Current Drug Therapy

ACE inhibitors and ARBs: Managing potassium and renal function

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Release date: September 1, 2019
Expiration date: August 31, 2020
Estimated time of completion: 1 hour

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ABSTRACT

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are used primarily to treat hypertension and are also useful for conditions such as heart failure and chronic kidney disease, independent of their effect on blood pressure. This article reviews the indications for ACE inhibitors and ARBs and offers advice for managing their adverse effects, particularly declining renal function and hyperkalemia.

KEY POINTS

  • ACE inhibitors and ARBs reduce proteinuria by lowering the intraglomerular pressure, reducing hyperfiltration.
  • These drugs tend to raise the serum potassium level and reduce the glomerular filtration rate (GFR). Monitoring the serum potassium and creatinine levels and the GFR is therefore imperative.
  • Despite the benefits, concern for adverse effects including hyperkalemia and a rise in serum creatinine has led to reluctance to prescribe these drugs, and they are underused in the patients who may derive the greatest benefit.


 

References

A highly active, water- and alcohol-soluble, basic pressor substance is formed when renin and renin-activator interact, for which we suggest the name “angiotonin.”

—Irvine H. Page and O.M. Helmer, 1940.1

The renin-angiotensin-aldosterone system regulates salt and, in part, water homeostasis, and therefore blood pressure and fluid balance through its actions on the heart, kidneys, and blood vessels.2 Drugs that target this system—angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)—are used primarily to treat hypertension and also to treat chronic kidney disease and heart failure with reduced ejection fraction.

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Controlling blood pressure is important, as hypertension increases the risk of myocardial infarction, cerebrovascular events, and progression of chronic kidney disease, which itself is a risk factor for cardiovascular disease. However, the benefit of these drugs is only partly due to their effect on blood pressure. They also reduce proteinuria, which is a graded risk factor for progression of kidney disease as well as morbidity and death from vascular events.3

Despite the benefits of ACE inhibitors and ARBs, concern about their adverse effects—especially hyperkalemia and a decline in renal function—has led to their underuse in patients likely to derive the greatest benefit.3

ACE INHIBITORS AND ARBs

The renin-angiotensin-aldosterone system and drugs that inhibit it.

Figure 1. The renin-angiotensin-aldosterone system and drugs that inhibit it.

The renin-angiotensin-aldosterone system is activated when hypoperfusion to the glomerular afferent arteriole, reduced sodium delivery to the distal convoluted tubule, or increased sympathetic activity stimulates the renal juxtaglomerular apparatus to produce renin (Figure 1). This leads to a cascade of effects culminating in sodium retention and potassium excretion, thus increasing blood pressure.

ACE inhibitors, as their name indicates, inhibit conversion of angiotensin I to angiotensin II by ACE, resulting in vasodilation of the efferent arteriole and a drop in blood pressure. Inhibition of ACE, a kininase, also results in a rise in kinins. One of these, bradykinin, is associated with some of the side effects of this class of drugs such as cough, which affects 5% to 20% of patients.4 Elevation of bradykinin is also believed to account for ACE inhibitor-induced angioedema, an uncommon but potentially serious side effect. Kinins are also associated with desirable effects such as lowering blood pressure, increasing insulin sensitivity, and dilating blood vessels.

ARBs were developed as an alternative for patients unable to tolerate the adverse effects of ACE inhibitors. While ACE inhibitors reduce the activity of angiotensin II at both the AT1 and AT2 receptors, ARBs block only the AT1 receptors, thereby inhibiting their vasoconstricting activity on smooth muscle. ARBs also raise the levels of renin, angiotensin I, and angiotensin II as a result of feedback inhibition. Angiotensin II is associated with release of inflammatory mediators such as tumor necrosis factor alpha, cytokines, and chemokines, the consequences of which are also inhibited by ARBs, further preventing renal fibrosis and scarring from chronic inflammation.3

What is the evidence supporting the use of ACE inhibitors and ARBs?

ACE inhibitors and ARBs, used singly, reduce blood pressure and proteinuria, slow progression of kidney disease, and improve outcomes in patients who have heart failure, diabetes mellitus, or a history of myocardial infarction.5–11

While dual blockade with the combination of an ACE inhibitor and an ARB lowers blood pressure and proteinuria to a greater degree than monotherapy, dual blockade has been associated with higher rates of complications, including hyperkalemia.12–17

RISK FACTORS FOR HYPERKALEMIA

ACE inhibitors and ARBs raise potassium, especially when used in combination. Other risk factors for hyperkalemia include the following—and note that some of them are also indications for ACE inhibitors and ARBs:

Renal insufficiency. The kidneys are responsible for over 90% of potassium removal in healthy individuals,18,19 and the lower the GFR, the higher the risk of hyperkalemia.3,20,21

Heart failure

Diabetes mellitus6,21–23

Endogenous potassium load due to hemolysis, rhabdomyolysis, insulin deficiency, lactic acidosis, or gastrointestinal bleeding

Exogenous potassium load due to dietary consumption or blood products

Other medications, eg, sacubitril-valsartan, aldosterone antagonists, mineralocorticoid receptor antagonists, potassium-sparing diuretics, beta-adrenergic antagonists, nonsteroidal anti-inflammatory drugs, heparin, cyclosporine, trimethoprim, digoxin

Hypertension

Hypoaldosteronism (including type 4 renal tubular acidosis)

Addison disease

Advanced age

Lower body mass index.

Both hypokalemia and hyperkalemia are associated with a higher risk of death,20,21,24 but in patients with heart failure, the survival benefit from ACE inhibitors, ARBs, and mineralocorticoid receptor antagonists outweighs the risk of hyperkalemia.25–27 Weir and Rolfe28 concluded that patients with heart failure and chronic kidney disease are at greatest risk of hyperkalemia from renin-angiotensin-aldosterone system inhibition, but the increases in potassium levels are small (about 0.1 to 0.3 mmol/L) and unlikely to be clinically significant.

Hyperkalemia tends to recur. Einhorn et al20 found that nearly half of patients with chronic kidney disease who had an episode of hyperkalemia had 1 or more recurrent episodes within a year.

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