For a patient with resistant hypertension on three antihypertensive agents including a thiazide diuretic, which α‑1 blocker—doxazosin or prazosin—is the more appropriate choice?

Doxazosin vs Prazosin in Resistant Hypertension

Doxazosin is the superior choice over prazosin for resistant hypertension due to its once-daily dosing, longer duration of action, and equivalent antihypertensive efficacy, making it more practical for adherence in a population where medication non-compliance accounts for approximately 50% of treatment resistance. 1

Pharmacologic Rationale for Doxazosin

• Doxazosin offers once-daily administration (1–16 mg daily) compared to prazosin's 2–3 times daily dosing (2–20 mg total), which directly addresses the adherence crisis that underlies half of all resistant hypertension cases. 1

• Both agents work through identical mechanisms—selective α₁-adrenoceptor blockade reducing peripheral vascular resistance without affecting cardiac output or heart rate—but doxazosin's longer half-life maintains antihypertensive effect over a full 24-hour dosing interval. 2, 3

• Comparative trials demonstrate equivalent blood pressure reduction between doxazosin and prazosin, eliminating any efficacy-based reason to choose the less convenient agent. 3

Critical Context: Alpha-Blockers Are Fourth-Line Agents

• Alpha-1 blockers are explicitly designated as secondary or fourth-line agents in resistant hypertension, not part of the foundational three-drug regimen. 1

• The ACC/AHA guidelines position alpha-blockers after optimizing the core regimen (ACE inhibitor or ARB + long-acting calcium channel blocker + thiazide-like diuretic) and after adding spironolactone 25–50 mg daily, which reduces office systolic BP by approximately 13–20 mmHg in the PATHWAY-2 trial. 1, 4

• Spironolactone is the preferred fourth-line agent when serum potassium <4.5 mmol/L and eGFR >45 mL/min/1.73 m²; alpha-blockers should only be considered when spironolactone is contraindicated or not tolerated. 1, 4

When to Use Doxazosin Specifically

• Doxazosin becomes the appropriate alpha-blocker choice when the patient has concomitant benign prostatic hyperplasia (BPH), providing dual therapeutic benefit. 1

• Consider doxazosin as a fourth-line alternative when mineralocorticoid receptor antagonists are contraindicated due to hyperkalemia (K⁺ ≥4.5 mmol/L), severe renal dysfunction (eGFR ≤45 mL/min/1.73 m²), or intolerable side effects (gynecomastia with spironolactone). 4

Safety Considerations and Monitoring

• Both doxazosin and prazosin carry significant orthostatic hypotension risk, especially in older adults, which is a class effect of all α₁-blockers. 1

• Start doxazosin at 1 mg once daily and titrate gradually to minimize first-dose hypotension; counsel patients to take the initial dose at bedtime and rise slowly from sitting or lying positions. 1

• Do not use alpha-blockers as first-, second-, or third-line agents in uncomplicated resistant hypertension—this is a common prescribing error that delays more effective therapy. 4

Optimizing the Foundation Before Adding Any Fourth Agent

• Before considering any alpha-blocker, verify the patient is on maximally tolerated doses of: (1) ACE inhibitor or ARB, (2) amlodipine 10 mg daily, and (3) chlorthalidone 12.5–25 mg or indapamide 1.5–2.5 mg daily (not hydrochlorothiazide, which is markedly less effective). 1, 4

• Switching from hydrochlorothiazide to chlorthalidone provides superior 24-hour BP control and is the single most critical optimization step in resistant hypertension. 4, 5

• If eGFR <30 mL/min/1.73 m² or volume overload is present, replace thiazide-like diuretics with a loop diuretic (furosemide or torsemide), as thiazides lose efficacy at low GFR. 4

Practical Algorithm

1. Confirm true resistant hypertension with ambulatory or home BP monitoring (excludes white-coat effect in ~50% of cases) and verify medication adherence. 4, 5

2. Optimize the three-drug foundation (RAS blocker + amlodipine + chlorthalidone) at maximal tolerated doses and address lifestyle factors (sodium <2,400 mg/day, weight loss, alcohol restriction). 4, 5

3. Add spironolactone 25 mg daily as the preferred fourth agent if K⁺ <4.5 mmol/L and eGFR >45 mL/min/1.73 m²; monitor potassium and creatinine at 5–7 days, then every 3–6 months. 4, 5

4. If spironolactone is contraindicated or not tolerated, choose doxazosin 1–16 mg once daily over prazosin due to superior adherence profile; prioritize doxazosin especially if BPH is present. 1, 4

5. Target BP <130/80 mmHg and reassess response within 2–4 weeks of any medication adjustment. 4, 5

Common Pitfalls to Avoid

• Do not prescribe prazosin when doxazosin is available—the twice- or thrice-daily dosing undermines adherence in a population already struggling with medication compliance. 1

• Do not add an alpha-blocker before optimizing the diuretic—inadequate diuretic therapy is the most common reason for treatment failure in resistant hypertension. 4, 6

• Do not continue hydrochlorothiazide—switching to chlorthalidone or indapamide is mandatory for adequate BP control. 4, 5

• Do not use alpha-blockers as third-line agents—they are explicitly fourth-line only, after spironolactone has been considered. 1, 4