What are Angiotensin-Converting Enzyme (ACE) inhibitors?

Angiotensin-Converting Enzyme (ACE) Inhibitors

ACE inhibitors are medications that block the conversion of angiotensin I to angiotensin II, reducing blood pressure, improving cardiac function, and providing organ protection in conditions like heart failure, hypertension, and diabetic nephropathy. 1, 2

Mechanism of Action

• Primary mechanism: Inhibit angiotensin-converting enzyme (ACE), blocking the conversion of angiotensin I to angiotensin II

  • Reduces angiotensin II-induced aldosterone secretion from the adrenal cortex
  • Decreases vasopressor activity and promotes natriuresis 2, 3

• Secondary mechanisms:

  • Enhance kinin action (ACE is identical to kininase, an enzyme that degrades bradykinin)
  • Augment kinin-mediated prostaglandin production 1, 4
  • This may explain why ACE inhibitors modify cardiac remodeling more favorably than ARBs in heart failure 1

Clinical Applications

Heart Failure

• First-line therapy in patients with reduced left ventricular ejection fraction (<40-45%) with or without symptoms 1
• Reduce mortality, hospitalization, and improve symptoms and functional capacity 1
• Should be prescribed to all patients with heart failure due to LV systolic dysfunction unless contraindicated 1
• Recommended in asymptomatic left ventricular dysfunction to delay or prevent heart failure development 1

Hypertension

• First-line therapy for hypertension, particularly effective in:
  • Patients with diabetes (target BP <130/80 mmHg) 1
  • Patients with concurrent heart failure or kidney disease 1
• Effective even in low-renin hypertension, though black patients may have smaller average response to monotherapy 2, 3

Diabetic Nephropathy

• First-line therapy for prevention and progression of nephropathy in patients with microalbuminuria or clinical nephropathy 1

Common ACE Inhibitors and Dosing

Drug	Initial Daily Dose	Maximum Dose	Mean Doses in Clinical Trials
Captopril	6.25 mg 3 times	50 mg 3 times	122.7 mg/d
Enalapril	2.5 mg twice	10-20 mg twice	16.6 mg/d
Lisinopril	2.5-5 mg once	20-40 mg once	32.5-35.0 mg/d
Ramipril	1.25-2.5 mg once	10 mg once	N/A
Trandolapril	1 mg once	4 mg once	N/A

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Adverse Effects

Common Adverse Effects

• Cough (up to 20% of patients) - due to increased bradykinin levels 1, 5
• Small increases in serum potassium (approximately 0.1 mEq/L) 2, 3
• Hypotension, particularly in volume-depleted patients 2
• Taste disturbances 1

Serious Adverse Effects

• Angioedema (<1% of patients, more common in Black patients) - life-threatening reaction requiring permanent discontinuation of all ACE inhibitors 1
• Functional renal insufficiency - especially in patients with:
  • Bilateral renal artery stenosis
  • Stenosis of dominant or single kidney
  • Severe extracellular fluid volume depletion 1
• Hyperkalemia - risk increases when combined with potassium-sparing diuretics or aldosterone antagonists 4, 6

Monitoring and Management

Before Initiation

• Check baseline renal function, potassium, and blood pressure
• Identify high-risk patients:
  • Preexisting hypotension (systolic BP <90 mmHg)
  • Impaired renal function (serum creatinine >2.5 mg/dL)
  • Bilateral renal artery stenosis
  • Volume depletion 1

During Treatment

• Monitor renal function and potassium:
  • 1-2 weeks after initiation
  • 1-2 weeks after each dose increment
  • At 3-6 month intervals during maintenance 1
• More frequent monitoring for patients with:
  • Renal dysfunction
  • Electrolyte disturbances
  • Concomitant medications affecting renal function 1

Contraindications

• Absolute contraindications:

  • Previous angioedema with ACE inhibitor use
  • Bilateral renal artery stenosis
  • Pregnancy 1
  • Anuric renal failure 1

• Relative contraindications (use with caution):

  • Very low blood pressure (systolic <80 mmHg)
  • Serum creatinine >3 mg/dL
  • Serum potassium >5.5 mEq/L 1

Clinical Pearls

• ACE inhibitors should be titrated to target doses shown effective in clinical trials, not just to symptomatic improvement 1
• When initiating therapy in heart failure patients, start with low doses and gradually increase 1
• In hypertension, combining ACE inhibitors with thiazide diuretics produces approximately additive blood pressure lowering effects 2
• ARBs may be considered as alternative therapy for patients who develop cough or angioedema with ACE inhibitors 1, 5
• ACE inhibitors are preferred over ARBs for heart failure due to greater experience and evidence supporting their effectiveness 1