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Azelastine - Selective H1 Antihistamine

Azelastine (CAS 58581-89-8) - Properties, Pharmacology, and Clinical Applications

1. Introduction

Azelastine is a phthalazinone derivative belonging to the class of second-generation antihistamines. It is a selective histamine H1 receptor antagonist with additional mast cell-stabilizing and anti-inflammatory properties. Available as a hydrochloride salt (CAS 79307-93-0) for pharmaceutical formulations, azelastine is widely used as a nasal spray for allergic and non-allergic rhinitis and as an ophthalmic solution for allergic conjunctivitis. Its rapid onset of action (within 15 minutes) and favorable safety profile make it a first-line treatment for allergic conditions.

2. Chemical and Physical Properties

Azelastine base (CAS 58581-89-8) has the molecular formula C₂₂H₂₄ClN₃O and a molecular weight of 381.90 g/mol. The hydrochloride salt (CAS 79307-93-0) is the clinically used form. Key properties include:

  • Appearance: White to off-white crystalline powder

  • Melting Point (HCl salt): 225–229°C (decomposes)

  • Water Solubility (HCl salt): Approximately 35 mg/L

  • Solubility: Soluble in DMSO and methanol; slightly soluble in ethanol

  • pKa: 9.36 (predicted)

  • log P: 3.28 (predicted)

The compound is a racemic mixture, with no noted difference in pharmacologic activity between its enantiomers.

3. Mechanism of Action

Azelastine is a relatively selective histamine H1 receptor antagonist. It binds with high affinity (Ki ≈ 1 nM) to the H1 receptor, competitively blocking the effects of histamine on effector cells. In addition to its antihistaminic properties, azelastine:

  • Inhibits the release of histamine and other mediators (e.g., leukotrienes and platelet-activating factor, PAF) from mast cells and basophils

  • Decreases chemotaxis and activation of eosinophils

  • Stabilizes mast cell membranes

  • Inhibits phospholipase A and leukotriene C4 synthase

The major active metabolite, N-desmethylazelastine, also exhibits H1 receptor antagonist activity.

4. Pharmacokinetics

Following intranasal administration, the systemic bioavailability of azelastine hydrochloride is approximately 40%. Key pharmacokinetic parameters include:

  • Peak Plasma Concentration (tmax): Approximately 2–4 hours

  • Plasma Protein Binding: Approximately 88% for azelastine and 97% for N-desmethylazelastine

  • Elimination Half-life (Intranasal): Azelastine 22–25 hours; N-desmethylazelastine 52–57 hours

  • Clearance: 0.5 L/h/kg

  • Metabolism: Oxidatively metabolized in the liver by cytochrome P450 enzymes to the principal active metabolite, N-desmethylazelastine

  • Excretion: Approximately 75% of an oral dose is excreted in feces, with less than 10% as unchanged drug

5. Clinical Applications

Azelastine is indicated for the symptomatic treatment of:

  • Seasonal Allergic Rhinitis: Treatment of hay fever and related symptoms

  • Perennial Allergic Rhinitis: Year-round allergic rhinitis

  • Non-Allergic (Vasomotor) Rhinitis: Symptomatic relief of non-allergic rhinitis

  • Allergic Conjunctivitis: Relief of ocular itching associated with allergic conjunctivitis

Azelastine is available as a nasal spray (0.1% and 0.15% formulations) and as an ophthalmic solution (0.05%). It was first approved by the FDA on November 1, 1996. Combination products with fluticasone propionate (e.g., Dymista®) are also available for enhanced efficacy in allergic rhinitis.

6. Safety and Adverse Effects

Azelastine is considered a safe drug with no serious side effects at recommended doses. Common adverse effects include:

  • Bitter taste: Reported in approximately 12% of patients (associated with post-nasal drip)

  • Somnolence: Less than 1% incidence

  • Headache: Mild and transient

  • Nasal irritation: Mild and generally well-tolerated

Pregnancy: FDA Pregnancy Category C. Animal studies have shown developmental toxicity at high oral doses (approximately 560 times the maximum recommended daily intranasal dose). There are no adequate and well-controlled studies in pregnant women; the drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

7. Storage and Handling

Azelastine hydrochloride should be stored as a powder at –20°C for long-term storage. The compound should be protected from light and moisture, stored in tightly sealed containers. Use appropriate personal protective equipment (gloves, safety goggles) when handling the raw material.

8. Conclusion

Azelastine is a well-established, rapid-acting topical antihistamine with a unique dual mechanism of action: H1 receptor antagonism and mast cell stabilization. Its rapid onset of action (within 15 minutes), long duration of effect, and favorable safety profile make it a first-line treatment for allergic rhinitis and conjunctivitis. The availability of both nasal and ophthalmic formulations, as well as fixed-dose combinations, provides flexible treatment options for patients with allergic conditions. Ongoing research continues to explore its potential in novel delivery systems and expanded clinical applications.

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