A 58-year-old patient on prazosin develops orthostatic hypotension worst with the first dose. The mechanism underlying this 'first-dose phenomenon' is best explained by:
- A Selective blockade of prejunctional alpha-2 receptors leading to norepinephrine surge
- B Inability to activate baroreceptor-mediated reflex tachycardia due to prejunctional alpha-1 blockade on sympathetic nerve terminals
- C Loss of venous tone from alpha-1 blockade without compensatory increase in heart rate due to blunted baroreflex from baseline hypertension ✓
- D Direct negative chronotropic effect via cardiac alpha-1 receptor blockade
Correct answer: C. Loss of venous tone from alpha-1 blockade without compensatory increase in heart rate due to blunted baroreflex from baseline hypertension
Explanation
Prazosin causes marked venous pooling via alpha-1 blockade on venous smooth muscle. In hypertensive patients, the baroreceptor reflex is already blunted (resetting), so the compensatory tachycardia is inadequate, causing profound orthostatic hypotension with the first dose. Prazosin does not block prejunctional alpha-2 (option A is incorrect; terazosin/doxazosin have even less selectivity). Option B confuses receptor subtypes.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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