A 58-year-old man from Delhi presents with a 2-year history of lower urinary tract symptoms (LUTS) including nocturia (×4 per night), weak urinary stream, and hesitancy. Digital rectal examination reveals a smooth, enlarged prostate (grade II). PSA is 2.8 ng/mL. He is started on an alpha blocker. After 2 weeks of treatment, he reports marked improvement in flow rate and nocturia. However, he now complains of dizziness on standing and a single episode of syncope while getting out of bed in the morning. Blood pressure supine: 140/88 mmHg; standing: 108/62 mmHg. Which of the following alpha blockers is MOST likely responsible for this adverse effect, and what is the mechanism?

Explanation

## Mechanism of Orthostatic Hypotension with Non-selective Alpha Blockers **Key Point:** Non-selective α1-blockers like **terazosin** and doxazosin cause significant orthostatic hypotension due to systemic vasodilation. Terazosin is the most likely culprit here because the stem describes a patient who has been on treatment for 2 weeks with marked symptomatic improvement — consistent with a non-uroselective agent that also causes postural hypotension. ### Why Terazosin (Option A) is the Correct Answer Option A states "Terazosin; selective α1 blockade with gradual dose titration reducing first-dose effect." Despite dose titration, terazosin (a non-uroselective α1-blocker) still causes **cumulative orthostatic hypotension** because it blocks α1-adrenergic receptors on systemic vascular smooth muscle, impairing the reflex vasoconstriction needed to maintain blood pressure on standing. The clinical picture — syncope on rising from bed, supine BP 140/88 mmHg, standing BP 108/62 mmHg (drop of 32 mmHg systolic) — is classic for a **non-uroselective alpha blocker** causing orthostatic hypotension. ### Pathophysiology 1. **α1-blockade on systemic arterioles** → reduced peripheral vascular resistance → vasodilation 2. **Impaired orthostatic vasoconstriction** → blood pools in lower extremities on standing 3. **Morning orthostasis** is worst due to nocturnal fluid redistribution and reduced sympathetic tone 4. **Supine BP preserved** because sympathetic tone is adequate in recumbency ### Comparison of Alpha Blockers by Selectivity and Orthostatic Risk | Agent | Selectivity | Orthostatic Risk | First-Dose Effect | |-------|-------------|------------------|-------------------| | **Terazosin** | Non-selective (α1A + α1B) | **High** | **Significant** | | **Doxazosin** | Non-selective (α1A + α1B) | **High** | **Significant** | | **Tamsulosin** | Uroselective (α1A >> α1B) | Low | Minimal | | **Alfuzosin** | Uroselective (α1A >> α1B) | Low | Minimal | ### Why the Other Options Are Incorrect - **Option B (Doxazosin; non-selective α1 and α2 blockade):** Doxazosin is NOT an α2-blocker. It is a selective α1-blocker (non-uroselective). The mechanism described — "unopposed β-adrenergic vasodilation" via α2-blockade — is pharmacologically incorrect for doxazosin. This makes Option B factually wrong. - **Option C (Tamsulosin):** Tamsulosin is uroselective (α1A-preferring) and has minimal systemic vascular effects; it rarely causes orthostatic hypotension. It would NOT explain this presentation. - **Option D (Alfuzosin):** Similarly uroselective with reduced orthostatic risk; not the likely culprit. **High-Yield (KD Tripathi, Essentials of Medical Pharmacology):** Terazosin and doxazosin are long-acting, non-uroselective α1-blockers used in BPH and hypertension. They cause significant orthostatic hypotension, especially in the morning. Tamsulosin and alfuzosin are uroselective and preferred when cardiovascular side effects must be minimized. **Clinical Pearl:** The first dose of non-uroselective α-blockers (terazosin, doxazosin) should be given at bedtime with slow dose titration. Even with titration, cumulative orthostatic hypotension can occur, as seen in this patient. Switching to a uroselective agent (tamsulosin/alfuzosin) is the recommended management. ## Management Approach ``` Orthostatic hypotension on alpha blocker ↓ Which agent? Non-selective (terazosin/doxazosin) → Switch to uroselective (tamsulosin/alfuzosin) Already uroselective → Assess volume status, other antihypertensives ``` **Exam Tip:** If a patient on an alpha blocker for BPH develops orthostatic syncope, the culprit is a **non-uroselective agent** (terazosin or doxazosin). The mechanism is α1-blockade on systemic vasculature impairing orthostatic vasoconstriction — NOT α2-blockade (which is not a property of these drugs).