Treatment Considerations With Aldosterone Receptor Antagonists

Authors

  • Domenic A. Sica MD,

    1. From the Division of Nephrology, Department of Medicine and Pharmacology, Clinical Pharmacology and Hypertension, Virginia Commonwealth University Health System, Richmond, VA;
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  • John M. Flack MD, MPH

    1. the Division of Translational Research and Clinical Epidemiology, Department of Medicine and Physiology, Wayne State University, School of Medicine, Detroit, MI
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Domenic A. Sica, MD, Division of Nephrology, Department of Medicine and Pharmacology, Clinical Pharmacology and Hypertension, Virginia Commonwealth University Health System, Richmond, VA 23298-0160
E-mail: dsica@airwaves.org

Two aldosterone receptor antagonists (ARAs) are in common use in the United States: spironolactone and eplerenone. Although both compounds are now generic, the price of generic eplerenone in most instances is considerably higher than the price of generic spironolactone. A third ARA, canrenone, is presently available outside the United States. Although spironolactone and eplerenone are comparably effective, structure/function relationships as well as metabolite/half-life considerations provide the basis for differentiating these drugs.

Spironolactone

Spironolactone was the first diuretic specifically engineered to oppose a renal transport process involved in sodium (Na+) handling. Beyond the issue of efficacy, one must consider three aspects when judging the risk/benefit ratio of spironolactone: (1) timing of effect, (2) duration of action, and (3) side effect profile. Spironolactone’s onset of action is characteristically slow, with a peak response rate that can occur ≥48 hours after the initial dose. This lag time most likely occurs because spironolactone, and more importantly its active metabolites (which have a long half-life), take several days to reach a steady state. The duration of the spironolactone effect may also substantially differ relative to natriuresis and antikaliuresis, with the latter often persisting for several days after its discontinuation. This observation probably also relates to the extended half-life of spironolactone’s metabolites. Structurally, spironolactone contains elements of the progesterone molecule and, as such, is not specific for the mineralocorticoid receptor. This explains its therapy-limiting progestogenic and antiandrogenic side effects (eg, gynecomastia, nipple tenderness, erectile dysfunction, and menstrual irregularities).1,2

Eplerenone

The development of eplerenone was the result of a search to find an ARA with more specificity for blocking the mineralocorticoid receptor without its accompanying sexual side effects. Eplerenone has up to a 500-fold lower affinity for androgen and progestin receptors than spironolactone, which translates into a several-fold decrease in the progestogenic and/or antiandrogenic adverse effects.2 Eplerenone has proven to be an effective antihypertensive compound3,4 and has an evidence-based specific indication for use in both the acute myocardial infarction patient with reduced systolic function and heart failure (HF).5

Hypertension

The greatest positive hypertension treatment experience with ARAs exists for spironolactone, which has been used with or without a thiazide diuretic in the treatment of essential hypertension and more recently as add-on therapy for resistant hypertension.6–10 Spironolactone lowers blood pressure (BP) similarly in hypertensive patients with and without primary aldosteronism, although a higher dose is required in those with primary aldosteronism.7 Preliminary evidence shows that spironolactone not only lowers BP but also reduces the apnea-hypopnea index in patients with resistant hypertension and sleep apnea.11 Eplerenone has similar blood pressure–reducing ability when compared head-to-head with spironolactone either in the treatment of essential hypertension or for hypertension associated with idiopathic hyperaldosteronism.12,13 However, the mg-for-mg BP-lowering effect of eplerenone is less than that of spironolactone. The magnitude of the BP reduction with 50 mg of spironolactone administered twice daily is comparable with that seen with eplerenone administered 200 mg twice daily or 400 mg once daily, and is 1.3 to 2 times greater than that seen with eplerenone administered 50 mg twice daily or 100 mg once daily.12

The add-on effect for BP reduction with spironolactone occurs within weeks, persists indefinitely, and occurs independent of ethnicity and urinary aldosterone excretion. When spironolactone (12.5–50 mg/d) was added to a regimen composed of a diuretic, an angiotensin-converting enzyme (ACE) inhibitor, or an angiotensin-receptor blocker (ARB), a mean decrease in BP of 21±20/10±14 mm Hg and 25±20/12±12 mm Hg was observed at 6 weeks and 6 months of therapy, respectively.7 The efficacy of aldosterone blockade in patients with resistant hypertension suggests that aldosterone excess (relative or absolute) is a common cause of resistant hypertension.7–10

With the resurgence of use of ARAs in the management of various forms of hypertension, a number of questions have arisen as to the safe and effective use of these compounds.14 The remainder of this piece addresses some of the most commonly posed questions in the use of these compounds.

Which Patient Will Benefit Most From ARA Therapy?

Clinical experience with spironolactone and eplerenone suggests that these compounds are particularly effective antihypertensive agents in patients with low-renin hypertension.3 There do not appear to be any sex-specific differences in response to these compounds. Spironolactone and eplerenone can be prescribed in combination with a kaliuretic diuretic to prevent hypokalemia and/or hypomagnesemia and at the same time obtain an additional hypotensive or natriuretic effect.15,16 Currently, spironolactone is used with increasing regularity in patients with resistant hypertension, with or without primary aldosteronism, who are receiving multidrug regimens that include a diuretic and any other of the several drug classes, eg, an ACE inhibitor, an ARB, and/or a calcium channel blocker.8–10 Neurohumoral screening with high plasma aldosterone values and suppressed plasma renin activity values are markers for likelihood of a therapeutic response but not the magnitude of response per se; however, the response to an ARA can still be significant even without fully suppressed plasma renin activity values and elevated plasma aldosterone values.17,18

What is the Optimal Dosing Frequency for an ARA?

Spironolactone is usually administered once a day. There is no specific pharmacokinetic reason for twice-daily dosing of spironolactone, and 1 dose per day is as effective as multiple doses per day in the treatment of hypertension.19,20 Considering the lengthy half-life of spironolactone (and its active metabolites) in patients with cirrhosis, the once-daily or alternate-day administration of spironolactone may be sufficient to produce the desired diuresis.21 If spironolactone therapy is deemed necessary for patients with renal failure, hyperkalemia can be a dose-limiting side effect. In patients with renal failure, spironolactone can be administered on alternate days to lessen exposure and the likelihood of hyperkalemia and, in so doing, a determination may be made as to the durability of the BP-lowering effect. In patients with hypertension, the initial starting dose of eplerenone is 50 mg/d. It is recommended that eplerenone be increased to 50 mg twice daily (and not 100 mg once daily) if BP is inadequately controlled with the starting dose, as the antihypertensive effect of eplerenone is somewhat greater when it is administered twice daily.12 This aspect of the response to eplerenone may relate to its lack of active metabolites as well as a relatively short duration of action.

Under What Circumstances Can ARAs Be Used as Effective Diuretics?

All ARAs are weak natriuretic agents when acutely administered to either normotensive or hypertensive patients. The natriuretic effect of these agents is greatest when aldosterone levels are high (primary or secondary hyperaldosteronism). This is particularly the case when spironolactone (eplerenone has not been similarly studied) is given to patients with cirrhosis and ascites or HF, circumstances in which secondary hyperaldosteronism is frequently present.22 Natriuretic effects with spironolactone are dose dependent and increase even as doses reach several hundred milligrams. The diuretic effect of spironolactone takes several days to maximize, which likely relates to the time needed for its metabolites to reach steady-state. Spironolactone is of some utility in patients with cirrhosis and ascites because an initial mild diuresis is sought, secondary hyperaldosteronism is characteristically present, and hypokalemia is detrimental.23 Spironolactone is a useful adjunct agent when given together with diuretics working at more proximal nephron locations, such as thiazide and/or loop diuretics, a process termed sequential nephron blockade.24 A final consideration with spironolactone is that once therapy is discontinued, its diuretic effect can sometimes persist for several days, which is likely related to the slow clearance of its active metabolites.

Does Eplerenone Have Any Active Metabolites and Is Its Metabolic Profile Clinically Pertinent?

Unlike spironolactone, no active metabolites have been identified for eplerenone. Eplerenone pharmacokinetics are not altered in a meaningful fashion in patients with chronic kidney disease, the elderly, or patients with hepatic dysfunction.25 The primary route of elimination for eplerenone is via cytochrome P450 (CYP) 3A4-mediated metabolism. Eplerenone does not, however, interfere with the metabolism of CYP3A4 substrates. Whereas spironolactone has a limited number of drug-drug interactions, eplerenone interacts with a number of medications. The metabolism of eplerenone can be slowed when coadministered with CYP3A4 inhibitors; thus, eplerenone should be administered with extreme caution (if at all) when potent inhibitors of the CYP3A4 system, such as ketoconazole and itraconazole, are being given. In that regard, the area under the curve (AUC) for eplerenone increases 5-fold when coadministered with ketoconazole. Less potent inhibitors of the CYP3A4 system, eg, erythromycin and verapamil, will double the AUC for eplerenone when coadministered long term. The starting dose of eplerenone should be empirically reduced from 50 mg/d to 25 mg/d when such inhibitors are coadministered.26 Of note, the drug-drug interaction with verapamil and eplerenone can be exploited in a manner such that less eplerenone needs to be given to achieve the same plasma concentration with an attendant cost savings for the otherwise costly eplerenone.

Do ARAs Have Any Effect on Magnesium Homeostasis?

Unlike other diuretics, eg, thiazide and loop diuretics, ARAs do not cause magnesium (Mg++) wasting, and they actually have been shown to increase total body Mg++ stores. The degree to which these compounds cause Mg++ retention is but a small fraction of the potassium (K+) retention they are capable of producing. The Mg++-sparing feature of these compounds is most evident when Mg++-wasting diuretics are used for volume control in patients with either cirrhosis or HF.27 Whereas this Mg++-sparing effect is of undefined significance in the patient with hypertension, it is a particularly useful feature in the patient with HF; therein the disease state–related increase in aldosterone activity often leads to hypomagnesemia and an increased likelihood of arrhythmias. Even at low doses (about 25 mg/d), spironolactone can noticeably increase both plasma and erythrocyte Mg++ and thus reduce the risk of ventricular and atrial premature beats and atrial fibrillation/flutter.16

Is There a Specific Level of Renal Function at Which an ARA Should Not Be Used?

Amiloride and triamterene block Na+ channels at the luminal membrane. For these drugs to work, they must be filtered and secreted to reach their renal locus of action. Accordingly, as renal failure advances, these compounds have progressively limited access to their site of action and are less and less effective. Alternatively, spironolactone works on the basolateral membrane of tubular cells and does not rely on glomerular filtration or secretion to gain exposure to its site of action; thus, unlike amiloride and triamterene, spironolactone can remain active even at fairly advanced stages of renal failure. Spironolactone can be carefully used in renal failure with appropriate laboratory monitoring of serum K+. The glomerular filtration rate (GFR) is an important determinant of whether and how spironolactone can be used.

For example, a patient with a GFR of 50 mL/min and a serum K+ value of 5 mEq/L would be likely to develop therapy-limiting hyperkalemia with spironolactone or eplerenone; however, a different patient with a GFR of 30 mL/min and a serum K+ value of 3.4 mEq/L could be cautiously treated with an ARA. The package insert for spironolactone does not specify a level of renal failure at which this compound is contraindicated; thus, spironolactone dosing in renal failure can be viewed as discretionary.

The package insert for eplerenone is more restrictive in its recommendations for use in the patient with renal failure.26 Eplerenone is contraindicated in all patients with a creatinine clearance of <30 mL/min or a serum K+ >5.5 mmol/L or in patients with type 2 diabetes with microalbuminuria and a creatinine clearance of <50 mL/min. The package insert for eplerenone implies that the level of renal function at which it is contraindicated is set at a point to avoid patients becoming routinely hyperkalemic with its use. The studies on which this contraindication was based were in type 2 diabetics with microalbuminuria and used a 200-mg dose of eplerenone with or without concurrent ACE inhibitor therapy.28 This is far from the routine dose of eplerenone, which is more typically in the 50- to 100-mg/d range;29 thus, this contraindication is needlessly cautious. Nevertheless, when spironolactone or eplerenone is used in the setting of decreased renal function, serum K+ values should be monitored more frequently than in the non–renal failure setting. Spironolactone- or eplerenone-treated patients with renal failure should be made aware of circumstances likely to independently increase their serum K+ (eg, volume contraction, nonsteroidal anti-inflammatory drug use, and an excessively high intake of K+ either in the diet or as supplements).

How Can Hyperkalemia With ARAs Be Best Avoided or Managed?

Spironolactone and eplerenone at doses of 25 mg and 50 mg, respectively, appear to be safe starting doses relative to the development of hyperkalemia as long as the background level of renal failure is not too severe. Typically, it takes 2 to 4 weeks to arrive at a stable state of K+ balance after beginning an ARA, which should be considered when serum K+ values are obtained during therapy. Serum K+ sampling should occur more regularly if an ARA is given in combination with either an ACE inhibitor or an ARB. The circumstances that most commonly disrupt K+ homeostasis after a steady state has been reached for ARA effect are marked by rapid volume loss (and a sudden reduction in GFR), eg, diarrhea or upper gastrointestinal illness. Under such circumstances, patients should discontinue ARA therapy until the intercurrent illness has resolved and K+ status has been re-evaluated.

Several treatment options are available to lessen the risk of clinically relevant hyperkalemia with ARA therapy. Dietary restriction of K+ should be instituted and K+ supplements reduced/discontinued and patients should be questioned about the use of salt substitutes (about 60 mmol of K+ chloride per teaspoon). Combining an ARA with a K+-losing diuretic may lower the baseline serum K+ value; however, K+-losing diuretics should be used only if diuretic-related volume losses do not reduce the GFR because this can significantly reduce urinary K+ excretion. The dose of each compound can also be empirically reduced in the hyperkalemic ARA-treated patient, or the same dose can be given on an alternate-day basis. It is unclear in the patient prone to hyperkalemia development with ARA therapy whether simply reducing the dose is sufficient to correct this tendency. If spironolactone therapy is the basis for hyperkalemia development, then an empiric switch to eplerenone can be considered based on eplerenone’s shorter half-life, however, head-to-head studies comparing equivalent doses of eplerenone and spironolactone for hyperkalemia risk are not available.

Generally speaking, clinicians should remain vigilant for the detection of hyperkalemia in patients taking ARAs with heparin, a commonly used agent in hospitalized settings that has antialdosterone effects; other RAS blockers such as ACE inhibitors and ARBs; and trimethoprim-sulfamethoxazole, an antibiotic associated with an almost 7-fold increase (adjusted odds ratio, 6.7; 95% confidence interval, 4.5–10.0) in hyperkalemia-related hospitalizations in older individuals.30

What Are the Most Common Non-Electrolyte Side Effects That Occur With ARAs?

The most common side effect with spironolactone is that of breast complaints, with a minimum of 10% of men noting breast tenderness at a dose of 50 mg/d. In general practice, this percentage is likely to be higher. An example of this is in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure–Lowering Arm (ASCOT-BPLA) where gynecomastia or breast discomfort was recorded as an adverse event secondary to spironolactone in 114 male participants and no women (overall 6%), resulting in discontinuation in 52 participants (3%; all men). This compares with a frequency of gynecomastia or breast discomfort of 0.6% among ASCOT-BPLA participants who did not receive spironolactone at any stage. In ASCOT, the recording of adverse events potentially relating to spironolactone was investigator-dependent; therefore, the true frequency of spironolactone-related adverse events is likely to have been underestimated.10

Breast symptoms can include a symmetric or asymmetric increase in size (occasionally unilateral), the development of nipple and/or breast tenderness, and/or the appearance of discrete breast masses. Prior studies have found that the breast changes with spironolactone are dose dependent, with a >50% incidence with spironolactone doses ≥150 mg. Gynecomastia is generally corrected on discontinuation of the drug; however, the time required for reversibility can be prolonged, particularly if gynecomastia is at an advanced stage. The nipple symptoms with spironolactone disappear before there is any reduction in breast size. Gynecomastia occurs much less frequently with eplerenone and it can be substituted for spironolactone in the patient with gynecomastia with the expectation that breast symptoms/structural change will remit over time.31

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