Sacubitril

Sacubitril skeletal

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Sacubitril activation

Sacubitril synth process (corrected)

Sacubitril is a medication used in combination with valsartan to treat heart failure. It is specifically indicated for patients with chronic heart failure who have reduced ejection fraction, a measure of the percentage of blood leaving the heart each time it contracts. Sacubitril is classified as a neprilysin inhibitor. Neprilysin is an enzyme that breaks down natriuretic peptides, which are hormones that help to regulate blood pressure and fluid balance. By inhibiting neprilysin, sacubitril increases the levels of these peptides, leading to reduced blood pressure and decreased fluid overload, which are beneficial effects in heart failure management.

Mechanism of Action

Sacubitril does not directly lower blood pressure or improve heart function. Instead, it works by inhibiting the enzyme neprilysin, which is responsible for the degradation of natriuretic peptides such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). These peptides play a crucial role in cardiovascular homeostasis by promoting natriuresis (the excretion of sodium in urine), diuresis (increased urine production), and vasodilation (widening of blood vessels). The inhibition of neprilysin by sacubitril leads to increased levels of these peptides, thereby exerting beneficial effects in patients with heart failure.

Clinical Use

Sacubitril, in combination with valsartan (marketed under the brand name Entresto), is approved for the treatment of heart failure with reduced ejection fraction. Clinical trials have demonstrated that this combination is more effective in reducing the risk of cardiovascular death and hospitalization for heart failure than angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin II receptor blockers (ARBs) alone.

Side Effects

The most common side effects of sacubitril/valsartan include hypotension (low blood pressure), hyperkalemia (high potassium levels in the blood), and renal impairment. Patients may also experience dizziness, cough, and fatigue. Due to the risk of angioedema (swelling under the skin), sacubitril/valsartan is not recommended for patients with a history of angioedema related to previous therapy with ACE inhibitors or ARBs.

Contraindications

Sacubitril/valsartan is contraindicated in patients with a history of angioedema related to previous therapy with ACE inhibitors or ARBs. It is also contraindicated in patients with hypersensitivity to any component of the medication. Due to the risk of fetal harm, sacubitril/valsartan should not be used during pregnancy.

Pharmacokinetics

Sacubitril is administered orally. It is a prodrug that is converted to its active form, LBQ657, by esterases in the blood. The combination of sacubitril and valsartan has a synergistic effect, with valsartan blocking the effects of angiotensin II, a potent vasoconstrictor, and sacubitril enhancing the levels of natriuretic peptides.

Conclusion

Sacubitril, particularly when used in combination with valsartan, represents a significant advancement in the treatment of heart failure with reduced ejection fraction. By inhibiting neprilysin and enhancing the effects of natriuretic peptides, it offers a novel approach to managing this condition, with clinical trials demonstrating its superiority over traditional therapies in reducing cardiovascular death and hospitalization for heart failure.