Overlapping Spironolactone Dosing in Primary Aldosteronism and Resistant Essential Hypertension

A 65‐year‐old man presented to our hypertension clinic with refractory hypertension and hypokalemia. At age 11 he was beaten up, suffering a left renal injury that required hospitalization. Subsequent diastolic blood pressures (BPs) rose to 105 mm Hg throughout high school and into college, gradually resolving off of medication. He had been treated with antihypertensive therapy for more than 25 years with poor control. Amlodipine and nifedipine were not tolerated due to edema. Hypokalemia was noted and prior to spironolactone initiation, the patient required 100 mEq of potassium replacement daily. On spironolactone 25 mg, potassium was reduced to 40 mEq daily. A daughter of the patient, age 20, was being treated for hypertension, but there was no family history of stroke or myocardial infarction. He was treated with a regimen of lisinopril 40 mg, hydrochlorothiazide (HCTZ) 25 mg, atenolol 75 mg, terazosin 10 mg, and potassium chloride (KCl) 40 mEq daily. BPs had recently improved, but were still within the range of 150/90 mm Hg.

The patient was taken off spironolactone and potassium was advanced to 100 mEq daily in preparation for testing for primary aldosteronism. A month later, his BP was 181/91 mm Hg. The laboratory workup included sodium 143 mEq/L (normal 135–145 mEq/L), potassium 3.5 mEq/L (normal 3.5–5.0 mEq/L), carbon dioxide 32.4 mEq/L (normal 21–31 mEq/L), creatinine 1.2 mg/dL (0.7–1.3 mg/dL), fasting glucose 111 mg/dL (normal 70–99 mg/dL), aldosterone 12.0 ng/dL (normal≤28 ng/dL), peripheral renin activity (PRA) 0.07 ng/mL/hour (0.25–5.82 ng/mL/hour), aldosterone/PRA ratio 171.43 (normal 0.9–28.9), 24‐hour urine aldosterone 12.1 μg/24 hours (normal 2.3–21 μg/24 hours), 24‐hour urine‐free cortisol 59 μg/24 hours (normal<138 μg/24 hours), 24‐hour urine metanephrines normal, and 17 ketosteroid fractionation normal. Genetic testing for glucocorticoid‐remediable aldosteronism was negative. A computed tomography (CT) scan of the adrenal glands was normal. An intravenous saline suppression test had to be discontinued due to systolic pressures <200 mm Hg.

When the spironolactone dose was advanced to 50 mg daily, BPs became 130 to 132/70 to 74 mm Hg within 2 weeks and remained stable with a continuing need for 40 mEq daily potassium replacement (Figure 1).

Figure 1.

 Sequential therapy indicating dose‐related response to spironolactone: up to month 2 on lisinopril 40 mg, hydrochlorothiazide 25 mg, atenolol 75 mg, terazosin 10 mg, potassium chloride (KCl) 40 mEq; at month 2, spironolactone 25 mg added and KCl reduced to 40 mEq; at month 4, spironolactone increased to 50 mg.

Case Discussion

Spironolactone Dosing for Primary Hyperaldosteronism and Resistant Essential Hypertension

Spironolactone is used to treat both primary hyperaldosteronism and resistant hypertension in the absence of secondary etiologies. The dose ranges for these two conditions overlap significantly. In a study of 76 patients with African American participation, spironolactone 12.5 mg to 50 mg was similarly effective in those with and without biochemical evidence of primary hyperaldosteronism. ¹ The mean dosage was 30 mg/d in this study, but patients with primary aldosteronism were more likely to require the 50‐mg dose. The mean BP reduction at 6 months in patients taking a mean of 4.1 antihypertensive medications at baseline was 25/12 mm Hg without significant difference between those with and those without hyperaldosteronism, and without significant difference between African American and white patients. ¹ A post hoc analysis of patients in the Anglo‐Scandinavian Cardiac Outcomes Trial (ASCOT) demonstrated that the best fourth drug, following the comparison protocol regimens, was spironolactone 25 mg to 50 mg. ²

Although the spironolactone dose spectrum used to treat essential hypertension resistant to 3 or 4 drugs is usually 12.5 mg to 50 mg, ¹ , ² dosages to treat primary hyperaldosteronism are more commonly higher. Successful spironolactone daily dose ranges for treatment of primary hyperaldosteronism have been reported at 12.5 mg to 100 mg, ³ , ⁴ 25 mg to 50 mg, ⁵ 25 mg to 200 mg, ⁶ 100 mg to 300 mg, ⁷ 50 mg to 400 mg, ⁸ and 100 mg to 400 mg. ⁹ Medical treatment of primary hyperaldosteronism due to adrenal adenoma has been reported using spironolactone 100 mg to 200 mg. ¹⁰ Usually, however, dosages >100 mg daily carry little additional impact on BP. ³

Spironolactone Monotherapy for Essential Hypertension: An Older Experience

Although more recent studies have used spironolactone 12.5 mg to 50 mg to treat hypertension resistant to 3 or 4 drugs, ¹ , ² older studies have used higher doses to treat essential hypertension. In 182 patients where secondary etiologies were excluded, there was a dose response for spironolactone monotherapy to 150 mg/d. ¹¹ However, dose‐related side effects limit the usage of this drug. Whereas gynecomastia occurs in 6.9% of men in doses up to 50 mg, gynecomastia occurs in 52.2% of men treated with 150 mg/d. ¹¹

Clinical Implications of BP Response to Spironolactone and Surgical Resection of Adrenal Adenoma and Unilateral Hyperplasia

Although BP reduction in response to spironolactone has been used to affirm a diagnosis of primary hyperaldosteronism, ¹² the current discussion indicates that this is clearly not the case. ¹ , ² , ³ , ⁴ In cases of confirmed primary hyperaldosteronism due to adrenal adenoma, BP reduction in response to spironolactone may indicate successful response to adenoma resection. ¹³ , ¹⁴ , ¹⁵ Conversely, the lack of response to spironolactone may indicate lack of significant BP reduction following adenoma resection. ¹⁴ However, spironolactone response has been observed to occur in the absence of BP reduction following adrenalectomy for unilateral adrenal hyperplasia. ¹⁵

Primary Hyperaldosteronism or Resistant Essential Hypertension?

Biochemical characteristics of primary hyperaldosteronism including relative hypernatremia with serum sodium >142 mEq/L and mild metabolic alkalosis with serum bicarbonate >31 mEq/L were noted in this case. ⁹ An elevated serum glucose level was also observed and occurs in approximately 25% of patients with primary hyperaldosteronism. ⁹ Hypokalemia occurs in fewer than 50% of primary hyperaldosteronism cases, ⁵ in 5% to 17% of patients with bilateral adrenal hyperplasia, and 50% to 74% with adrenal adenoma. ¹⁶ The list of secondary hypertension etiologies occurring with hypokalemia, which includes pheochromocytoma, Cushing’s syndrome, and Liddle’s syndrome, was excluded for this patient. However, the severity of hypokalemia in this case, requiring potassium 100 mEq/d, in the absence of other etiologies, was suggestive of primary hyperaldosteronism.

An extremely high aldosterone/renin ratio (ARR) also suggested a diagnosis of primary hyperaldosteronism. Although an ARR >20 is commonly used as a cutoff, ⁵ the Endocrine Society uses a “common” ARR threshold >30 and an upper limit >40 as suggestive of primary hyperaldosteronism, recommending confirmatory testing. ¹⁷ However, serum and urine aldosterone levels for this patient were in the high normal range despite potassium replacement, and this finding was surprising given the large potassium replacement requirement. Several authors indicate that a serum aldosterone level should be at least 15 ng/dL in the presence of an elevated ARR in order to distinguish primary hyperaldosteronism from routine low renin essential hypertension. ⁵ , ¹⁸

This patient was taking lisinopril, which can lower aldosterone levels, but was also taking low‐dose HCTZ, which can increase aldosterone. Dihydropyridine calcium channel blockers may delay the diagnosis of primary aldosteronism by lowering aldosterone levels,¹⁹ but this individual experienced edema intolerance to these agents. The Table describes medications that may interfere with ARR. ¹⁷ This patient was not able to tolerate confirmatory testing with saline suppression, so that the diagnosis of primary hyperaldosteronism was highly likely, but not definitive.

Table.

 Medications That Interfere With the ARR

Medication	Aldosterone	Renin	ARR
ACE inhibitor	↓	↑↑	↓
ARB	↓	↑↑	↓
Thiazide	→↑	↑↑	↓
CCB	→↓	↑	↓
β‐Blocker	↓	↓↓	↑

Abbreviations: ACE, angiotensin‐converting enzyme; ARB, angiotensin receptor blocker; ARR, aldosterone/renin ratio; CCB, calcium channel blocker. ¹⁷

Spironolactone 50 mg Daily Can Be an Adequate Dose for Both Primary Hyperaldosteronism and Resistant Essential Hypertension

Although the spironolactone dose response ranges for primary hyperaldosteronism and resistant hypertension overlap, an incomplete response to 25 mg/d and a completely therapeutic response to 50 mg/d along with the biochemical workup suggest that this patient had primary hyperaldosteronism. Dosages up to 50 mg are generally well tolerated, as they were with this patient. Figure 2 describes the distribution of spironolactone doses used in a southern California Kaiser Permanente database of 685,704 adult patients with hypertension, including some with primary hyperaldosteronism. Figure 3 portrays a schematic overview of the overlap in dosing for these two conditions. A 50‐mg dose of spironolactone is on the high end of complete BP responders for resistant essential hypertension and in the middle range for complete responders with primary aldosteronism.

Figure 2.

 Distribution of spironolactone dosing for an adult hypertension population of 685,704 patients.

Figure 3.

 Schematic view of blood pressure response to increasing doses of spironolactone in two populations: resistant essential hypertension (green) and primary aldosteronism (blue).