A patient on clonidine for hypertension suddenly stops the drug. He presents with severe rebound hypertension, agitation, and sweating. The mechanism of this rebound is best explained by:

• A Upregulation of postsynaptic beta-adrenoceptors during clonidine therapy
• B Upregulation of presynaptic alpha-2 receptors leading to massive norepinephrine release on withdrawal
• C Downregulation of presynaptic alpha-2 receptors and excess norepinephrine release on withdrawal ✓
• D Loss of central alpha-2 agonism in the nucleus tractus solitarius causing peripheral vasoconstriction

Explanation

Chronic clonidine therapy leads to downregulation (desensitisation) of presynaptic alpha-2 autoreceptors. On abrupt withdrawal, these downregulated receptors cannot adequately suppress norepinephrine release, resulting in a catecholamine surge, hypertensive crisis and sympathomimetic symptoms. Clonidine acts primarily in the brainstem (locus coeruleus and nucleus tractus solitarii) to reduce sympathetic outflow; option D is partly correct in mechanism of action but does not explain the withdrawal rebound. Beta-receptor upregulation is associated with beta-blocker withdrawal.

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

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