Clonidine produces antihypertensive action mainly by stimulating α2A-adrenoceptors in the rostral ventrolateral medulla (RVLM). When clonidine is abruptly withdrawn, which receptor-level mechanism underlies the rebound hypertension?

• A Upregulation of postsynaptic α1-adrenoceptors secondary to prolonged α2 stimulation
• B Increased renin release via activation of β1-receptors that were previously suppressed
• C Direct rebound activation of imidazoline I1 receptors in the kidney causing sodium retention
• D Downregulation of presynaptic α2-adrenoceptors leading to excessive norepinephrine release and sympathetic surge ✓

Explanation

Chronic clonidine therapy leads to downregulation (desensitisation) of presynaptic α2-adrenoceptors that normally serve as autoreceptors, limiting norepinephrine release. On abrupt withdrawal, these receptors are under-represented, their inhibitory control is lost, and a torrential norepinephrine surge produces severe rebound hypertension. Management requires reinstituting clonidine or using phentolamine (α-blocker) with a β-blocker; β-blocker alone can worsen hypertension by unopposed α effects.

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

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