A patient on clonidine for hypertension suddenly stops the drug. Which mechanism best explains the rebound hypertension observed?

• A Upregulation and supersensitivity of central alpha-2 receptors following chronic agonist exposure
• B Competitive displacement of clonidine from imidazoline I1 receptors
• C Downregulation of presynaptic alpha-2 receptors causing increased norepinephrine release ✓
• D Reflex increase in renin release following cessation of alpha-2 agonism

Explanation

Chronic clonidine use leads to downregulation (desensitization) of presynaptic alpha-2 autoreceptors. These receptors normally provide negative feedback on norepinephrine release. When clonidine is abruptly withdrawn, the downregulated autoreceptors fail to suppress sympathetic outflow, resulting in a surge of norepinephrine release and rebound hypertension that may exceed pre-treatment levels. Management requires gradual dose tapering, or reinstituting clonidine and slow weaning. Upregulation of postsynaptic alpha-2 receptors would actually blunt this effect, not worsen it.

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

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