ANGIOTENSIN RECEPTOR NEPRYLISIN INHIBITORS (PPT) – Dr. Akif Baig

Angiotensin Receptor Neprilysin Inhibitors (ARNIs)

Introduction: Angiotensin Receptor Neprilysin Inhibitors (ARNIs) represent a novel class of drugs that have revolutionized the management of heart failure with reduced ejection fraction (HFrEF). ARNIs combine two mechanisms: blockade of the angiotensin II receptor and inhibition of neprilysin, an enzyme responsible for degrading natriuretic peptides. The most notable ARNI currently available is Sacubitril/Valsartan, marketed under the brand name Entresto.

Mechanism of Action:

1. Sacubitril:
   • Sacubitril is a prodrug that, upon activation, inhibits neprilysin. Neprilysin is an enzyme responsible for degrading several vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin. By inhibiting neprilysin, sacubitril increases the levels of these peptides, leading to vasodilation, natriuresis (excretion of sodium), diuresis, and inhibition of fibrosis.
2. Valsartan:
   • Valsartan is an angiotensin II receptor blocker (ARB). It selectively blocks the AT1 receptors, which mediate the harmful effects of angiotensin II, such as vasoconstriction, sodium retention, and aldosterone secretion. By blocking the AT1 receptor, valsartan reduces blood pressure, limits cardiac remodeling, and prevents fluid retention.

The combination of sacubitril and valsartan in ARNIs results in a synergistic effect, where the increase in natriuretic peptides complements the suppression of the renin-angiotensin system, leading to better control of heart failure symptoms and improved survival.

Indications:

• Heart Failure with Reduced Ejection Fraction (HFrEF):
  • ARNIs are recommended for patients with symptomatic chronic heart failure (NYHA Class II-IV) with reduced ejection fraction (LVEF ≤40%). They are often used to replace an ACE inhibitor or ARB in patients who remain symptomatic despite optimal therapy.

Dosage:

• Initial Dose:
  • Sacubitril/Valsartan 49/51 mg twice daily.
  • In patients not previously on an ACE inhibitor or ARB, or with moderate renal impairment, a lower dose of 24/26 mg twice daily can be used initially.
• Target Dose:
  • 97/103 mg twice daily after 2-4 weeks, based on tolerability and renal function.

Contraindications:

• History of angioedema: ARNIs can increase the risk of angioedema due to increased levels of bradykinin.
• Concomitant use with ACE inhibitors: ARNIs should not be used with ACE inhibitors because of the risk of life-threatening angioedema. A washout period of 36 hours is required when switching from an ACE inhibitor to an ARNI.
• Pregnancy and breastfeeding.
• Severe hepatic impairment.

Pharmacokinetics:

• Absorption: Sacubitril and valsartan reach peak plasma concentrations in about 1.5 to 2 hours after oral administration.
• Metabolism: Sacubitril is converted to its active metabolite LBQ657 by esterases. Valsartan undergoes minimal metabolism.
• Excretion: Both sacubitril and valsartan are primarily excreted in the urine and feces.

Key Trials:

1. PARADIGM-HF Trial:
   • This landmark trial compared Sacubitril/Valsartan to Enalapril in patients with HFrEF.
   • Results showed a 20% reduction in cardiovascular death and heart failure hospitalization in the Sacubitril/Valsartan group compared to Enalapril.
   • This trial solidified ARNIs as a first-line therapy in the treatment of HFrEF.

Side Effects:

• Hypotension: Due to potent vasodilation.
• Hyperkalemia: Related to suppression of the renin-angiotensin system.
• Renal impairment: Can occur, particularly in patients with pre-existing renal disease.
• Angioedema: Increased risk due to elevated bradykinin levels.

Monitoring:

• Blood Pressure: Regular monitoring for hypotension, especially in the first few weeks of therapy.
• Renal Function: Serum creatinine and potassium levels should be monitored due to the risk of renal impairment and hyperkalemia.
• Symptoms of angioedema: Patients should be educated on the signs of angioedema and advised to seek immediate medical attention if it occurs.

Table: Key Differences Between ACE Inhibitors, ARBs, and ARNIs