond H1 blockade 4
• The rapid onset of action (15 minutes) makes it suitable for both scheduled and as-needed dosing 6

Important Clinical Considerations

• Sedation risk: While azelastine has been associated with sedative properties compared with placebo, the effect tends to be milder than that observed with first-generation antihistamines 5
• Common side effects: Bitter taste (reported in 19.7% of patients) and somnolence (11.5%) are the most common adverse effects 5
• Dosing: Typically administered as 2 sprays in each nostril twice daily for patients 12 years of age and older 5

Understanding azelastine's complex mechanism of action helps explain its clinical efficacy in treating both allergic and non-allergic rhinitis, and its ability to address symptoms that may not respond to simple antihistamines.