Second-generation antihistamines (cetirizine, loratadine, fexofenadine) cause less sedation than first-generation agents because:
- A They are zwitterions or P-glycoprotein substrates with poor CNS penetration, and they do not block muscarinic receptors ✓
- B They are selective H2 receptor antagonists, avoiding central H1 receptor blockade
- C They have shorter half-lives, allowing sedative effects to dissipate before peak wakefulness hours
- D They are prodrugs activated peripherally, with no active metabolite crossing the blood-brain barrier
Correct answer: A. They are zwitterions or P-glycoprotein substrates with poor CNS penetration, and they do not block muscarinic receptors
Explanation
Second-generation H1 antihistamines are selective H1 blockers with structural features that limit CNS penetration: they are zwitterions at physiological pH (e.g., cetirizine) and/or are substrates of P-glycoprotein (efflux transporter at the blood-brain barrier) that actively pumps them out. They also lack significant muscarinic, alpha-adrenergic, or serotonergic receptor activity, eliminating additional sedative/anticholinergic adverse effects. Loratadine (prodrug) is converted to desloratadine, which is still a peripherally-restricted H1 blocker.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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