Managing Side Effects of Mineralocorticoid Receptor Antagonists in Hypertension and Kidney Disease

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• Hyperkalemia Risk with MRAs
• Spironolactone Metabolites and Kidney Disease
• Managing High Potassium Levels
• Estrogenic Side Effects of MRAs
• High Dose Considerations in Special Conditions
• New Drug Finerenone for Kidney Disease
• Full Transcript

Hyperkalemia Risk with MRAs

Mineralocorticoid receptor antagonists (MRAs) like spironolactone and eplerenone carry a significant risk of causing hyperkalemia, or high potassium levels in the blood. Dr. David Ellison, MD, emphasizes that this is the primary concern with these medications. The risk is substantially increased when these drugs are given to patients with pre-existing kidney disease. Hyperkalemia risk is also amplified when MRAs are combined with ACE inhibitors or angiotensin receptor blockers (ARBs), common medications for heart and kidney conditions.

Spironolactone Metabolites and Kidney Disease

Dr. David Ellison, MD, clarifies a critical pharmacological difference between spironolactone and eplerenone. The active inhibitors of the mineralocorticoid receptor are not spironolactone itself but its metabolites. In patients with normal kidney function, these metabolites do not accumulate to problematic levels. However, in patients with kidney disease, these metabolites can build up to high concentrations. This accumulation leads to a potent and prolonged blockade of the receptor.

Dr. David Ellison, MD, explains that this metabolite buildup makes hyperkalemia particularly difficult to treat in kidney disease patients on spironolactone. The hyperkalemic effect can persist for up to a week because the active metabolites remain in the system. This prolonged activity is not an issue with eplerenone, which is why it is theoretically a safer choice, though it may be slightly less effective in some clinical scenarios.

Managing High Potassium Levels

When a patient on an MRA develops hyperkalemia, the goal is to manage the potassium level while continuing the beneficial drug therapy. Dr. David Ellison, MD, outlines several clinical strategies. One approach is to increase the dose of loop diuretics if the patient is volume overloaded, as these drugs promote potassium excretion. Another modern strategy involves the use of new oral potassium binder medications.

These potassium binders work in the gut to prevent the absorption of dietary potassium into the bloodstream. Dr. David Ellison, MD, notes that using these binders allows physicians to continue spironolactone or eplerenone therapy while preventing the development of severe, dangerous hyperkalemia, particularly in high-risk heart failure and kidney failure populations.

Estrogenic Side Effects of MRAs

Beyond hyperkalemia, mineralocorticoid receptor antagonists can cause estrogenic side effects due to the structural similarities between steroid hormones. Dr. David Ellison, MD, highlights that spironolactone can bind to estrogen receptors, leading to complications like gynecomastia (breast enlargement in men) and menstrual irregularities in women. These side effects can be quite bothersome for patients and affect medication adherence.

These estrogenic effects are dose-dependent. They are less common at the lower doses (25-50 mg) typically used for heart failure but become more frequent at higher doses. Importantly, Dr. Ellison points out that eplerenone is a more specific mineralocorticoid receptor blocker and does not cause these estrogenic side effects, representing a key clinical advantage for affected patients.

High Dose Considerations in Special Conditions

Dr. David Ellison, MD, discusses specific patient populations that often require much higher doses of MRAs, which increases the likelihood of side effects. Patients with primary aldosteronism, a condition of adrenal hormone overproduction, often need high-dose spironolactone therapy. Similarly, patients with liver cirrhosis who develop ascites and edema also have high aldosterone levels and frequently require spironolactone doses of 100-200 mg per day or more.

At these high doses, the estrogenic side effects of gynecomastia and menstrual irregularities become very common and can be particularly troubling for patients. This presents a significant clinical challenge, balancing the undeniable benefits of aldosterone blockade in these conditions against the impact of these adverse effects on a patient's quality of life.

New Drug Finerenone for Kidney Disease

Dr. David Ellison, MD, introduces finerenone, a novel non-steroidal mineralocorticoid receptor antagonist approved by the FDA within the last two years. Finerenone was specifically developed and approved to slow the progression of chronic kidney disease (CKD), particularly diabetic kidney disease. This represents an emerging and important new indication for aldosterone blockade therapy beyond hypertension and heart failure.

Early evidence suggests that finerenone may be less likely to cause hyperkalemia than spironolactone, though Dr. Ellison cautions that direct head-to-head comparison studies are not yet available. The advent of finerenone provides clinicians with another valuable tool for managing CKD while potentially mitigating the classic side effect profile associated with older MRAs.

Full Transcript

Dr. David Ellison, MD: For spironolactone, eplerenone, or the mineralocorticoid receptor antagonists, completely different side effects. First of all, these drugs can cause hyperkalemia. If you give them to patients with kidney disease, or who are also on ACE inhibitors or angiotensin receptor blockers, hyperkalemia is pretty common. This is really the bugaboo of these drugs.

One point to make about spironolactone is that it's actually not the spironolactone itself that's the major inhibitor of mineralocorticoid receptors. It's metabolites of spironolactone. In people with normal kidney function, those metabolites don't build up very much. But in a patient with kidney disease, those metabolites can accumulate to high levels.

If you have a patient with kidney disease who's on spironolactone and gets hyperkalemic, that hyperkalemia can be very difficult to treat. It can last for even up to a week, because those metabolic byproducts of the spironolactone are hanging around and still inhibiting the mineralocorticoid receptor. That doesn't occur with eplerenone.

Theoretically, that would make eplerenone a better drug. But it seems like eplerenone is a little less effective in many situations, so many people still tend to use spironolactone.

In terms of the hyperkalemia, this is a big problem, as I mentioned, in the heart failure patient population and also in patients with kidney failure. But I mentioned that we also think these drugs, mineralocorticoid blockers, have other beneficial effects throughout the body. So the goal would be to try and continue these drugs.

But what if a patient develops hyperkalemia? What should you do? One thing we do is push doses of loop diuretics if we think the patient is volume overloaded, because those tend to make you excrete potassium. The other is there are a couple of new classes of potassium binding drugs. People take these oral potassium binders, and there are two of these that people can take that bind the potassium in the gut, so you don't absorb the potassium into your bloodstream.

Many people will use those drugs to try and continue the spironolactone and prevent the development of severe hyperkalemia.

Another really important side effect of the mineralocorticoid receptor blockers that needs to be mentioned is that they do have estrogenic side effects. Because estrogen is a steroid hormone, aldosterone is a steroid hormone; there's some cross binding.

People who take spironolactone can get gynecomastia and menstrual irregularities. This can be quite bothersome to patients. The side effects are not as common using the smaller doses that we use in patients with heart failure, typically 25 to 50 milligrams, but they do occur.

These do not occur with eplerenone, which is a more specific mineralocorticoid receptor blocker. But again, because spironolactone has a lot of evidence in favor of it, people will often turn to spironolactone as the first-line diuretic drug.

That said, when you have a patient with primary aldosteronism, and we haven't talked too much about the situation of cirrhosis of the liver, but patients who develop cirrhosis and ascites and edema with cirrhosis have very high aldosterone levels too.

For patients with primary aldosteronism or cirrhotic ascites, many times we have to use very high doses of spironolactone up to 100-200 or more milligrams a day. Then you see the side effects of the gynecomastia and the menstrual irregularities very commonly, and these side effects can be quite troubling.

So that's only true for those mineralocorticoid receptor blocking drugs, and especially spironolactone.

I should mention there's a brand new mineralocorticoid receptor drug called finerenone. It was just approved by the FDA within the last two years. Finerenone is being marketed because it was shown to slow the rate of progression of chronic kidney disease.

This is another approach to therapy of patients with chronic kidney disease and diabetic kidney disease that really appears to be beneficial. There's some evidence that finerenone is less likely to cause hyperkalemia than spironolactone, although there have been no head-to-head comparisons.

Finerenone was approved to prevent the progression or to slow the progression of chronic kidney disease. That's another indication for these diuretics that we haven't talked about yet. I would say it's an emerging indication for aldosterone blockade.