What is the best treatment approach for a patient with hypertension unresponsive to nifedipine (calcium channel blocker) and elevated 24-hour cortisol levels, indicating hypercortisolism?

Treatment of Hypertension with Elevated 24-Hour Cortisol

The priority is to address the underlying hypercortisolism causing the resistant hypertension, as treating Cushing's syndrome is essential for blood pressure control and preventing cardiovascular morbidity and mortality. 1

Immediate Diagnostic Confirmation

Before initiating treatment, confirm Cushing's syndrome with:

• 24-hour urinary free cortisol excretion (preferably multiple collections) 1
• Midnight salivary cortisol as an additional confirmatory test 1
• Measure ACTH levels to determine if the hypercortisolism is ACTH-dependent (pituitary or ectopic tumor) or ACTH-independent (adrenal source) 1

Treatment Strategy Based on Etiology

If ACTH-Independent (Adrenal Source)

Surgical management is the definitive treatment:

• Laparoscopic adrenalectomy for benign adrenal adenomas causing Cushing's syndrome 1
• Suspect malignancy if the tumor is >5 cm, inhomogeneous with irregular margins, or shows local invasion 1
• Postoperative corticosteroid supplementation is mandatory until recovery of the hypothalamus-pituitary-adrenal axis 1

If ACTH-Dependent (Pituitary or Ectopic)

• If an ectopic tumor is identified and resectable, surgical removal is recommended 1
• If the primary tumor is unresectable, consider bilateral laparoscopic adrenalectomy or medical management 1

Medical Management of Hypercortisolism

When surgery is not immediately feasible or as bridge therapy:

Ketoconazole is the first-line adrenostatic agent at doses of 400-1200 mg/day due to easy availability and relatively tolerable toxicity profile 1

Alternative agents include:

• Mitotane for more severe cases 1
• Octreotide for ectopic Cushing syndrome if the tumor is Octreoscan-positive, though it may be less effective in controlling ectopic ACTH 1

Antihypertensive Management During Hypercortisolism

While addressing the underlying Cushing's syndrome, specific antihypertensive choices are critical:

Preferred Agents

• Mineralocorticoid receptor antagonists (spironolactone or eplerenone) are highly effective, as glucocorticoids activate mineralocorticoid receptors contributing to hypertension 2
• ACE inhibitors are good antihypertensive options in Cushing's syndrome 2
• Angiotensin II receptor blockers (ARBs) are effective alternatives 2

Agents to Avoid or Use with Caution

• Thiazide diuretics and furosemide should be avoided in Cushing's syndrome 2
• Calcium channel antagonists (including nifedipine) are usually ineffective for hypertension in hypercortisolism 2
• Adrenergic blockade is typically ineffective 2

Monitoring and Follow-Up

• Monitor serum potassium and renal function closely when using mineralocorticoid receptor antagonists, especially with baseline potassium >4.5 mEq/L or eGFR <45 mL/min/1.73 m² 1
• Reassess blood pressure control within 1-2 weeks after initiating medical therapy 3
• Target blood pressure <130/80 mm Hg once hypercortisolism is controlled 1

Critical Pitfalls to Avoid

• Do not rely solely on calcium channel blockers (like nifedipine) to control hypertension in Cushing's syndrome, as they fail to address the underlying pathophysiology 2
• Do not delay evaluation for surgical cure in adrenal adenomas, as hypertension may persist even after medical management 1
• Avoid abrupt discontinuation of corticosteroid supplementation post-adrenalectomy, as this can precipitate adrenal crisis 1
• Hypertension usually resolves with surgical removal of the tumor, but some patients require continued antihypertensive treatment postoperatively 2