Angiotensin-Converting Enzyme (ACE) Inhibitors
ACE inhibitors are medications that inhibit the angiotensin-converting enzyme, blocking the conversion of angiotensin I to angiotensin II, resulting in vasodilation, decreased aldosterone secretion, and reduced blood pressure, with proven benefits in hypertension, heart failure, and diabetic nephropathy. 1, 2, 3
Mechanism of Action
ACE inhibitors work through several key mechanisms:
- Inhibit the enzyme that converts angiotensin I to angiotensin II (a potent vasoconstrictor)
- Decrease aldosterone secretion from the adrenal cortex
- Prevent the degradation of bradykinin (a vasodilator)
- Reduce vasopressor activity and promote vasodilation
- Suppress the renin-angiotensin-aldosterone system (RAAS) 2, 3
These effects lead to:
- Decreased systemic vascular resistance
- Reduced blood pressure
- Improved cardiac output
- Natriuresis (increased sodium excretion)
- Small increases in serum potassium
Types and Pharmacokinetics
ACE inhibitors differ in their chemical structure, potency, bioavailability, and pharmacokinetic properties:
| ACE Inhibitor | Initial Dose | Maximum Dose | Dosing Frequency | Distinctive Characteristics |
|---|---|---|---|---|
| Captopril | 6.25 mg | 50 mg TID | 3 times/day | Rapid and short-acting, contains sulfhydryl group |
| Enalapril | 2.5 mg | 10-20 mg BID | 2 times/day | Prodrug requiring hepatic activation |
| Lisinopril | 2.5-5 mg | 20-40 mg | 1 time/day | Not a prodrug, renal elimination |
| Ramipril | 1.25-2.5 mg | 10 mg | 1 time/day | Higher lipophilicity, good tissue penetration |
| Perindopril | 2 mg | 8-16 mg | 1 time/day | High tissue affinity |
| Trandolapril | 1 mg | 4 mg | 1 time/day | Long half-life |
Key pharmacokinetic differences:
- Captopril and lisinopril are the only ACE inhibitors that are not prodrugs
- Most ACE inhibitors are eliminated primarily through the kidneys
- Lisinopril is the only ACE inhibitor that doesn't require hepatic metabolism
- ACE inhibitors vary in their lipophilicity and tissue penetration 1, 2, 3
Clinical Applications
ACE inhibitors are indicated for several cardiovascular and renal conditions:
Heart Failure with Reduced Ejection Fraction (<40%):
- Reduce mortality and hospitalizations
- Improve symptoms and functional capacity
- Should be prescribed to all eligible patients 1
Hypertension:
Post-Myocardial Infarction:
- Reduce ventricular remodeling and cardiovascular mortality 1
Diabetic Nephropathy:
Adverse Effects
Common adverse effects include:
- Dry Cough: Occurs in up to 20% of patients due to bradykinin accumulation
- Angioedema: Rare (<1%), more common in African Americans and women
- Hypotension: More frequent at treatment initiation and in volume-depleted patients
- Hyperkalemia: Approximately 15% of patients may experience increases in potassium >0.5 mEq/L
- Renal Function Deterioration: Particularly in patients with bilateral renal artery stenosis or dehydration 4, 1
Contraindications
- Absolute: History of angioedema with ACE inhibitors, bilateral renal artery stenosis, pregnancy, anuric renal failure
- Relative: Systolic blood pressure <80 mmHg, serum creatinine >3 mg/dL, serum potassium >5.5 mEq/L 1
Monitoring Recommendations
- Check baseline renal function, potassium, and blood pressure before initiating therapy
- Monitor renal function and potassium 1-2 weeks after initiation, after each dose increase, and at 3-6 month intervals during maintenance
- Evaluate blood pressure regularly, especially in high-risk patients 4, 1
Special Considerations
ACE inhibitors can cause functional acute renal failure, especially in patients with:
- Extracellular fluid volume depletion
- Bilateral renal artery stenosis
- Stenosis of a dominant or single kidney
- Preexisting hypotension 4
ACE inhibitors are less effective as monotherapy in Black hypertensive patients (typically a low-renin population) 2, 3
When ACE inhibitors cannot be tolerated due to cough, angiotensin receptor blockers (ARBs) are a reasonable alternative with similar efficacy but fewer side effects 1