eMedicine Specialties > Endocrinology > Adrenal Gland

Hyperaldosteronism, Primary: Treatment & Medication

Author: Gabriel I Uwaifo, MBBS, Clinical and Research Attending, Assistant Professor of Medicine and Endocrinology, MedStar Clinical Research Center, MedStar Research Institute and Washington Hospital Center
Coauthor(s): Nicholas J Sarlis, MBBS, MD, PhD, FACP, Medical Director, Department of Oncology-US Medical Affairs Department, Sanofi-Aventis Pharmaceuticals
Contributor Information and Disclosures

Updated: Sep 25, 2009

Treatment

Medical Care

Medical management is the treatment of choice for the IAH variant of primary hyperaldosteronism (PH).

Among the major goals of therapy are (1) normalization of blood pressure, (2) normalization of levels of serum potassium and other electrolytes, and (3) normalization of serum aldosterone levels. Evidence exists to show that chronic hyperaldosteronism in and of itself, in the absence of elevated blood pressure (eg, as occurs in secondary hyperaldosteronism), is associated with increased risk for cardiac injury, including ischemic and fibrotic injury. Furthermore, studies have shown that patients with PH are more likely to have left ventricular hypertrophy, stroke, and acute coronary syndromes than are patients with similar degrees of hypertension from other causes.

In patients with heart failure who have secondary hyperaldosteronism, aldosterone antagonism by spironolactone and eplerenone has been demonstrated to confer survival benefit.21

  • By inhibiting the intracellular calcium flux in the adrenocortical cells, the dihydropyridine calcium channel blockers reduce the production of aldosterone in response to a variety of stimulants, including potassium, ACTH, and angiotensin-II. Nifedipine is the most extensively studied of these medications; however, although nifedipine causes a significant improvement in patients with hypertension, it does not address the pathophysiology of the condition. The PRA, aldosterone levels, plasma volume, and serum potassium concentrations remain essentially unchanged while using nifedipine.
  • ACE inhibitors and angiotensin receptor blockers are also potential treatment options.
  • Mineralocorticoid antagonists, such as spironolactone, achieve remarkable blood pressure control and normalization of the above-mentioned parameters, particularly in patients with aldosteronomas. The salutary effects of spironolactone appear to be due mainly to its impact on salt and water balance rather than to its antagonism of aldosterone in the kidney. The combination of spironolactone and thiazides often provides even better blood pressure control than does spironolactone alone. Because of the estrogenlike adverse effects of spironolactone, including impotence and gynecomastia, the incentive to develop a similarly effective antialdosterone agent without these adverse effects is considerable. Eplerenone is a selective antialdosterone agent that may fulfill this promise, because it is a specific aldosterone receptor antagonist without the additional antiandrogen effects associated with spironolactone.
  • Less ideal medical treatment options include other potassium-sparing diuretics, such as triamterene and amiloride. Amiloride acts at the level of the distal convoluted tubule (DCT) but does not bind to mineralocorticoid receptors.
  • Medical therapy is also a viable treatment option in patients who have lateralizable disease but who are poor surgical candidates because of other coexisting comorbidities. It is also a viable treatment option in the rare setting of bilateral functional adrenal adenomas that would otherwise require bilateral adrenalectomy.
  • In the subgroup of patients with GRA, the treatment of choice is the administration of the lowest possible dose of glucocorticoid that can be used to achieve adequate blood pressure control. Because of the potential adverse effects that can result from even subtle glucocorticoid excess, using short-acting glucocorticoids, such as prednisone and hydrocortisone (rather than dexamethasone), is generally best.

Surgical Care

Surgery is the treatment of choice for the lateralizable variants of primary hyperaldosteronism (PH), including typical aldosteronomas, RRAs, and PAH.22

  • Preoperatively, once the biochemical and anatomical diagnoses are made and confirmed, the patient should be started on a 3- to 5-week course of spironolactone. This serves as an additional diagnostic tool (in confirming the diagnosis of PH) and as a means of predicting the blood pressure response that can be expected postsurgery.
  • An adrenalectomy can be performed via a formal laparotomy or by using a laparoscopic technique (with performance of the latter becoming increasingly common). The laparoscopic option now makes it possible to offer surgical therapy to relatively frail patients who would be unable to withstand a formal laparotomy. Ongoing studies are systematically evaluating the place of adrenal-conserving operations versus total unilateral adrenalectomy in these patients.23
    • Among the options being studied are (1) partial adrenalectomy, in which a wedge resection of the gland with the adenoma is performed along with aldosteronoma enucleation, and (2) medulla-sparing adrenalectomy, in which an attempt is made to retain the adrenal medullary tissue while removing the cortex.
    • About 60-70% of patients are rendered normotensive following curative surgery for aldosteronomas when evaluated 1 year postoperatively. The percentage of patients who remain normotensive 5 years postoperatively is about 53%. The resolution of hypertension (HTN) following adrenalectomy invariably occurs in the setting of a family history in which hypertension is absent, and/or the preoperative use of 2 or fewer antihypertensives. Following surgery, however, virtually all patients with an aldosteronoma have significant reductions in aldosterone secretion and blood pressure and also demonstrate a correction of hypokalemia.24,25,26
    • Adrenalectomy has very little utility in the setting of IAH. In reported cases in which this had been done unintentionally, the effects on blood pressure, hypokalemia, and aldosterone hypersecretion were minimal, further underpinning the necessity of making a correct diagnosis before making a case for adrenalectomy.
  • Persistence of HTN following apparent surgical treatment of lateralizable disease is most common in patients older than 45 years, in those who had HTN for more than 5 years prior to surgery, and in persons who did not respond preoperatively to spironolactone.24,25
  • Other possibilities to consider are an incomplete resection of the adenoma with remaining remnant hyperplastic tissue or the possibility that the patient may have coexistent essential HTN (which is a prevalent condition). The coexistence of hypertensive nephrosclerosis in some of these patients is also a distinct possibility. The coexistence of other secondary causes of HTN also needs to be considered; renal artery stenosis is an important consideration.
  • Prior to surgery, patients should receive at least 8-10 weeks of medical therapy in order to decrease blood pressure and to correct the metabolic syndromes that are often associated with PH. Postoperatively, metabolic profiles should be closely monitored. Most patients do not develop permanent hypomineralocorticoidism and therefore do not require fludrocortisone replacement.
  • For patients who develop hypoaldosteronism, the symptoms may persist for a long time and may be akin to the delay observed in adrenal glucocorticoid recovery following chronic ACTH suppression by exogenous steroids (see image below and Image 3). However, if significant hyperkalemia develops, potassium supplements should be discontinued, and the patient can be started on furosemide at doses of 80-160 mg daily.
  • A few reports of the use of percutaneous injection of ethanol or acetic acid into aldosteronomas as a treatment modality exist; in these cases, the treatment was usually administered to patients for whom surgery was contraindicated.27 This technique is neither popular nor well validated. Furthermore, it requires the technical expertise of a highly skilled interventional radiologist.
Transitional zone adrenocortical steroids.

Transitional zone adrenocortical steroids.

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Transitional zone adrenocortical steroids.

Transitional zone adrenocortical steroids.


Diet

  • A low-salt diet, although helpful in achieving blood pressure control in primary hyperaldosteronism, may be associated with false-negative results on biochemical testing.
  • A high-salt diet makes the achievement of blood pressure control more difficult and may cause false-positive results on biochemical testing.

Medication

In nonsurgical primary hyperaldosteronism (PH), medical therapy is the treatment of choice. The drug that is the treatment of first choice for most variants of nonsurgical PH is spironolactone, which is used to achieve normoaldosteronism and to assist with blood pressure control. In patients who are unable to tolerate spironolactone, other potassium-sparing diuretics, such as amiloride and triamterene, can be used.21

GRA is treated with small doses of glucocorticosteroids (ie, hydrocortisone, prednisone). At optimal doses, glucocorticosteroids normalize aldosterone and blood pressure.

Various antihypertensives may be added to achieve adequate blood pressure control. The dihydropyridine calcium channel blockers (eg, nifedipine) directly inhibit aldosterone production; however, while producing significant improvement in patients with hypertension, they do not address pathophysiology. PRA, aldosterone levels, plasma volume, and serum potassium concentrations remain essentially unchanged, despite nifedipine use.

Aldosterone antagonists

These agents compete with aldosterone receptor sites, reducing edema and ascites.


Spironolactone (Aldactone)

Competitively binds receptors at aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Increased excretion of sodium and water, while retaining potassium. Provides diuretic and antihypertensive effects. Administered alone or with other diuretic agent that acts on proximal renal tubule.

Adult

25-200 mg/d PO in single or divided doses

Pediatric

3.3 mg/kg PO qd or divided q6-12h

Administration of ACE inhibitors, potassium, ACTH, or corticosteroids may cause hyperkalemia; potentiation of orthostatic hypotension may occur with alcohol, barbiturates, or narcotics; reduces vascular responsiveness to pressor amines (eg, norepinephrine); caution with regional or general anesthesia; increased responsiveness to nondepolarizing skeletal muscle relaxants (eg, tubocurarine) may occur; diuretic agents reduce renal clearance of lithium; coadministration of NSAIDs may cause hyperkalemia; may increase serum digoxin levels (monitor and adjust dose accordingly)

Documented hypersensitivity; anuria; acute renal insufficiency; severe renal dysfunction; hyperkalemia

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hepatic or renal insufficiency; may cause dilutional hyponatremia, mild acidosis, and gynecomastia; advise patients to avoid potassium supplements and foods containing high levels of potassium, including salt substitutes


Eplerenone (INSPRA)

Selectively blocks aldosterone at the mineralocorticoid receptors in epithelial (eg, kidney) and nonepithelial (eg, heart, blood vessels, brain) tissues, thus decreasing blood pressure and sodium reabsorption.

Adult

50 mg PO qd; may increase dose after 4 wk, not to exceed 100 mg/d

Pediatric

Not established

CYP450 3A4 substrate; potent CYP3A4 inhibitors (eg, ketoconazole) increase serum levels about 5-fold, less potent CYP3A4 inhibitors (eg, erythromycin, saquinavir, verapamil, fluconazole) increase serum levels about 2-fold; grapefruit juice increases serum levels about 25%; coadministration with potassium supplements, salt substitutes, or drugs known to increase serum potassium level (eg, amiloride, spironolactone, triamterene, ACE inhibitors, angiotensin II inhibitors) increases risk of hyperkalemia

Documented hypersensitivity; hyperkalemia or coadministration with drugs causing increased potassium; type 2 diabetes with microalbuminuria; moderate to severe renal insufficiency (ie, CrCl <50 mL/min or serum creatinine level >2 mg/dL [males] or >1.8 mg/dL [females])

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause hyperkalemia, headache, or dizziness; caution with hepatic insufficiency

Potassium-sparing diuretics

These agents are used as second-line medication for the treatment of primary hyperaldosteronism (PH) due to nonlateralizing disease and/or lateralizing disease for which surgery is otherwise contraindicated or refused. They often must be used with other antihypertensives to achieve the best blood pressure control, because they are not potent antihypertensives.


Triamterene (Dyrenium)

Potassium-sparing diuretic with relatively weak natriuretic properties. Exerts diuretic effect on distal renal tubule to inhibit reabsorption of sodium in exchange for potassium and hydrogen. Increases sodium excretion and reduces excessive loss of potassium and hydrogen associated with hydrochlorothiazide. Not a competitive antagonist of mineralocorticoids, and potassium-conserving effect is observed in patients with Addison disease (ie, without aldosterone). Onset and duration of activity are similar to those of hydrochlorothiazide. No predictable antihypertensive effect demonstrated. Rapidly absorbed following oral administration. Peak plasma levels are achieved within 1 h of dosing. Primarily metabolized to sulfate conjugate of hydroxytriamterene. Plasma and urine levels of this metabolite greatly exceed triamterene levels.

Adult

100-300 mg PO qd

Pediatric

Not established

Coadministration with other potassium-conserving agents, (eg, spironolactone, amiloride HCl, other formulations containing triamterene) may significantly increase serum potassium levels; lithium should generally not be administered with diuretics because they reduce lithium renal clearance and add a high risk of lithium toxicity; acute renal failure has been reported in patients receiving indomethacin and formulations containing triamterene; administer nonsteroidal anti-inflammatory agents with caution (monitor serum potassium levels frequently); may interfere with measurement of quinidine

Documented hypersensitivity; elevated serum potassium levels (>5.5 mEq/L); impaired renal function (eg, anuria, acute and chronic renal insufficiency, significant renal impairment); diabetes (hyperkalemia has been reported in patients with diabetes with the use of potassium-conserving agents, even in the absence of apparent renal impairment; accordingly, avoid triamterene in patients with diabetes)

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Major adverse effects involve the CNS, as well as the GI, cardiovascular, renal, hematologic, and ophthalmic systems
GI effects (eg, jaundice [intrahepatic cholestatic jaundice], pancreatitis, nausea, appetite disturbance, taste alteration, vomiting, diarrhea, constipation, anorexia, gastric irritation, cramping)
CNS effects (eg, drowsiness, fatigue, insomnia, headache, dizziness, dry mouth, depression, anxiety, vertigo, restlessness, paresthesias)
Cardiovascular effects (eg, tachycardia, shortness of breath, chest pain, orthostatic hypotension [may be aggravated by alcohol, barbiturates, narcotics])
Renal effects (eg, acute renal failure, acute interstitial nephritis, renal stones composed of triamterene in association with other calculus materials, urine discoloration)
Hematologic effects (eg, leukopenia, agranulocytosis thrombocytopenia, aplastic anemia, hemolytic anemia, megaloblastosis)
Ophthalmic effects (eg, xanthopsia, transient blurred vision)
Hypersensitivity (eg, anaphylaxis, photosensitivity, rash, urticaria, purpura, necrotizing angiitis [vasculitis, cutaneous vasculitis], fever, respiratory distress [including pneumonitis])
Other effects (eg, muscle cramps and weakness, decreased sexual performance, sialadenitis)
If adverse reactions are moderate to severe, reduce or withdraw therapy; if hyperkalemia is suspected (warning signs include paresthesia, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, and shock), obtain ECG; monitoring serum potassium levels is important because mild hyperkalemia may not be associated with ECG changes; if administered in presence of diabetes, serum electrolyte levels must be monitored frequently
Avoid potassium-conserving therapy in severely ill patients in whom respiratory or metabolic acidosis may occur; acidosis may be associated with rapid elevations in serum potassium levels; frequent evaluations of acid/base balance and serum electrolytes are necessary; caution in patients with impaired hepatic function or progressive liver disease because minor alterations of fluid and electrolyte balance may precipitate hepatic coma; has been reported in renal stones in association with other calculus components; caution in patients with a history of renal lithiasis
Weak folic acid antagonist and may contribute to the appearance of megaloblastosis in instances in which folic acid stores are decreased; periodic blood counts are recommended


Amiloride (Midamor)

A pyrazine-carbonyl-guanidine unrelated chemically to other known antikaliuretic or diuretic agents. Potassium-conserving (antikaliuretic) drug that, compared with thiazide diuretics, possesses weak natriuretic, diuretic, and antihypertensive activity. Effects have been partially additive to effects of thiazide diuretics in some clinical studies. When administered with a thiazide or loop diuretic, shown to decrease the enhanced urinary excretion of magnesium that occurs when a thiazide or loop diuretic is used alone.
Amiloride has potassium-conserving activity in patients receiving kaliuretic-diuretic agents. Amiloride is not an aldosterone antagonist, and its effects are observed in the absence of aldosterone. Exerts potassium-sparing effect through inhibition of sodium reabsorption at distal convoluted tubule, cortical collecting tubule, and collecting duct; this decreases net negative potential of tubular lumen and reduces potassium and hydrogen secretion and their subsequent excretions.
Amiloride usually begins to act within 2 h after an oral dose. Effect on electrolyte excretion reaches a peak between 6-10 h and lasts about 24 h. Peak plasma levels are obtained in 3-4 h, and plasma half-life varies from 6-9 h. Not metabolized by liver; excreted unchanged by kidneys. About 50% of a dose of amiloride is excreted in urine and 40% in stool within 72 h. Has little effect on glomerular filtration rate or renal blood flow. Because liver does not metabolize amiloride HCl, drug accumulation is not anticipated in patients with hepatic dysfunction; however, accumulation can occur if hepatorenal syndrome develops.
Amiloride should rarely be used alone. Used as single agents, potassium-sparing diuretics, including amiloride, result in an increased risk of hyperkalemia (approximately 10% with amiloride). Should be used alone only when persistent hypokalemia has been documented and only with careful titration of the dose and close monitoring of serum electrolyte levels.

Adult

5-20 mg/d PO

Pediatric

Not established

Concomitant therapy with potassium supplementation in the form of medication, potassium-containing salt substitutes, or potassium-rich diet can be associated with rapid increases in serum potassium levels; if potassium supplementation is used, careful monitoring of the serum potassium level is necessary; risk of hyperkalemia may be increased when coadministered with an ACE inhibitor (if concomitant use of these agents is indicated because of demonstrated hypokalemia, use caution and frequently monitor serum potassium level); lithium generally should not be administered with diuretics because it may reduce renal clearance and add a high risk of lithium toxicity; indomethacin and potassium-sparing diuretics, including amiloride, may be associated with increased serum potassium levels, carcinogenicity, mutagenicity, and impairment of fertility; no evidence of tumorigenic effect when administered for 92 wk to mice at doses up to 10 mg/kg/d (25 times the maximum daily human dose); also administered for 104 wk to male and female rats at doses up to 6-8 mg/kg/d (15 and 20 times the maximum daily dose for humans, respectively) and showed no evidence of carcinogenicity; devoid of mutagenic activity in various strains of Salmonella typhimurium with or without a mammalian liver microsomal activation system (Ames test)

Documented hypersensitivity; elevated serum potassium levels (>5.5 mEq/L); patients receiving other potassium-conserving agents (eg, spironolactone, triamterene); potassium supplementation in the form of medication, potassium-containing salt substitutes, or a potassium-rich diet (except in severe and/or refractory cases of hypokalemia); impaired renal function, acute or chronic renal insufficiency, and evidence of diabetic nephropathy; carefully monitor serum electrolyte, creatinine, and BUN levels in patients with evidence of renal function impairment (BUN level >30 mg/dL or serum creatinine levels >1.5 mg/dL)

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Potassium retention associated with use of an antikaliuretic agent accentuated in presence of renal impairment and may result in rapid development of hyperkalemia; in patients with diabetes, hyperkalemia reported with use of all potassium-conserving diuretics, including amiloride, even in patients without evidence of diabetic nephropathy (if used, serum electrolyte levels and renal function must be monitored frequently); discontinue at least 3 d before glucose tolerance testing

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References
Further Reading
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Keywords

primary hyperaldosteronism, aldosteronism, hyperaldosteronism, hypertension, adrenal, adrenal hyperplasia, adrenal glands, adrenal adenoma, aldosterone, adrenal tumor, adrenal tumors, secondary hypertension, Conn's syndrome, hyperaldosteronism primary, autonomous hyperaldosteronism, primary adrenal hyperplasia, idiopathic adrenal hyperplasia, Conn syndrome, adrenal aldosteronoma, aldosteronoma, bilateral adrenal hyperplasia, renin responsive adenoma, RRA, aldosterone-producing renin-responsive adenomas, aldosterone-producing adenomas

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Contributor Information and Disclosures

Author

Gabriel I Uwaifo, MBBS, Clinical and Research Attending, Assistant Professor of Medicine and Endocrinology, MedStar Clinical Research Center, MedStar Research Institute and Washington Hospital Center
Gabriel I Uwaifo, MBBS is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Medical Association, American Society of Hypertension, and Endocrine Society
Disclosure: Nothing to disclose.

Coauthor(s)

Nicholas J Sarlis, MBBS, MD, PhD, FACP, Medical Director, Department of Oncology-US Medical Affairs Department, Sanofi-Aventis Pharmaceuticals
Nicholas J Sarlis, MBBS, MD, PhD, FACP is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Physicians, American Federation for Medical Research, American Head and Neck Society, American Medical Association, American Society for Therapeutic Radiology and Oncology, American Society of Clinical Oncology, American Thyroid Association, Association for Psychological Science, Endocrine Society, European Society for Medical Oncology, New York Academy of Sciences, and Royal Society of Medicine
Disclosure: Sanofi-Aventis Salary Employment

Medical Editor

Frederick H Ziel, MD, Associate Professor of Medicine, David Geffen School of Medicine at UCLA; Physician-In-Charge, Endocrinology/Diabetes Center, Director of Medical Education, Kaiser Permanente Woodland Hills; Chair of Endocrinology, Co-Chair of Diabetes Complete Care Program, Southern California Permanente Medical Group
Frederick H Ziel, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society for Bone and Mineral Research, California Medical Association, Endocrine Society, and International Society for Clinical Densitometry
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS, Professor of Medicine (Endocrinology, Adj), Johns Hopkins School of Medicine; Affiliate Research Professor, Bioinformatics and Computational Biology Program, School of Computational Sciences, George Mason University; Principal, C/A Informatics, LLC
Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Nutrition, American College of Physician Executives, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Informatics Association, American Society for Bone and Mineral Research, American Society of Law Medicine and Ethics, Endocrine Society, and International Society for Clinical Densitometry
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

 
 
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