Aldosterone antagonists: Uses, common brands, and safety info

Aldosterone antagonists (also called aldosterone receptor antagonists) are an underappreciated and underutilized class of medications. Considering they are useful for such common and critical illnesses as resistant hypertension (high blood pressure), congestive heart failure, and cirrhosis, it is surprising that they are relatively unknown. Over the course of this review, we will cover examples of aldosterone antagonists, their uses and advantages, as well as their adverse effects and costs.

What are aldosterone antagonists?

Aldosterone antagonists are oral medications that are taken once or twice a day. They function as diuretics, removing fluid from the blood by way of the kidneys, but this action is carried out without excessive potassium loss. By blocking the effects of the hormone aldosterone, these drugs can help a failing heart. And by blocking other androgen hormones, they can reduce acne. 

How do aldosterone antagonists work?

High blood pressure

The renin-angiotensin-aldosterone system is a series of bodily reactions that play a crucial role in blood pressure and fluid regulation. Our kidneys produce renin that breaks down angiotensinogen into angiotensin I, which is then converted to angiotensin II by angiotensin converting enzyme (ACE). Angiotensin II causes blood vessels to constrict and raise blood pressure and also triggers the adrenal glands to produce aldosterone, a hormone that among other things causes sodium and fluid reabsorption by the kidney, further raising blood pressure. The system presents multiple opportunities for pharmacologic intervention to alter it, including ACE inhibitors, angiotensin receptor blockers (ARBs), and aldosterone antagonists.

Heart failure and cirrhosis

Aldosterone antagonists block receptors for aldosterone. Aldosterone is a mineralocorticoid, which is a steroid hormone that regulates salt balance. The drug class is therefore also called mineralocorticoid receptor antagonists (MRAs). By blocking aldosterone effects within the kidney, these medications promote salt and water loss in the urine. Consequently, they are an effective diuretic in conditions such as heart failure and cirrhosis and an effective anti-hypertensive when combined with other medications. Their potassium-sparing effect can also be beneficial since harmful hypokalemia (low serum potassium levels) and resultant ventricular arrhythmias (heart rhythm problems) can be avoided. This characteristic puts them in stark contrast to other diuretics, like loop and thiazide varieties, which cause potassium loss and risk hypokalemia.

Heart disease

The effects of aldosterone antagonists in heart disease are more complex than simply being diuretics. The drugs only have a Food and Drug Administration (FDA) indication for severely symptomatic patients with systolic heart failure associated with a weakened heart, one with a low ejection fraction (percentage of blood volume pumped out with each heartbeat). The New York Heart Association (NYHA) symptom categories III and IV are included in the indication. Aldosterone seems to play a role in detrimental hypertrophy (enlargement) and fibrosis (scarring and stiffening) of these hearts. In fact, a clinical study called RALES found that spironolactone reduced serum markers of myocardial fibrosis and reduced mortality and hospitalization rates, compared to placebo (inactive pill), in patients with heart failure with reduced ejection fraction. Fibrosis can be quite problematic in the healing stages after an acute myocardial infarction (heart attack), so MRAs are used in some circumstances of heart failure after an acute myocardial infarction.

Primary hyperaldosteronism 

Aldosterone antagonists have another important medical niche. Primary hyperaldosteronism is a condition in which the adrenal glands overproduce aldosterone. This can naturally lead to hypertension and hypokalemia due to excess aldosterone. It is also associated with heightened risk of heart attacks and strokes, which may result from aldosterone effects on blood vessels like the coronary arteries. Aldosterone blockage is a vital therapy for primary hyperaldosteronism when adrenal surgery is not an option.

What are aldosterone antagonists used for?

• Congestive heart failureoff-label

• Hypertension

• Edema (swelling)

• Primary hyperaldosteronism

• Renal (kidney) and cardiovascular disease progression risk reduction in patients with Type 2 diabetes mellitus associated with chronic kidney disease

• Primary hirsutism (unexplained excess facial or bodily hair growth in females) (off-label)

• Acne

RELATED: Should I take spironolactone for acne?

Types of aldosterone antagonists

Non-specific aldosterone antagonists

Aldactone is the major brand name drug that functions as a non-specific mineralocorticoid receptor antagonist. The drug’s blockage of aldosterone receptors in the kidney, heart, and blood vessels explain its indications for heart failure, edema, hypertension, and primary hyperaldosteronism. 

The lack of specificity for these receptors can be a blessing or a curse. In addition to being an MRA, aldactone also blocks receptors of androgens (hormones that regulate male characteristics) and production of testosterone. This feature has led to off-label use of Aldactone for females with acne and hirsutism, two conditions driven in part by androgen effects. The anti-androgenic effect of spironolactone can contribute to Aldactone’s adverse events like impotence and loss of libido for men.

The hormonal effects of Aldactone extend even further, activating progesterone receptors. Unfortunately, the dose-dependent results of this activity can be breast tenderness and menstrual irregularities in women and gynecomastia (breast tissue growth) in men.

Carospir is another spironolactone, which, unlike Aldactone, has no generic alternative. It is a liquid formulation of the drug. Carospir is not bioequivalent to Aldactone, meaning the dosing is not identical. Carospir may require a low dose to get the same effectiveness.

Aldactazide combines the non-selective MRA aldactone with the thiazide diuretic hydrochlorothiazide. The complementary diuretic mechanisms of its two components make Aldactazide an option for hypertension or edema management.

Specific aldosterone antagonists

Inspra is an MRA with much higher specificity for blocking aldosterone receptors. The FDA indications for Inspra include heart failure with a reduced ejection fraction after a heart attack. The drug is also indicated for hypertension treatment, typically as an add-on therapy when other medications are not fully effective.

The lack of other hormonal effects by Inspra means that it is not used in cases of female acne or hirsutism. Likewise, it means that the drug typically does not cause gynecomastia, breast tenderness, and menstrual irregularities.

The lesser-known and used aldosterone receptor blocker is Kerendia. Like Inspra, it is specific in its hormonal activity, which limits its side benefits and adverse effects. However, it is also limited to a single, narrow FDA indication. Kerendia is prescribed to reduce the risk of progression of renal or cardiovascular disease in individuals with Type 2 diabetes mellitus and chronic kidney disease. A newly approved medication, Kerendia’s indication is based on a study in 2020 comparing patients randomized to the drug or placebo.

Who can take aldosterone antagonists?

Can men take aldosterone antagonists?

Men can take MRAs when indicated. They should be aware of their risk of gynecomastia, impotence, and loss of libido when prescribed Aldactone.

Can women take aldosterone antagonists?

Usage of aldosterone receptor blockers can be helpful for women with heart failure, hypertension, and edema. Unlike men, women could be prescribed Aldactone off-label for hirsutism and acne. They should understand the incidence of menstrual irregularities and breast pain with Aldactone.

Can you take aldosterone antagonists while pregnant or breastfeeding?

Due to the potential for detrimental effects, aldosterone antagonists are not recommended during pregnancy. Regarding breastfeeding, Aldactone is listed as compatible, although clinical trials of use in this situation are limited. Inspra has cautionary notes about use in breastfeeding due to the lack of available safety data. The manufacturer of Kerendia recommends against breastfeeding during and for one day after use of the drug.

Can children take aldosterone antagonists?

None of the MRAs have FDA approval for pediatric use. Aldactone is used off-label in some cases.

Can seniors take aldosterone antagonists?

Seniors can take aldosterone antagonists. The likelihood of longer medication lists and coinciding health problems makes drug interactions and contraindications more of a concern for seniors.

Are aldosterone antagonists safe?

Black box warnings

Spironolactone products have a black box warning from the FDA related to a finding of increased tumors in studies of rats. Aldactazide contains a second warning, stipulating that fixed-dose combination diuretic therapy is not the first choice for hypertension or edema therapy.

Recalls

• Spironolactone (March 2021)

Restrictions

The enthusiasm for avoiding potassium excretion by using aldosterone antagonists compared to other diuretics is markedly tempered by a risk of hyperkalemia (high serum potassium levels). Follow-up serum potassium tests are usually recommended, along with serum creatinine levels to monitor renal function. This is a more significant concern for certain patients, such as those with kidney disease or those taking other medications that increase serum potassium levels, such as ACE inhibitors, ARBs, and nonsteroidal anti-inflammatory drugs (NSAIDs). The concern regarding hyperkalemia has a large part in the following contraindications (reasons for not using) aldosterone antagonists:

• Hypersensitivity allergic reactions to the drug or drug class in the past

• Pre-existing hyperkalemia

• Addison’s disease (adrenal insufficiency)

• Renal (kidney) impairment—definitions of what severity constitutes a contraindication is MRA drug-specific and, in some cases, indication-specific

• Acute or severe hepatic (liver) impairment

• Hypercalcemia (high serum calcium levels) and sulfa allergy history with Aldactazide (related to hydrochlorothiazide component)

• Type 2 diabetes mellitus with microalbuminuria specifically contraindicates Inspra use for hypertension

Tell your healthcare provider if you have any of the conditions above before taking aldosterone antagonists.

Are aldosterone antagonists controlled substances?

The Drug Enforcement Administration (DEA) does not list MRAs as controlled substances.

Common aldosterone antagonists side effects

• Hyperkalemia

• Abnormal renal function markers (lower glomerular filtration rate and elevated serum creatinine level)

• Hypotension (low blood pressure)

• Fatigue, dizziness, or headache

• Diarrhea, nausea, vomiting, or abdominal pain

• Cough, fever, or flu-like symptoms

• Hyponatremia (low serum sodium level)

• Vaginal bleeding or menstrual irregularity

• Gynecomastia, breast pain, or sexual dysfunction

• Rash or itch

• Additional hydrochlorothiazide-related side effects with Aldactazide

How much do aldosterone antagonists cost?

Brand-name aldosterone antagonists, such as Aldactone and Inspra, can cost about $100 and $470 for a one-month supply. The generic versions, spironolactone, and eplerenone, are priced at about $18 and $140 respectively for the same supply. Signing up for a free SingleCare discount card and presenting it to your pharmacist can help you to save money on these drug expenses.