VPEP Module 2 Infographic

Feature	ACE Inhibitors	Angiotensin Receptor Blockers
Site of action	Blocks ACE enzyme (Step 2)	Blocks AT1 receptor (Step 3)
Bradykinin effect	Rises — ACE also degrades bradykinin	No change — ACE unaffected
Dry cough	Yes — 5–20% of patients	No
Angioedema	Yes — bradykinin-mediated	Rare — not bradykinin-driven
Hyperkalemia	Yes	Yes
Pregnancy	Contraindicated	Contraindicated
Prodrug	Most agents yes	No — active as given
Elimination	Primarily renal	Primarily hepatic/biliary

Feature

ACE Inhibitors

Angiotensin Receptor Blockers

Site of action

Blocks ACE enzyme (Step 2)

Blocks AT1 receptor (Step 3)

Bradykinin effect

Rises — ACE also degrades bradykinin

No change — ACE unaffected

Dry cough

Yes — 5–20% of patients

Angioedema

Yes — bradykinin-mediated

Rare — not bradykinin-driven

Hyperkalemia

Yes

Pregnancy

Contraindicated

Prodrug

Most agents yes

No — active as given

Elimination

Primarily renal

Primarily hepatic/biliary

Released from Atria

Atrial Natriuretic Peptide

Trigger: atrial wall stretch (volume overload)
Effects: natriuresis, vasodilation, reduced aldosterone
Opposes the renin-angiotensin-aldosterone system

Released from Ventricles

Brain Natriuretic Peptide

Trigger: ventricular wall stretch (elevated filling pressure)
Heart failure biomarker — rises with severity
Falsely elevated by neprilysin inhibition (use NT-proBNP instead)

Degrading Enzyme

Neprilysin

Cleaves and inactivates natriuretic peptides and bradykinin
Inhibited by sacubitril → natriuretic peptides rise
Also degrades brain natriuretic peptide — blocks monitoring use

Fixed-Dose Combination · Heart Failure with Reduced Ejection Fraction

Sacubitril (neprilysin inhibitor) + Valsartan (AT1 receptor blocker) — PARADIGM-HF: 20% reduction in cardiovascular death/heart failure hospitalization vs enalapril

Sacubitril Component

Prodrug → active neprilysin inhibitor
Blocks natriuretic peptide degradation
Raises bradykinin (same as ACE inhibitors)
Net: more natriuresis, more vasodilation

Valsartan Component

AT1 receptor blocker
Reduces angiotensin II-driven vasoconstriction
Reduces aldosterone secretion
Net: less renin-angiotensin-aldosterone system activation

Rule	Reason
Never combine with ACE inhibitor	Both raise bradykinin → additive angioedema risk, potentially fatal
36-hour washout (both directions)	Sacubitril metabolite persists; overlap with ACE inhibitor causes bradykinin surge
Contraindicated in pregnancy	Valsartan suppresses fetal renin-angiotensin-aldosterone system → fetal renal dysgenesis
Monitor for hypotension	Most common adverse effect — titrate dose slowly, especially with diuretics
Use NT-proBNP, not BNP	Sacubitril blocks brain natriuretic peptide degradation → brain natriuretic peptide falsely elevated regardless of heart failure status

Rule

Reason

Never combine with ACE inhibitor

Both raise bradykinin → additive angioedema risk, potentially fatal

36-hour washout (both directions)

Sacubitril metabolite persists; overlap with ACE inhibitor causes bradykinin surge

Contraindicated in pregnancy

Valsartan suppresses fetal renin-angiotensin-aldosterone system → fetal renal dysgenesis

Monitor for hypotension

Most common adverse effect — titrate dose slowly, especially with diuretics

Use NT-proBNP, not BNP

Sacubitril blocks brain natriuretic peptide degradation → brain natriuretic peptide falsely elevated regardless of heart failure status