Allergy Pharmacotherapy
Pharmacology of allergic disease treatment from antihistamines and mast cell stabilizers to epinephrine, corticosteroids, and allergen immunotherapy.
## Allergic Immune Response
Type I hypersensitivity (immediate allergy) is mediated by IgE antibodies bound to mast cells and basophils via high-affinity FcepsilonRI receptors. Allergen cross-linking of surface IgE triggers degranulation, releasing histamine, tryptase, prostaglandins, leukotrienes, and cytokines. Early-phase reactions occur within minutes (vasodilation, edema, bronchospasm). Late-phase reactions at 4-8 hours involve eosinophil and T-cell recruitment.
## Antihistamines
**First-generation H1 antagonists** (diphenhydramine, chlorpheniramine, hydroxyzine) cross the blood-brain barrier, causing sedation and anticholinergic effects (dry mouth, urinary retention, constipation). They are inverse agonists that stabilize the inactive conformation of the H1 receptor.
**Second-generation H1 antagonists** (cetirizine, loratadine, fexofenadine, levocetirizine, desloratadine) are peripherally selective with minimal CNS penetration. They are preferred for chronic allergic conditions due to once-daily dosing and minimal sedation. Cetirizine has slightly higher sedation potential than fexofenadine.
Antihistamines are most effective when taken prophylactically before allergen exposure, as they compete with histamine at unoccupied receptors rather than displacing bound histamine.
## Mast Cell Stabilizers
**Cromolyn sodium** and **nedocromil** stabilize mast cell membranes, preventing degranulation. They are used prophylactically for allergic rhinitis (nasal spray) and asthma (inhaled). Mechanism involves chloride channel blockade and inhibition of sensory nerve activation. Effectiveness requires consistent use; they have no role in acute symptom relief.
## Leukotriene Modifiers
**Montelukast** and **zafirlukast** are cysteinyl leukotriene receptor (CysLT1) antagonists. Leukotrienes LTC4, LTD4, and LTE4 cause prolonged bronchoconstriction, mucus secretion, and eosinophil recruitment. Montelukast is used for allergic rhinitis and mild persistent asthma, particularly exercise-induced bronchoconstriction. The FDA has added a boxed warning regarding neuropsychiatric events (mood changes, suicidality) with montelukast.
## Epinephrine
**Epinephrine (adrenaline)** is the first-line treatment for anaphylaxis. It acts on alpha-1 (vasoconstriction, reversing hypotension and angioedema), beta-1 (increased cardiac output), and beta-2 (bronchodilation, mast cell stabilization) adrenergic receptors. Intramuscular injection into the anterolateral thigh provides the fastest absorption. Auto-injectors deliver 0.3 mg (adult) or 0.15 mg (pediatric). Delay in administration is the primary cause of anaphylaxis mortality.
## Allergen Immunotherapy
Subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) induce immune tolerance by gradually increasing allergen exposure. This shifts the immune response from Th2 (IL-4, IL-5, IgE) toward Th1 and T-regulatory cell dominance, increasing blocking IgG4 antibodies. Treatment duration is 3-5 years. SCIT is effective for allergic rhinitis, venom allergy, and allergic asthma. SLIT tablets (grass, ragweed, dust mite) offer home-based alternatives.
## Key Takeaways
- Second-generation antihistamines are first-line for chronic allergic conditions due to peripheral selectivity
- Epinephrine is irreplaceable as first-line anaphylaxis treatment; delay increases mortality
- Allergen immunotherapy induces long-term tolerance through Th2-to-Treg immune shift
- Montelukast carries an FDA boxed warning for neuropsychiatric adverse events