Anti-Allergic Drugs (Pharmacology)

Overview: Histamine & Allergic Reactions

Histamine is the primary mediator of allergic reactions. It is synthesized by decarboxylation of histidine (by histidine decarboxylase) and stored in mast cells and basophils. On release, it binds to H1 and H2 receptors causing the spectrum of allergic symptoms.

H1 receptor effects: Smooth muscle contraction, ↑ capillary permeability, vasodilation (via NO), bronchoconstriction, pruritus H2 receptor effects: Gastric acid secretion, some cardiac effects

Classification of Anti-Allergic Drugs

I. H1-RECEPTOR BLOCKERS (Antihistamines)

The cornerstone of anti-allergic pharmacotherapy. Divided into two generations:

First-Generation H1 Blockers

Mechanism: Competitive H1 receptor antagonists (inverse agonists). They stabilize the inactive form of H1 receptors. They cross the blood-brain barrier (lipophilic) and block muscarinic, α-adrenergic, and serotonin receptors as well.

Chemical Classes & Drugs:

Class	Examples	Key Features
Ethanolamines	Diphenhydramine (Benadryl), Dimenhydrinate, Doxylamine	High sedation, significant anticholinergic effects
Alkylamines	Chlorpheniramine, Brompheniramine, Triprolidine	Less sedation, CNS stimulation possible
Piperazines	Hydroxyzine (Vistaril), Meclizine, Cyclizine	Hydroxyzine: anxiolytic; Meclizine: motion sickness
Phenothiazines	Promethazine (Phenergan)	Strong antiemetic, high sedation
Piperidines	Cyproheptadine	Also blocks 5-HT; used for appetite stimulation
Ethylenediamines	Clemastine	Moderate sedation

Pharmacokinetics:

Oral: well absorbed; onset 15–30 min
Duration: 4–6 hours
Metabolized by CYP450 in liver

Therapeutic Uses:

Allergic rhinitis, urticaria, atopic dermatitis
Motion sickness (dimenhydrinate, meclizine)
Nausea/vomiting (promethazine)
Sleep aid (diphenhydramine, doxylamine)
Anaphylaxis (adjunct to epinephrine)
Common cold (drying of secretions)

Adverse Effects:

CNS: Sedation, impaired cognition, dizziness (most common)
Anticholinergic: Dry mouth, urinary retention, blurred vision, constipation, tachycardia
Paradoxical CNS excitation in children (insomnia, tremors)
Appetite stimulation (cyproheptadine)
Toxic doses: Convulsions, hyperthermia

Second-Generation H1 Blockers

Mechanism: Selective peripheral H1 blockers. Made polar (carboxyl groups added) → do not cross the blood-brain barrier → minimal sedation. No significant anticholinergic effects.

Drugs:

Drug	Brand	Notes
Loratadine	Claritin	Least sedating; metabolized to desloratadine
Desloratadine	Clarinex	Active metabolite of loratadine
Fexofenadine	Allegra	Least sedating; no CYP450 interaction
Cetirizine	Zyrtec	Carboxylated hydroxyzine; mild sedation possible
Levocetirizine	Xyzal	Active enantiomer of cetirizine
Azelastine	Astelin	Nasal spray; also ophthalmic formulation
Olopatadine	Pataday	Ophthalmic; used for allergic conjunctivitis
Bepotastine	Bepreve	Ophthalmic
Alcaftadine	Lastacaft	Ophthalmic
Ketotifen	Zaditor	Ophthalmic; mast cell stabilizer properties

Therapeutic Uses:

Seasonal/perennial allergic rhinitis (first-line)
Urticaria, allergic skin conditions
Allergic conjunctivitis (topical agents)

Adverse Effects:

Minimal sedation (fexofenadine, loratadine, desloratadine = least sedating)
Cetirizine/levocetirizine: mild drowsiness in some patients
No anticholinergic effects

II. MAST CELL STABILIZERS

Mechanism: Prevent degranulation of mast cells → inhibit release of histamine, leukotrienes, and other mediators. Work best as prophylactic agents.

Drug	Route	Use
Cromolyn sodium	Inhaled / nasal / ophthalmic	Allergic rhinitis, asthma prophylaxis, conjunctivitis
Nedocromil	Inhaled	Asthma prophylaxis
Lodoxamide	Ophthalmic	Allergic conjunctivitis
Ketotifen	Oral / ophthalmic	Also H1 blocker

Key point: Must be used before allergen exposure. Not useful for acute attacks.

III. CORTICOSTEROIDS

The most potent anti-inflammatory/anti-allergic drugs.

Mechanism: Bind glucocorticoid receptors → ↓ cytokine production, ↓ eosinophil survival, ↓ mast cell mediator release, ↓ vascular permeability.

Drug	Route	Use
Fluticasone, Mometasone, Budesonide	Intranasal	First-line for allergic rhinitis
Beclomethasone, Flunisolide	Inhaled	Asthma
Prednisolone, Dexamethasone	Oral/IV	Severe allergy, anaphylaxis, asthma exacerbation
Hydrocortisone, Triamcinolone	Topical	Urticaria, atopic dermatitis

IV. LEUKOTRIENE RECEPTOR ANTAGONISTS (LTRAs)

Mechanism: Block cysteinyl leukotriene (LTC4, LTD4, LTE4) receptors → ↓ bronchoconstriction, ↓ mucus secretion, ↓ airway inflammation.

Drug	Use
Montelukast (Singulair)	Allergic rhinitis, asthma; safe in children
Zafirlukast	Asthma

Zileuton blocks 5-lipoxygenase → ↓ leukotriene synthesis (upstream mechanism).

V. EPINEPHRINE (Adrenaline)

Drug of choice for anaphylaxis.

Mechanism: α1 agonist → vasoconstriction, ↓ edema; β2 agonist → bronchodilation; β1 → ↑ cardiac output.

Route: IM (vastus lateralis) or IV in severe cases (EpiPen).

VI. ANTI-IgE THERAPY (Biologics)

Drug	Mechanism	Use
Omalizumab (Xolair)	Monoclonal antibody against free IgE → ↓ mast cell/basophil activation	Severe allergic asthma, chronic urticaria
Dupilumab (Dupixent)	Blocks IL-4Rα → inhibits IL-4 and IL-13 signaling	Atopic dermatitis, asthma
Mepolizumab, Benralizumab	Anti-IL-5 / anti-IL-5Rα → ↓ eosinophils	Eosinophilic asthma

VII. β2-AGONISTS (for Allergic Bronchospasm)

Drug	Type	Use
Salbutamol (Albuterol)	Short-acting (SABA)	Acute bronchospasm
Salmeterol, Formoterol	Long-acting (LABA)	Asthma maintenance (with ICS)

Summary Comparison: 1st vs 2nd Generation Antihistamines

Feature	1st Generation	2nd Generation
CNS penetration	Yes	Minimal
Sedation	High	Low to none
Anticholinergic effects	Yes	No
Duration	4–6 hrs	12–24 hrs
Selectivity	Non-selective	Peripheral H1 selective
Examples	Diphenhydramine, Chlorpheniramine, Promethazine	Loratadine, Fexofenadine, Cetirizine

Key Exam Points

Epinephrine = drug of choice in anaphylaxis (not antihistamines)
Fexofenadine = least sedating, no QTc prolongation
Diphenhydramine = prototype 1st-gen; also used as sleep aid and antiemetic
Promethazine = contraindicated in children < 2 years (respiratory depression)
Meclizine/Dimenhydrinate = motion sickness
Cyproheptadine = serotonin antagonist + appetite stimulant
Cromolyn = prophylaxis only, not for acute attacks
Montelukast = safe in children with allergic rhinitis + asthma
Omalizumab = for IgE-mediated severe allergic disease

Sources: Lippincott Illustrated Reviews: Pharmacology; Katzung's Basic and Clinical Pharmacology, 16th Ed.

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