What is the drug of choice for treating pheochromocytoma?

Drug of Choice in Pheochromocytoma

Phenoxybenzamine is the traditional drug of choice for preoperative management of pheochromocytoma, though doxazosin is an equally effective alternative with fewer side effects and dramatically lower cost. 1, 2

Preoperative Alpha-Blockade: The Foundation of Treatment

All patients with pheochromocytoma require alpha-adrenergic blockade for 10-14 days before surgery to prevent potentially fatal hypertensive crises and arrhythmias during tumor manipulation. 1, 2, 3

Blood Pressure Targets

• Supine BP: <130/80 mmHg 1, 2, 3
• Standing systolic BP: >90 mmHg (to avoid orthostatic hypotension) 1, 2, 3

Alpha-Blocker Options

Phenoxybenzamine (Non-selective, Non-competitive)

• FDA-approved specifically for pheochromocytoma 4
• Standard dosing: 10 mg twice daily, titrated every 2-4 days 1
• Provides slightly better intraoperative hemodynamic control with less blood pressure rise during phenylephrine challenge (linear regression coefficient 0.008 vs 0.018, P=0.01) 5
• Results in more pronounced postoperative hypotension requiring aggressive fluid management 6, 5
• Significantly more side effects: orthostatic hypotension, peripheral edema, nasal congestion 6
• Prohibitively expensive: median daily cost $442.20 vs $5.06 for doxazosin 5

Doxazosin (Selective α1-blocker, Competitive)

• Equally effective for blood pressure control with 12.2% vs 11.1% time outside BP targets (P=0.75) 7
• Excellent or good efficacy in 79.2% of patients (66.7% as monotherapy, 91.7% with added beta-blocker) 8
• Fewer side effects than phenoxybenzamine 6, 8
• Dramatically lower cost (>98% cost reduction) 5
• May require more supplemental antihypertensive agents 6

Clinical Decision Algorithm

Start with doxazosin for most patients given equivalent efficacy, better tolerability, and vastly lower cost. 6, 5, 7 Consider phenoxybenzamine only if:

• Doxazosin fails to achieve BP targets despite dose escalation 1
• Patient has extremely high catecholamine levels requiring maximal blockade 1
• Cost is not a barrier 5

Critical Sequencing: Never Beta-Block First

Beta-blockers must NEVER be initiated before adequate alpha-blockade as this causes unopposed alpha-adrenergic stimulation leading to severe hypertensive crisis. 1, 2, 3 Beta-blockers (typically esmolol or propranolol) are added only after alpha-blockade is established to control tachyarrhythmias. 1

Adjunctive Medications

Calcium Channel Blockers

• Nifedipine slow-release or other calcium antagonists can be added if BP targets not reached with alpha-blockade alone 1
• May be used as alternative or complementary therapy to alpha-blockers, particularly in pregnancy 1

Metyrosine (Alpha-methylparatyrosine)

• Inhibits catecholamine synthesis 1, 9
• Reserved for refractory cases or when surgery is contraindicated 9

Preoperative Preparation Beyond Pharmacology

• High-sodium diet plus 1-2 liters IV saline 24 hours before surgery 2, 3
• Compression stockings to prevent orthostatic hypotension 2
• Duration: minimum 10-14 days of medical preparation 1, 2

Intraoperative Management

For hypertensive crises during surgery:

• Phentolamine (IV alpha-blocker) 1, 10
• Magnesium sulfate 1, 10
• Nitroprusside or nitroglycerin 1, 10
• Calcium antagonists 1, 10

For tachycardia: Esmolol (short-acting IV beta-blocker) 1, 10

Common Pitfalls to Avoid

1. Never biopsy a suspected pheochromocytoma - can precipitate fatal hypertensive crisis 10
2. Never start beta-blockers before alpha-blockade - causes unopposed vasoconstriction 1, 2, 3
3. Anticipate postoperative hypoglycemia from sudden catecholamine withdrawal - monitor glucose closely 1, 10
4. Prevent postoperative hypotension with aggressive preoperative hydration 1, 2, 10

Special Population: Pregnancy

For pheochromocytoma in pregnancy (0.002% incidence but 50% maternal/fetal mortality if undiagnosed):

• First 24 weeks: laparoscopic adrenalectomy after 10-14 days alpha-blockade 1, 3
• Third trimester: medical management until fetal viability, then cesarean section with simultaneous tumor removal 1, 3

Evidence Quality Note

The most recent high-quality randomized controlled trial (PRESCRIPT, 2020) found no significant difference in primary outcome (time outside BP targets: 11.1% vs 12.2%, P=0.75) between phenoxybenzamine and doxazosin, though phenoxybenzamine showed slightly better hemodynamic stability scores (P=0.02) without translating to improved clinical outcomes (30-day cardiovascular complication rates 8.8% vs 6.9%, P=0.68). 7 This supports using the more tolerable and affordable doxazosin as first-line therapy.