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How Allergy Medications Work: Mechanisms of Antihistamines, Corticosteroids, and Biologics

Allergy pharmacotherapy targets specific nodes in the allergic inflammatory cascade. Understanding mechanisms guides rational selection, combination, and patient counseling.

The Allergic Cascade (Simplified)

  1. Sensitization: Allergen → dendritic cell → Th2 → IL-4/IL-13 → B cell class switch → allergen-specific IgE → binds FcεRI on mast cells/basophils.
  2. Early Phase (minutes): Re-exposure → allergen cross-links IgE → mast cell degranulation → histamine, tryptase, PGD2, LTC4 → vascular permeability, smooth muscle contraction, mucus, sensory nerve activation.
  3. Late Phase (4–8 hours): Cytokines (IL-4,5,13) → eosinophil/basophil/Th2 recruitment → sustained inflammation, tissue remodeling.
  4. Chronic: Epithelial barrier disruption, neural hyperresponsiveness, structural changes.

Drug Classes and Mechanisms

1. H1 Antihistamines (Inverse Agonists at H1 Receptor)

  • First-Generation (diphenhydramine, chlorpheniramine, hydroxyzine): Lipophilic, cross BBB → sedation, anticholinergic, cognitive impairment. Short duration (4–6h).
  • Second-Generation (cetirizine, loratadine, fexofenadine, levocetirizine, desloratadine, bilastine, rupatadine): P-glycoprotein substrate → limited CNS penetration; minimal sedation. Long duration (24h). Cetirizine fastest onset (~1h); fexofenadine least sedating.
  • Intranasal (azelastine, olopatadine): Rapid onset (15–30 min); additional mast cell stabilization.
  • Ophthalmic (ketotifen, olopatadine, alcaftadine, bepotastine): Local H1 blockade + mast cell stabilization.

2. Intranasal Corticosteroids (INS)

  • Bind glucocorticoid receptor → translocate to nucleus → transrepress pro-inflammatory genes (cytokines, chemokines, adhesion molecules), transactivate anti-inflammatory genes.
  • Reduce mast cells, eosinophils, Th2 cells, B cells in mucosa; restore epithelial integrity.
  • Most effective single agent for all nasal symptoms (congestion > antihistamines). Onset 12h; maximal 1–2 weeks.
  • Low bioavailability (mometasone <1%, fluticasone furoate <0.5%) → minimal systemic effects at recommended doses.

3. Leukotriene Modifiers

  • Montelukast (LT receptor antagonist): Blocks CysLT1 receptor → inhibits bronchoconstriction, mucus, eosinophil recruitment. Adjunct for AR + asthma, AERD.
  • Zileuton (5-lipoxygenase inhibitor): Blocks LT synthesis; hepatotoxicity monitoring required.

4. Mast Cell Stabilizers

  • Cromolyn sodium (nasal, ophthalmic, inhaled): prevents degranulation; no effect on established symptoms; prophylactic use; QID dosing limits adherence.

5. Biologics (Targeted Immunomodulators)

  • Omalizumab (anti-IgE): Binds free IgE → ↓ FcεRI expression on mast cells/basophils/eosinophils. Approved: severe allergic asthma, chronic spontaneous urticaria, CRSwNP.
  • Dupilumab (anti-IL-4Rα): Blocks IL-4/IL-13 signaling → broad type 2 inhibition. Approved: moderate-severe atopic dermatitis, asthma, CRSwNP, eosinophilic esophagitis.
  • Mepolizumab/Reslizumab/Benralizumab (anti-IL-5/IL-5R): Eosinophil depletion. Severe eosinophilic asthma, EGPA, CRSwNP (mepolizumab).
  • Tezepelumab (anti-TSLP): Upstream alarmin blockade; broad eosinophilic/non-eosinophilic asthma.

6. Allergen Immunotherapy (AIT)

Only disease-modifying; induces Tregs, IgG4 blocking antibodies, shifts Th2→Th1. SCIT or SLIT. 3–5 year course; sustained remission.

Combination Therapy Principles

  • INS + intranasal antihistamine (azelastine/fluticasone combo) > either alone.
  • INS + oral antihistamine for breakthrough ocular/skin symptoms.
  • Biologic + INS for CRSwNP/asthma.
  • Avoid oral antihistamine + intranasal antihistamine duplication (no added benefit).

Match mechanism to phenotype: INS for congestion-predominant; antihistamine for itch/sneeze-predominant; biologic for severe refractory type 2 inflammation.

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