Sacubitril is a medication prescribed to manage chronic heart failure, a condition where the heart muscle cannot pump enough blood to meet the body’s demands. It is always administered as part of a fixed-dose combination drug paired with another established heart medication. This combined treatment targets neurohormonal pathways in a new way. The mechanism of Sacubitril involves inhibiting a naturally occurring enzyme, leading to a cascade of beneficial effects.
Defining Neprilysin and Its Role in the Body
Neprilysin (NEP) is a naturally occurring enzyme found throughout the body, including the kidneys, lungs, and heart tissue. Its normal function is to break down and inactivate various signaling peptides, which helps manage blood pressure and fluid balance. Among the peptides Neprilysin degrades are the Natriuretic Peptides (NPs), specifically Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP).
These NPs are released by the heart in response to muscle stretch, acting as the body’s protective counter-system against volume and pressure overload. They promote fluid excretion and blood vessel widening, working to reduce the strain on the heart. In heart failure, the body releases these protective peptides, but elevated Neprilysin activity rapidly degrades them. This limits their beneficial effect and contributes to worsening symptoms.
How Sacubitril Blocks Enzyme Activity
Sacubitril itself is not the active drug; it is a chemical precursor known as a prodrug. Once ingested, Sacubitril must be metabolized by the body through esterase enzymes into its pharmacologically active form, Sacubitrilat. This conversion is rapid and ensures the therapeutic agent is available to target the enzyme.
Sacubitrilat functions as a potent and highly selective Neprilysin Inhibitor (NEPi). It achieves its effect by binding to the active site of the Neprilysin enzyme, effectively blocking the enzyme’s ability to cleave its substrates. The immediate biochemical consequence of this inhibition is an increase in the concentration of all peptides that Neprilysin normally breaks down. This blockade prevents the rapid metabolic clearance of the Natriuretic Peptides, allowing them to remain in circulation longer and at higher concentrations.
The Resulting Benefits for Heart Function
The primary physiological effect of inhibiting Neprilysin is the sustained elevation of Natriuretic Peptide levels, particularly ANP and BNP. These increased levels enhance the beneficial actions of the peptides on the cardiovascular and renal systems. They stimulate receptors that activate an intracellular messenger called cyclic guanosine monophosphate (cGMP), which mediates the protective effects.
One significant effect is enhanced natriuresis, the increased excretion of sodium and water by the kidneys. This process reduces overall fluid volume, which lowers blood pressure and decreases strain on the heart. The elevated NPs also promote systemic vasodilation, causing blood vessels to widen and lowering the resistance against which the heart must pump blood.
Natriuretic Peptides also counteract the long-term process of cardiac remodeling. They inhibit fibrosis, the buildup of scar tissue, and reduce hypertrophy, the abnormal thickening of the heart muscle. These actions help preserve the heart’s structure and function, alleviating symptoms like fluid retention and breathlessness.
Why Sacubitril Requires a Companion Drug
The design of Sacubitril’s therapy as a combination medication is rooted in the fact that Neprilysin degrades both beneficial and detrimental peptides. While inhibiting Neprilysin increases protective Natriuretic Peptides, it also causes a simultaneous rise in Angiotensin II. Angiotensin II is a potent vasoconstrictor that promotes fluid retention and cardiac remodeling, which would counteract the positive effects of the NPs if left unchecked.
Therefore, Sacubitril must be co-administered with an Angiotensin Receptor Blocker (ARB), specifically Valsartan. Valsartan works by directly blocking the AT1 receptor, the site where Angiotensin II exerts its harmful effects. This dual mechanism ensures the benefits of Neprilysin inhibition are fully realized while the negative effects of accumulating Angiotensin II are neutralized.
The combined drug strategy creates an Angiotensin Receptor-Neprilysin Inhibitor (ARNI). This provides a balanced approach to heart failure treatment by augmenting the protective natriuretic system and suppressing the harmful renin-angiotensin-aldosterone system.