Neprilysin inhibitors represent a class of medications developed to address various cardiovascular conditions. These drugs work by influencing the body’s natural systems that regulate blood pressure and fluid balance.
Understanding Neprilysin
Neprilysin is an enzyme present in the human body, also known as neutral endopeptidase. This enzyme plays a role in breaking down several beneficial peptides, including natriuretic peptides and bradykinin. Natriuretic peptides, such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), are hormones produced primarily by the heart in response to increased pressure or volume.
These peptides promote the excretion of sodium and water through the kidneys. They also cause blood vessels to widen, which helps to lower blood pressure. Bradykinin is another peptide degraded by neprilysin, known for its ability to relax and widen blood vessels, promoting healthy blood flow. By breaking down these substances, neprilysin contributes to the regulation of blood pressure, fluid balance, and overall cardiac function in a healthy individual.
How Neprilysin Inhibitors Function
Neprilysin inhibitors block neprilysin. This inhibition prevents the rapid breakdown of beneficial peptides, such as natriuretic peptides and bradykinin, allowing them to remain active in the body for longer periods. The prolonged presence of these peptides leads to several physiological effects that can be advantageous in certain medical conditions.
A significant effect is vasodilation (the widening of blood vessels). This occurs because natriuretic peptides and bradykinin can relax the smooth muscles in blood vessel walls, reducing resistance to blood flow and thereby lowering blood pressure. Additionally, the increased levels of natriuretic peptides enhance the kidneys’ ability to excrete sodium and water, reducing fluid retention. This process helps to alleviate congestion and lessen the workload on the heart.
Neprilysin inhibitors are often combined with other medications, such as angiotensin receptor blockers (ARBs), to enhance their therapeutic effects and manage potential counter-regulatory responses. For instance, neprilysin also breaks down angiotensin II, a peptide that can constrict blood vessels and increase blood pressure. Inhibiting neprilysin alone would lead to an increase in angiotensin II, which could counteract some of the desired benefits.
Combining a neprilysin inhibitor with an ARB like valsartan addresses this by blocking the harmful effects of angiotensin II while enhancing beneficial natriuretic peptides. This dual mechanism provides a more comprehensive approach to managing cardiovascular conditions by enhancing protective systems and mitigating detrimental ones. Sacubitril inhibits neprilysin, while valsartan directly blocks the angiotensin II type-1 receptor.
Conditions Treated with Neprilysin Inhibitors
Neprilysin inhibitors are primarily prescribed for the management of heart failure, particularly heart failure with reduced ejection fraction (HFrEF). HFrEF is a condition where the heart’s main pumping chamber, the left ventricle, cannot pump enough blood to meet the body’s needs. For patients with HFrEF, these inhibitors, often in combination with an angiotensin receptor blocker (ARNi), have demonstrated significant benefits.
Studies have shown that this combination can reduce the risk of cardiovascular death and hospitalization due to heart failure. Patients often experience improvements in symptoms, such as shortness of breath and fatigue, leading to an enhanced quality of life. The medication works by lessening the strain on the failing heart through vasodilation and reduced fluid overload.
Major medical guidelines recommend sacubitril-valsartan for symptomatic HFrEF patients to reduce morbidity and mortality. This recommendation applies to patients who are symptomatic despite treatment with other standard heart failure medications, and it can also be considered for those not previously treated with an ACE inhibitor or ARB. Beyond HFrEF, neprilysin inhibitors are also used to treat high blood pressure.
While heart failure remains the main approved indication, ongoing research explores other potential applications for neprilysin inhibitors. These investigations include examining their effects on various conditions. The broad role of neprilysin in various bodily functions suggests potential for future therapeutic developments, although current clinical application remains focused on cardiovascular health.
Important Considerations for Patients
Patients taking neprilysin inhibitors should be aware of potential side effects and important precautions. One common side effect is low blood pressure, also known as hypotension, which can cause dizziness or lightheadedness, particularly when standing up. This symptom may be more noticeable at the beginning of treatment but often lessens over about two weeks.
Changes in kidney function and elevated potassium levels in the blood (hyperkalemia) can also occur. Regular monitoring of kidney function and electrolyte levels is performed by healthcare providers to manage these potential effects. Another serious but less common side effect is angioedema, which involves swelling of the skin or underlying tissues, often in the face, lips, tongue, or throat.
Due to the increased risk of angioedema, neprilysin inhibitors should not be used in combination with ACE inhibitors. A washout period of at least 36 hours is necessary when switching from an ACE inhibitor to a neprilysin inhibitor combination. The medication is not recommended for individuals with a history of angioedema related to previous use of ACE inhibitors or angiotensin receptor blockers.
Pregnant individuals should avoid these medications as they can harm the developing fetus. Patients with certain kidney conditions may have contraindications due to increased risks of hypotension, hyperkalemia, and renal impairment. It remains important for patients to discuss their full medical history and all current medications with their healthcare professional to ensure personalized and safe management of their treatment.