NEPRIVAS 97/103

Indications

• Heart failure with reduced ejection fraction (HFrEF)
• Reduction of cardiovascular death and hospitalization in chronic heart failure patients

Dosage

Adults: The usual recommended dose of sacubitril/valsartan is 49 mg/51 mg taken twice daily. The dose

Mechanism of action

Sacubitril's active metabolite, LBQ657, inhibits neprilysin, a neutral endopeptidase that cleaves natriuretic peptides such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). By inhibiting neprilysin, sacubitril increases the concentrations of these peptides, which leads to vasodilation, natriuresis, and diuresis. Furthermore, when combined with valsartan, it also blocks the action of angiotensin II, resulting in decreased vascular resistance and blood pressure.

Pharmacodynamics

Clinical studies have demonstrated that sacubitril, especially in combination with valsartan, leads to significant increases in natriuresis and urine levels of cGMP. It has been shown to decrease plasma levels of NT-proBNP, aldosterone, and endothelin-1, indicating an overall beneficial effect on heart failure parameters. It has no significant effect on the QTc interval.

Pharmacokinetics

Sacubitril is rapidly converted to its active metabolite LBQ657, which is responsible for its therapeutic effects. It has a half-life of approximately 11 hours. The drug is metabolized primarily by hydrolysis and conjugation, and it is excreted mainly in the urine. The pharmacokinetics may be affected by renal function, necessitating dose adjustments in patients with significant renal impairment.

Contra-indications

• Hypersensitivity to sacubitril, valsartan or any of the excipients
• History of angioedema related to previous treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB)
• Concurrent use of ACE inhibitors
• Severe hepatic impairment
• Pregnancy

Adverse effects

• Hypotension
• Hyperkalemia
• Cough
• Dizziness
• Renal impairment
• Angioedema
• Fatigue

Interactions

• ACE inhibitors
• NSAIDs may reduce the antihypertensive effect
• Potassium-sparing diuretics may increase the risk of hyperkalemia
• Lithium levels may increase

Precautions

• Monitor renal function and potassium levels
• Use with caution in patients with a history of angioedema
• Adjust dose in patients with renal impairment
• Risk of hypotension in volume-depleted patients

Pregnancy

Contraindicated due to potential harm to the fetus.

Breast-feeding

Not recommended, as it is not known if sacubitril is excreted in human milk.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Tablets: 24 mg/26 mg, 49 mg/51 mg, 97 mg/103 mg (sacubitril/valsartan)

Indications

• Hypertension
• Heart failure
• Prevention of cardiovascular events in patients with established atherosclerotic cardiovascular disease

Dosage

Children: For neonates, 250–500 micrograms/kg every 8–12 hours, increased if necessary to 2–3

Adults: Initially 80 mg once daily, increased if necessary up to a maximum of 320 mg daily, based on clinical response.

Mechanism of action

Valsartan selectively binds to angiotensin receptor 1 (AT1), preventing angiotensin II from exerting its hypertensive effects, such as vasoconstriction and aldosterone secretion. This blockade results in reduced blood pressure, lower aldosterone levels, decreased cardiac activity, and increased sodium excretion. Additionally, valsartan modulates the renin-angiotensin-aldosterone system (RAAS), which is critical in cardiovascular and kidney function regulation.

Pharmacodynamics

Valsartan inhibits the hypertensive effects of angiotensin II, with an oral dose of 80 mg achieving approximately 80% inhibition of the pressor effect at peak, and about 30% inhibition persisting for 24 hours. It minimally affects plasma aldosterone levels and does not significantly alter total cholesterol, triglycerides, serum glucose, or uric acid levels. Hypotension is rare, but caution is advised in patients with an activated renin-angiotensin system, such as those on high-dose diuretics or with heart failure.

Pharmacokinetics

Valsartan is well absorbed after oral administration, with peak plasma concentrations occurring within 2 to 4 hours. It has an elimination half-life of approximately 6 hours, with a bioavailability of around 25% due to first-pass metabolism. Valsartan is primarily eliminated via the feces and to a lesser extent through urine, with renal impairment not significantly affecting its pharmacokinetics.

Contra-indications

• Biliary obstructive disorders
• Cholestasis

Adverse effects

• Anaemia
• Arrhythmias
• Chest pain
• Cystitis
• Depression
• Dyspnoea
• Flatulence
• Gastrointestinal disturbances
• Interstitial lung disease
• Liver disorder
• Pain in extremities
• Sepsis
• Taste alteration
• Tendon pain
• Visual impairment

Interactions

• Taxanes (unknown effect on exposure)

Precautions

• Caution in patients with heart failure
• Monitor for symptomatic hypotension in patients with activated renin-angiotensin system
• Adjust dose in hepatic impairment
• Initial lower doses in renal impairment

Pregnancy

Use only if potential benefit justifies potential risk to the fetus. Contraindicated in the second and third trimesters due to potential harm.

Breast-feeding

Not recommended due to potential adverse effects on the infant.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Valsartan 40 mg capsules
• Valsartan 80 mg capsules
• Oral suspension

Mechanism of action

Sacubitril's active metabolite, LBQ657 inhibits neprilysin, a neutral endopeptidase that would typically cleave natiuretic peptides, which includes: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and c-type natriuretic peptide (CNP). ANP and BNP are released under atrial and ventricle stress, which activate downstream receptors leading to vasodilation, natriuresis and diuresis. Under normal conditions, neprilysin breaks down other vasodilating peptides and also vasoconstrictors such as angiotensin I and II, endothelin-1 and peptide amyloid beta-protein. Therefore, the inhibition of neprilysin leads to reduced breakdown and increased concentration of endogenous natriuretic peptides in addition to increased levels of vasoconstricting hormones such as angiotensin II. (However, when combined with valsartan, would result in blocking of angiotensin II to its receptor, preventing the vasoconstrictive effects and resulting in a decrease in vascular resistance and blood pressure.) Cardiovascular and renal effects of sacubitril is a result of the increased levels of peptides that are normally degraded by neprilysin.

Pharmacodynamics

n a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of sacubitril + valsartan (Entresto) resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan. In a 21-day study in HFrEF patients, it significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1. In clinical studies, this combination had no effect on QTc interval.

Mechanism of action

Valsartan belongs to the angiotensin II receptor blocker (ARB) family of drugs, which selectively bind to angiotensin receptor 1 (AT1) and prevent angiotensin II from binding and exerting its hypertensive effects. These include vasoconstriction, stimulation and synthesis of aldosterone and ADH, cardiac stimulation, and renal reabsorption of sodium among others. Overall, valsartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium. Valsartan also affects the renin-angiotensin aldosterone system (RAAS), which plays an important role in hemostasis and regulation of kidney, vascular, and cardiac functions. Pharmacological blockade of RAAS via AT1 receptor blockade inhibits negative regulatory feedback within RAAS which is a contributing factor to the pathogenesis and progression of cardiovascular disease, heart failure, and renal disease. In particular, heart failure is associated with chronic activation of RAAS, leading to inappropriate fluid retention, vasoconstriction, and ultimately a further decline in left ventricular function. ARBs have been shown to have a protective effect on the heart by improving cardiac function, reducing afterload, increasing cardiac output and prevent ventricular hypertrophy. The angiotensin-converting enzyme inhibitor (ACEI) class of medications (which includes drugs such as [ramipril], [lisinopril], and [perindopril]) inhibits the conversion of angiotensin I to angiotensin II by inhibiting the ACE enzyme but does not prevent the formation of all angiotensin II. ARB activity is unique in that it blocks all angiotensin II activity, regardless of where or how it was synthesized. Valsartan is commonly used for the management of hypertension, heart failure, and type 2 diabetes-associated nephropathy, particularly in patients who are unable to tolerate ACE inhibitors. ARBs such as valsartan have been shown in a number of large-scale clinical outcomes trials to improve cardiovascular outcomes including reducing risk of myocardial infarction, stroke, the progression of heart failure, and hospitalization. Valsartan also slows the progression of diabetic nephropathy due to its renoprotective effects. Improvements in chronic kidney disease with valsartan include both clinically and statistically significant decreases in urinary albumin and protein excretion in patients diagnosed with type 2 diabetes and in nondiabetic patients diagnosed with chronic kidney disease. Valsartan also binds to the AT2 receptor, however AT2 is not known to be associated with cardiovascular homeostasis like AT1. Valsartan has about 20,000-fold higher affinity for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor. Valsartan, a nonpeptide tetrazole derivative, is an angiotensin II type 1 (AT1) receptor antagonist. Valsartan has pharmacologic actions similar to those of losartan; however, unlike losartan, valsartan is not a prodrug and its pharmacologic activity does not depend on hydrolysis in the liver. Valsartan blocks the physiologic actions of angiotensin II, including vasoconstrictor and aldosterone-secreting effects, by selectively inhibiting access of angiotensin II to AT1 receptors within many tissues, including vascular smooth muscle and the adrenal gland. By comparison, angiotensin-converting enzyme (ACE, kininase II) inhibitors block the conversion of angiotensin I to angiotensin II; however, the blockade of angiotensin II production by ACE inhibitors is not complete since the vasopressor hormone can be formed via other enzymes that are not blocked by ACE inhibitors. Because valsartan, unlike ACE inhibitors, does not inhibit ACE, the drug does not interfere with response to bradykinins and substance P; a beneficial consequence is the absence of certain ACE inhibitor-induced adverse effects (e.g., cough),

Pharmacodynamics

Valsartan inhibits the pressor effects of angiotensin II with oral doses of 80 mg inhibiting the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan. In multiple-dose studies in hypertensive patients, valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid. **Hypotension** Excessive hypotension was rarely seen (0.1%) in patients with uncomplicated hypertension treated with valsartan alone. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur. This condition should be corrected prior to administration of valsartan, or the treatment should start under close medical supervision. Caution should be observed when initiating therapy in patients with heart failure. Patients with heart failure given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. **Impaired Renal Function** Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on valsartan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on valsartan. **Hyperkalemia** Some patients with heart failure have developed increases in potassium. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of valsartan may be required.