A first-generation antihistamine (chlorpheniramine) causes more sedation than a second-generation antihistamine (cetirizine) because:

• A Chlorpheniramine has higher affinity for peripheral H1 receptors than cetirizine
• B Chlorpheniramine additionally blocks dopamine receptors in the basal ganglia causing sedation
• C Cetirizine is a substrate for P-glycoprotein and is actively excluded from the CNS, while chlorpheniramine freely crosses the blood-brain barrier ✓
• D Cetirizine is metabolised to an inactive compound in the CNS by monoamine oxidase

Explanation

Second-generation antihistamines like cetirizine, fexofenadine, and loratadine are substrates for P-glycoprotein (P-gp) efflux transporters at the blood-brain barrier, which actively pumps them back out of the CNS. This results in negligible CNS H1 receptor occupancy and minimal sedation. First-generation antihistamines (chlorpheniramine, diphenhydramine, promethazine) are lipophilic and are not P-gp substrates, allowing free CNS penetration and blockade of central H1 receptors mediating wakefulness, causing sedation.

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

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Written and medically reviewed by the StethoPrep medical team.