2nd generation H1 receptor antagonists

Mechanism: These drugs are inverse agonists at the H1 histamine receptor, stabilizing the inactive conformation and blocking histamine-mediated effects on vasodilation, vascular permeability, bronchoconstriction, and pruritus. Unlike first-generation antihistamines (diphenhydramine, chlorpheniramine), second-generation agents are more selective for peripheral H1 receptors and are substrates for P-glycoprotein, which pumps them out of the CNS, resulting in significantly reduced sedation and anticholinergic side effects. They also have minimal affinity for muscarinic, alpha-adrenergic, and serotonergic receptors, further reducing side effects like dry mouth, urinary retention, and cardiac arrhythmias (though terfenadine and astemizole, early second-gen drugs, were withdrawn due to QT prolongation via hERG channel blockade and risk of torsades de pointes, especially with CYP3A4 inhibitors).

Clinical uses: Allergic rhinitis (seasonal and perennial), allergic conjunctivitis, chronic urticaria, and mild allergic reactions. They are not useful for acute anaphylaxis (epinephrine is first-line) or motion sickness (first-gen agents with anticholinergic/antiemetic properties are preferred).

Key drugs: Loratadine, desloratadine, cetirizine, levocetirizine, fexofenadine. Cetirizine and its derivative levocetirizine have slightly more sedating potential than loratadine/fexofenadine due to minor CNS penetration.

Pharmacokinetics: Generally once-daily dosing due to longer half-lives compared to first-generation agents. Fexofenadine is a non-sedating, active metabolite of terfenadine with a better cardiac safety profile.

High-yield boards point: Compare and contrast with first-generation antihistamines (diphenhydramine, hydroxyzine) which cross the blood-brain barrier, causing sedation, and have significant antimuscarinic, antiemetic, and anti-alpha-adrenergic effects—useful for sleep aids, motion sickness, and allergic reactions but with more side effects (dry mouth, urinary retention, blurred vision, sedation).