Neprilysin is a naturally occurring enzyme that helps regulate several biological processes. A neprilysin inhibitor is a medication designed to block the action of this enzyme. The development of these inhibitors represents a newer approach in the management of heart failure. By blocking the neprilysin enzyme, these drugs help alleviate the strain on the heart and improve symptoms for patients with specific forms of chronic heart failure.
How Neprilysin Inhibitors Work
Neprilysin is a versatile enzyme known as a neutral endopeptidase, responsible for the breakdown of various peptides. Among the substances it degrades are natriuretic peptides, beneficial hormones produced by the heart and blood vessels. These peptides play a positive role in cardiovascular health by helping relax blood vessels, which can lower blood pressure and reduce the effort the heart must exert to pump blood.
Natriuretic peptides also promote natriuresis and diuresis, the processes of excreting sodium and water through the kidneys. This fluid removal decreases the overall volume of circulating blood, further reducing the workload on a strained heart. In a person with heart failure, the body produces more of these peptides to counteract the disease’s effects, but neprilysin continues to break them down, limiting their benefits.
A neprilysin inhibitor functions by blocking the active site of the neprilysin enzyme. This action prevents the enzyme from degrading natriuretic peptides. As a result, the levels of these beneficial peptides increase and can remain active in the body for longer. This amplification of their natural effects—vasodilation, sodium excretion, and reduced cardiac stress—is the primary mechanism by which these medications assist in managing heart failure.
Medical Uses for Neprilysin Inhibitors
The primary clinical use for neprilysin inhibitors is treating a specific form of chronic heart failure known as heart failure with reduced ejection fraction (HFrEF). HFrEF occurs when the heart’s main pumping chamber, the left ventricle, is weakened and unable to contract effectively. Consequently, the ventricle pumps out a smaller percentage of blood than a healthy heart with each beat.
For patients with this condition, a combination drug containing a neprilysin inhibitor has shown significant benefits in clinical studies. The landmark PARADIGM-HF trial showed that sacubitril/valsartan led to a notable reduction in cardiovascular death and hospitalization for heart failure compared to standard treatment. This medication is now recommended as a primary therapy for eligible patients with symptomatic HFrEF.
The use of this medication helps improve symptoms and enhance the quality of life for many individuals with this type of heart failure. By addressing underlying neurohormonal imbalances that drive the progression of HFrEF, these drugs offer a targeted approach to treatment.
The Combined Medication Approach
Neprilysin inhibitors are not administered as standalone drugs; they are always combined with an angiotensin II receptor blocker (ARB). This combined formulation, an angiotensin receptor-neprilysin inhibitor (ARNI), is necessary because of neprilysin’s broad activity. In addition to breaking down beneficial natriuretic peptides, neprilysin also degrades a substance called angiotensin II.
Angiotensin II is a peptide with detrimental effects on the cardiovascular system, particularly in heart failure. It causes blood vessels to constrict, which raises blood pressure, and promotes changes in the heart that can worsen its function over time. If a neprilysin inhibitor were used alone, it would block the breakdown of both natriuretic peptides and angiotensin II, leading to an accumulation of both.
The ARB component of the medication counteracts this issue. It selectively blocks the AT1 receptors, which are the sites where angiotensin II exerts its negative effects. This action prevents the increased levels of angiotensin II from causing vasoconstriction and other damage, allowing the beneficial effects of increased natriuretic peptides to prevail.
Potential Side Effects and Considerations
While effective, neprilysin inhibitor therapy has potential side effects that require patient monitoring. The most common adverse effects include low blood pressure (hypotension), which can cause dizziness, elevated blood potassium (hyperkalemia), and potential changes in kidney function. All of these necessitate regular blood tests.
A less common risk associated with this medication is angioedema. This is a serious condition characterized by swelling of the deep layers of skin, including the lips, face, and throat, which can obstruct breathing. The risk is linked to the accumulation of another substance that neprilysin breaks down, called bradykinin.
Due to this risk, neprilysin inhibitors must not be used concurrently with angiotensin-converting enzyme (ACE) inhibitors. Taking both drugs together or in close succession substantially increases the risk of developing life-threatening angioedema. For safety, a washout period of at least 36 hours is required when switching from an ACE inhibitor to a neprilysin inhibitor.