H1-antihistamines of the first generation (e.g., diphenhydramine) cause significant sedation while newer H1-antihistamines (e.g., fexofenadine) do not. The pharmacokinetic/pharmacodynamic basis for this difference is:
- A Second-generation agents are selective for peripheral H1 receptors but do not bind central H1 receptors
- B First-generation agents are lipophilic and readily cross the blood-brain barrier; fexofenadine is a substrate of P-glycoprotein efflux transporter which prevents CNS penetration despite being a potent H1 antagonist ✓
- C First-generation agents have high M1 receptor affinity causing sedation through anticholinergic mechanisms
- D Fexofenadine undergoes rapid CNS-selective metabolism that inactivates it before reaching histamine receptors
Correct answer: B. First-generation agents are lipophilic and readily cross the blood-brain barrier; fexofenadine is a substrate of P-glycoprotein efflux transporter which prevents CNS penetration despite being a potent H1 antagonist
Explanation
Fexofenadine is highly hydrophilic and zwitterionic, giving it poor passive blood-brain barrier penetration; additionally it is a substrate for the P-glycoprotein (ABCB1) efflux transporter expressed in brain capillary endothelium, which actively pumps it out of the CNS. First-generation antihistamines like diphenhydramine are lipophilic and are not P-gp substrates, freely entering the CNS and blocking central histamine H1 receptors that maintain wakefulness. Both generations are equipotent H1 antagonists at peripheral receptors.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.