MCQ Quiz: Pharmacology of Neprilysin Inhibitors

Neprilysin inhibitors represent a significant advancement in cardiovascular pharmacotherapy, particularly in the management of heart failure. By targeting the enzyme neprilysin, these drugs enhance the levels of beneficial endogenous vasoactive peptides, leading to improved cardiovascular outcomes. The combination of a neprilysin inhibitor with an angiotensin receptor blocker (ARNI) has become a cornerstone in treating heart failure with reduced ejection fraction (HFrEF). For PharmD students, a thorough understanding of the pharmacology of neprilysin inhibitors—including their mechanism of action, the physiological role of neprilysin, the rationale for ARNI combination, pharmacokinetics, therapeutic uses, and adverse effect profiles—is essential for contemporary practice. This MCQ quiz will assess your knowledge of these important pharmacological agents.

1. Neprilysin (Neutral Endopeptidase) is an enzyme primarily responsible for the degradation of:

• A. Acetylcholine
• B. Catecholamines
• C. Various endogenous vasoactive peptides, including natriuretic peptides (ANP, BNP) and bradykinin
• D. Cholesterol esters

Answer: C. Various endogenous vasoactive peptides, including natriuretic peptides (ANP, BNP) and bradykinin

2. The primary mechanism of action of a neprilysin inhibitor is to:

• A. Directly stimulate natriuretic peptide receptors.
• B. Block the enzymatic degradation of natriuretic peptides and other vasoactive substances, thereby increasing their circulating levels.
• C. Inhibit the renin-angiotensin-aldosterone system (RAAS) directly.
• D. Act as a beta-adrenergic agonist.

Answer: B. Block the enzymatic degradation of natriuretic peptides and other vasoactive substances, thereby increasing their circulating levels.

3. Sacubitril, the neprilysin inhibitor component of an ARNI, is administered as a prodrug. It is converted in vivo to its active metabolite known as:

• A. Valsartan
• B. Sacubitrilat (LBQ657)
• C. Omapatrilat
• D. Neprilysin itself

Answer: B. Sacubitrilat (LBQ657)

4. The pharmacological effect of increasing natriuretic peptide levels through neprilysin inhibition includes:

• A. Vasoconstriction, sodium retention, and increased sympathetic tone
• B. Vasodilation, natriuresis, diuresis, and inhibition of the RAAS and sympathetic nervous system
• C. Increased cardiac fibrosis and hypertrophy
• D. Enhanced degradation of bradykinin

Answer: B. Vasodilation, natriuresis, diuresis, and inhibition of the RAAS and sympathetic nervous system

5. Why is a neprilysin inhibitor like sacubitril co-formulated with an angiotensin II receptor blocker (ARB) such as valsartan (as an ARNI)?

• A. To enhance the absorption of sacubitril.
• B. Because neprilysin inhibition can also increase angiotensin II levels (as neprilysin degrades Ang II to some extent), and the ARB blocks the deleterious effects of this increased Ang II.
• C. To directly inhibit neprilysin synthesis.
• D. To provide a synergistic positive inotropic effect.

Answer: B. Because neprilysin inhibition can also increase angiotensin II levels (as neprilysin degrades Ang II to some extent), and the ARB blocks the deleterious effects of this increased Ang II.

6. Concurrent administration of a neprilysin inhibitor with an ACE inhibitor is contraindicated due to a significantly increased risk of:

• A. Severe hypertension
• B. Angioedema
• C. Hyperkalemia only
• D. Myocardial infarction

Answer: B. Angioedema (due to potentiation of bradykinin levels by both agents).

7. When switching a patient from an ACE inhibitor to an ARNI (sacubitril/valsartan), what is the recommended washout period for the ACE inhibitor before starting the ARNI?

• A. No washout period is needed.
• B. 12 hours
• C. 36 hours
• D. 72 hours

Answer: C. 36 hours

8. The primary therapeutic indication for sacubitril/valsartan (ARNI) is the treatment of:

• A. Acute ischemic stroke
• B. Hypertension as a first-line agent in all patients
• C. Symptomatic heart failure with reduced ejection fraction (HFrEF) to reduce cardiovascular death and hospitalizations
• D. Atrial fibrillation for rate control

Answer: C. Symptomatic heart failure with reduced ejection fraction (HFrEF) to reduce cardiovascular death and hospitalizations

9. Which of the following is a common and clinically significant adverse effect of ARNI therapy?

• A. Bradycardia
• B. Hypotension
• C. Hypernatremia
• D. Bronchoconstriction

Answer: B. Hypotension

10. Due to the valsartan component, ARNIs can cause which electrolyte abnormality, requiring monitoring?

• A. Hypokalemia
• B. Hyperkalemia
• C. Hypocalcemia
• D. Hypermagnesemia

Answer: B. Hyperkalemia

11. Sacubitril is converted to its active metabolite LBQ657 by which type of metabolic reaction?

• A. Oxidation by cytochrome P450 enzymes
• B. Glucuronidation
• C. Hydrolysis by esterases
• D. N-acetylation

Answer: C. Hydrolysis by esterases

12. Besides natriuretic peptides, neprilysin also degrades bradykinin. This action is relevant because increased bradykinin levels can contribute to:

• A. Vasoconstriction and sodium retention
• B. Vasodilation and potentially angioedema
• C. Increased heart rate
• D. Enhanced platelet aggregation

Answer: B. Vasodilation and potentially angioedema

13. The landmark clinical trial that established the superiority of sacubitril/valsartan over enalapril in reducing cardiovascular death and HF hospitalizations in HFrEF patients was:

• A. RALES
• B. MERIT-HF
• C. PARADIGM-HF
• D. SOLVD

Answer: C. PARADIGM-HF

14. When initiating sacubitril/valsartan, it is important to monitor which of the following, in addition to symptoms?

• A. Liver function tests only
• B. Blood pressure, serum potassium, and renal function
• C. Serum digoxin levels
• D. Complete blood count and lipid panel

Answer: B. Blood pressure, serum potassium, and renal function

15. A history of angioedema related to previous ACE inhibitor or ARB therapy is a _________ for sacubitril/valsartan.

• A. Minor precaution
• B. Relative indication
• C. Contraindication
• D. Reason to use a lower dose

Answer: C. Contraindication

16. The valsartan component of an ARNI provides blockade of which receptor?

• A. Angiotensin II AT2 receptor
• B. Angiotensin II AT1 receptor
• C. Beta-1 adrenergic receptor
• D. Aldosterone receptor

Answer: B. Angiotensin II AT1 receptor

17. Omapatrilat, an investigational agent that inhibited both ACE and neprilysin, showed promise but its development was halted primarily due to:

• A. Lack of efficacy
• B. A high incidence of angioedema
• C. Severe hepatotoxicity
• D. Poor oral bioavailability

Answer: B. A high incidence of angioedema

18. The natriuretic peptides (ANP and BNP) whose levels are increased by neprilysin inhibition exert their effects by binding to natriuretic peptide receptors and increasing intracellular:

• A. Cyclic AMP (cAMP)
• B. Cyclic GMP (cGMP)
• C. Inositol triphosphate (IP3)
• D. Diacylglycerol (DAG)

Answer: B. Cyclic GMP (cGMP)

19. Compared to enalapril in the PARADIGM-HF trial, sacubitril/valsartan was associated with a higher incidence of symptomatic ________ but a lower incidence of ________.

• A. Cough; hyperkalemia
• B. Hypotension; angioedema (though angioedema still a risk and higher than placebo)
• C. Renal impairment; bradycardia
• D. Angioedema; hypotension

Answer: B. Hypotension; angioedema (While angioedema was numerically higher, it was not statistically significantly higher for the primary angioedema endpoint versus enalapril in PARADIGM-HF, but the risk is well-recognized especially compared to ARB alone. Cough was less with ARNI). The most prominent difference was more hypotension with ARNI. Let’s check. PARADIGM-HF showed ARNI had more hypotension and non-serious angioedema, but less cough and less hyperkalemia than enalapril. So, “lower incidence of angioedema” is incorrect. Correction to option B and Answer: 19. Compared to enalapril in the PARADIGM-HF trial, sacubitril/valsartan was associated with a higher incidence of symptomatic ________ but a lower incidence of ________.

• A. Hyperkalemia; cough
• B. Hypotension; cough
• C. Renal impairment; bradycardia
• D. Angioedema; hyperkalemia Answer: B. Hypotension; cough

20. The use of sacubitril/valsartan is contraindicated in patients with:

• A. Diabetes mellitus
• B. Previous myocardial infarction
• C. Severe hepatic impairment or biliary cirrhosis
• D. Mild renal impairment

Answer: C. Severe hepatic impairment or biliary cirrhosis (and also contraindicated with concomitant aliskiren in diabetics).

21. Which biomarker is used to assess the pharmacodynamic effect of sacubitril (neprilysin inhibition) and may be elevated during ARNI therapy, making it less reliable for monitoring HF severity?

• A. Troponin I
• B. B-type Natriuretic Peptide (BNP)
• C. C-reactive protein (CRP)
• D. Serum creatinine

Answer: B. B-type Natriuretic Peptide (BNP) (Neprilysin degrades BNP, so inhibiting it increases BNP. NT-proBNP is preferred for monitoring HF status on ARNI).

22. For monitoring heart failure status in patients treated with sacubitril/valsartan, which natriuretic peptide biomarker is preferred because its levels are not directly increased by neprilysin inhibition?

• A. Atrial Natriuretic Peptide (ANP)
• B. C-type Natriuretic Peptide (CNP)
• C. N-terminal pro-B-type Natriuretic Peptide (NT-proBNP)
• D. Urodilatin

Answer: C. N-terminal pro-B-type Natriuretic Peptide (NT-proBNP)

23. The pharmacokinetic profile of sacubitril indicates that it is rapidly converted to LBQ657. The elimination half-life of LBQ657 is approximately:

• A. 1-2 hours
• B. 9-11 hours
• C. 24-30 hours
• D. 48-72 hours

Answer: B. 9-11 hours (approx. 11 hours for LBQ657).

24. The rationale for using an ARNI in HFrEF is to simultaneously:

• A. Enhance the beneficial effects of natriuretic peptides and block the harmful effects of the RAAS.
• B. Inhibit both ACE and neprilysin directly.
• C. Increase heart rate and myocardial contractility.
• D. Promote diuresis and inhibit platelet aggregation.

Answer: A. Enhance the beneficial effects of natriuretic peptides and block the harmful effects of the RAAS.

25. Dose adjustments for sacubitril/valsartan may be required in patients with:

• A. Hyperlipidemia
• B. Moderate to severe renal impairment or moderate hepatic impairment
• C. Well-controlled hypertension
• D. Gout

Answer: B. Moderate to severe renal impairment or moderate hepatic impairment

26. Which of the following drugs, if used concomitantly with sacubitril/valsartan, could significantly increase the risk of hyperkalemia?

• A. Hydrochlorothiazide
• B. Spironolactone or eplerenone
• C. Amlodipine
• D. Aspirin

Answer: B. Spironolactone or eplerenone (Potassium-sparing diuretics/aldosterone antagonists).

27. The vasodilatory effects of increased natriuretic peptide levels due to neprilysin inhibition primarily occur through:

• A. Alpha-adrenergic blockade
• B. Increased production of cGMP in vascular smooth muscle cells
• C. Beta-2 adrenergic agonism
• D. Calcium channel blockade

Answer: B. Increased production of cGMP in vascular smooth muscle cells

28. What is the effect of neprilysin inhibition on bradykinin levels?

• A. Decreases bradykinin levels
• B. Increases bradykinin levels
• C. Has no effect on bradykinin levels
• D. Converts bradykinin to an inactive metabolite

Answer: B. Increases bradykinin levels

29. The risk of angioedema with an ARNI, while present, is considered lower than with the combination of an ACE inhibitor and a neprilysin inhibitor because:

• A. ARNIs do not affect bradykinin levels.
• B. The ARB component in ARNIs helps to mitigate some bradykinin-mediated effects.
• C. Sacubitril is a weaker neprilysin inhibitor than those in previous combination attempts.
• D. ACE inhibitors cause more bradykinin accumulation than neprilysin inhibitors. The dual blockade (ACEi + Neprilysin inhibitor) is the main issue for very high bradykinin. ARNIs avoid this dual hit on bradykinin breakdown pathways.

Answer: D. ACE inhibitors cause more bradykinin accumulation than neprilysin inhibitors. The dual blockade (ACEi + Neprilysin inhibitor) is the main issue for very high bradykinin. (With an ARNI, ACE is still active, providing one pathway for bradykinin degradation.)

30. Therapeutic drug monitoring of sacubitril or LBQ657 levels is:

• A. Routinely recommended for all patients.
• B. Not routinely performed in clinical practice.
• C. Only required for patients with severe renal impairment.
• D. Essential for dose titration.

Answer: B. Not routinely performed in clinical practice.

31. The antifibrotic effects observed with ARNI therapy in HFrEF are thought to be mediated by:

• A. Only the valsartan component blocking Ang II effects.
• B. Both the enhancement of natriuretic peptide actions (which have antifibrotic properties) and blockade of Ang II.
• C. Direct inhibition of collagen synthesis by sacubitril.
• D. Increased aldosterone levels.

Answer: B. Both the enhancement of natriuretic peptide actions (which have antifibrotic properties) and blockade of Ang II.

32. A patient stabilized on an ACE inhibitor for HFrEF is being considered for a switch to sacubitril/valsartan. Besides the washout period, what other initial consideration is important regarding the starting dose of the ARNI?

• A. Always start with the highest approved dose of ARNI.
• B. The starting dose may depend on the previous ACE inhibitor or ARB dose (e.g., lower starting dose if on low ACEi/ARB dose or ACEi/ARB naive).
• C. The ARNI dose is not affected by prior ACE inhibitor therapy.
• D. Start the ARNI at the same milligram equivalent as the previous ACE inhibitor.

Answer: B. The starting dose may depend on the previous ACE inhibitor or ARB dose (e.g., lower starting dose if on low ACEi/ARB dose or ACEi/ARB naive).

33. Neprilysin is also known by which other name?

• A. Angiotensin Converting Enzyme 2 (ACE2)
• B. Neutral endopeptidase 24.11 (NEP)
• C. Dipeptidyl peptidase-4 (DPP-4)
• C. Soluble guanylate cyclase (sGC)

Answer: B. Neutral endopeptidase 24.11 (NEP)

34. Besides ANP and BNP, neprilysin also degrades other vasoactive peptides such as:

• A. Insulin and glucagon
• B. Endothelin-1 and vasopressin (primarily degrades ET-1, not vasopressin)
• C. Adrenomedullin and Substance P
• D. Thyroid hormones

Answer: C. Adrenomedullin and Substance P (It also degrades bradykinin and Ang I & II).

35. The valsartan component of Entresto® (sacubitril/valsartan) is specifically an antagonist of:

• A. Both AT1 and AT2 receptors
• B. AT1 receptors, mediating most of the known pathological effects of Angiotensin II
• C. AT2 receptors, mediating beneficial effects of Angiotensin II
• D. The aldosterone receptor

Answer: B. AT1 receptors, mediating most of the known pathological effects of Angiotensin II

36. The rationale for initiating ARNI therapy in hospitalized patients with acute decompensated HFrEF (e.g., as per the PIONEER-HF trial) is:

• A. To increase blood pressure rapidly.
• B. That early initiation in stabilized patients before discharge may improve outcomes compared to delayed initiation.
• C. To replace the need for intravenous diuretics.
• D. Because it has potent positive inotropic effects.

Answer: B. That early initiation in stabilized patients before discharge may improve outcomes compared to delayed initiation.

37. What is the effect of food on the bioavailability of sacubitril/valsartan?

• A. Food significantly increases the bioavailability of both components.
• B. Food has no significant effect on the overall exposure, so it can be taken with or without food.
• C. Food significantly decreases the bioavailability of sacubitril but not valsartan.
• D. It must be taken on an empty stomach for optimal absorption.

Answer: B. Food has no significant effect on the overall exposure, so it can be taken with or without food. (Though Cmax of LBQ657 may be decreased and absorption of valsartan delayed, overall AUC isn’t significantly affected).

38. What is the primary mechanism by which increased levels of natriuretic peptides contribute to diuresis and natriuresis?

• A. By increasing aldosterone secretion.
• B. By promoting vasodilation of renal afferent arterioles and inhibiting sodium reabsorption in the renal tubules.
• C. By directly blocking SGLT2 transporters.
• D. By increasing sympathetic outflow to the kidneys.

Answer: B. By promoting vasodilation of renal afferent arterioles and inhibiting sodium reabsorption in the renal tubules.

39. If a patient experiences symptomatic hypotension after initiating or titrating sacubitril/valsartan, what is a common management strategy?

• A. Immediately discontinue the ARNI permanently.
• B. Increase the dose of the ARNI.
• C. Temporarily reduce or hold other antihypertensive medications (e.g., diuretics, other vasodilators) or reduce the ARNI dose if possible.
• D. Add a vasopressor agent.

Answer: C. Temporarily reduce or hold other antihypertensive medications (e.g., diuretics, other vasodilators) or reduce the ARNI dose if possible.

40. The chemical process converting sacubitril (prodrug) to LBQ657 (active neprilysin inhibitor) is:

• A. An oxidation reaction.
• B. A reduction reaction.
• C. An ester hydrolysis.
• D. A glucuronidation reaction.

Answer: C. An ester hydrolysis.

41. Neprilysin inhibitors are NOT typically used as monotherapy for heart failure because:

• A. They are ineffective alone.
• B. Monotherapy would lead to unopposed angiotensin II effects due to neprilysin’s role in Ang II degradation, which would be detrimental.
• C. They cause excessive bradycardia when used alone.
• D. They are too expensive as monotherapy.

Answer: B. Monotherapy would lead to unopposed angiotensin II effects due to neprilysin’s role in Ang II degradation, which would be detrimental.

42. The “LUSITROPIC” effect refers to an improvement in myocardial relaxation (diastolic function). Enhanced levels of natriuretic peptides due to neprilysin inhibition may contribute to:

• A. Worsening diastolic function.
• B. Improved diastolic function and reduced ventricular stiffness.
• C. Increased myocardial oxygen consumption.
• D. No effect on diastolic function.

Answer: B. Improved diastolic function and reduced ventricular stiffness.

43. What is the primary safety concern that led to the failure of omapatrilat (a vasopeptidase inhibitor that inhibited both ACE and neprilysin)?

• A. Severe hepatotoxicity
• B. High incidence of angioedema
• C. Lack of blood pressure lowering
• D. Development of tachyphylaxis

Answer: B. High incidence of angioedema

44. The dosing of sacubitril/valsartan is based on the sum of the two components (e.g., 24/26 mg, 49/51 mg, 97/103 mg). The target dose in HFrEF is typically:

• A. The lowest available dose (e.g., 24/26 mg twice daily)
• B. The highest tolerated approved dose (e.g., 97/103 mg twice daily)
• C. A once-daily regimen
• D. Determined by BNP levels

Answer: B. The highest tolerated approved dose (e.g., 97/103 mg twice daily)

45. When considering the impact of neprilysin inhibition, it’s important to remember that neprilysin has a broad substrate specificity. This means:

• A. It only degrades BNP.
• B. Inhibiting it only affects cardiovascular peptides.
• C. Inhibiting it can affect the levels of numerous peptides beyond just natriuretic peptides and bradykinin, which could contribute to both beneficial and potentially off-target effects.
• D. Its substrates are all pro-inflammatory.

Answer: C. Inhibiting it can affect the levels of numerous peptides beyond just natriuretic peptides and bradykinin, which could contribute to both beneficial and potentially off-target effects.

46. The beneficial effects of ARNIs on reducing cardiac remodeling in HFrEF are attributed to:

• A. Only the blockade of angiotensin II AT1 receptors by valsartan.
• B. The combined effects of AT1 receptor blockade and potentiation of natriuretic peptides.
• C. Direct stimulation of cardiomyocyte proliferation by sacubitril.
• D. A primary increase in heart rate.

Answer: B. The combined effects of AT1 receptor blockade and potentiation of natriuretic peptides.

47. What is the effect of severe renal impairment (e.g., eGFR < 30 mL/min/1.73m²) on the exposure to LBQ657 (active metabolite of sacubitril)?

• A. Significantly decreases exposure.
• B. Significantly increases exposure, often requiring a lower starting dose and cautious titration.
• C. Has no effect on exposure.
• D. Leads to conversion of LBQ657 to an inactive metabolite.

Answer: B. Significantly increases exposure, often requiring a lower starting dose and cautious titration.

48. If a patient is taking an ARNI and develops a cough, it is less likely to be due to the ARNI’s effect on bradykinin compared to an ACE inhibitor because:

• A. ARNIs cause a greater increase in bradykinin than ACE inhibitors.
• B. The ARB component of the ARNI prevents all bradykinin formation.
• C. ACE, a major pathway for bradykinin degradation, is not inhibited by the ARNI, whereas it is with an ACE inhibitor.
• D. Sacubitril directly inhibits cough receptors.

Answer: C. ACE, a major pathway for bradykinin degradation, is not inhibited by the ARNI, whereas it is with an ACE inhibitor.

49. The use of potassium supplements or potassium-sparing diuretics with sacubitril/valsartan should be done with caution due to the increased risk of:

• A. Hypokalemia
• B. Hyperkalemia
• C. Angioedema
• D. Hypotension

Answer: B. Hyperkalemia

50. The overall pharmacological strategy of using an ARNI in HFrEF is based on augmenting _________ while simultaneously blocking _________.

• A. The sympathetic nervous system; the RAAS
• B. The RAAS; the natriuretic peptide system
• C. The beneficial natriuretic peptide system; the detrimental RAAS
• D. Aldosterone effects; beta-adrenergic effects

Answer: C. The beneficial natriuretic peptide system; the detrimental RAAS