H1 antihistamines of the first generation (e.g., diphenhydramine) cause sedation, whereas second-generation agents (e.g., cetirizine) are largely non-sedating. The most important pharmacokinetic reason for this difference is:

• A First-generation agents are more lipophilic and cross the blood-brain barrier more readily ✓
• B Second-generation agents are substrates for the P-glycoprotein efflux pump at the BBB
• C First-generation agents are more potent H1 antagonists with higher receptor affinity
• D Second-generation agents have a shorter plasma half-life, reducing CNS accumulation

Explanation

First-generation antihistamines (diphenhydramine, chlorpheniramine) are highly lipophilic amines that readily partition into CNS tissue, occupying H1 receptors on histaminergic neurons regulating wakefulness. Second-generation agents (cetirizine, loratadine, fexofenadine) are either zwitterionic (low lipophilicity) or active P-glycoprotein substrates that are actively effluxed from brain capillary endothelium, keeping CNS concentrations low. Both factors reduce their CNS penetration and sedative effect.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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