Mechanism of Action of Enalapril
Enalapril works by inhibiting angiotensin-converting enzyme (ACE), which prevents the conversion of angiotensin I to angiotensin II, thereby reducing vasoconstriction and aldosterone secretion, ultimately leading to decreased blood pressure and improved cardiovascular outcomes. 1
Primary Mechanism
Enalapril itself is a prodrug that requires hepatic activation to enalaprilat, its active metabolite, which is a more potent ACE inhibitor 1. The mechanism involves:
- Inhibition of ACE: ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to angiotensin II
- Reduction of angiotensin II: This leads to decreased vasopressor activity
- Decreased aldosterone secretion: Results in small increases in serum potassium
- Increased plasma renin activity: Due to removal of angiotensin II's negative feedback on renin secretion
Secondary Mechanisms
Beyond the primary RAAS inhibition, enalapril has additional mechanisms:
- Bradykinin potentiation: ACE is identical to kininase, an enzyme that degrades bradykinin 1. By inhibiting this enzyme, enalapril increases bradykinin levels, which may contribute to its vasodilatory effects
- Prostaglandin enhancement: Increased bradykinin levels augment kinin-mediated prostaglandin production 2
- Tissue ACE inhibition: Enalapril can inhibit ACE in various tissues, not just in circulation
Pharmacokinetics
- Absorption: Approximately 60% of oral enalapril is absorbed 1
- Peak concentration: Serum concentrations of enalapril peak within about one hour after oral administration 1
- Activation: Following absorption, enalapril is hydrolyzed to enalaprilat 1
- Peak activity: Serum concentrations of enalaprilat (active form) peak three to four hours after an oral dose 1
- Elimination: Primarily renal, with approximately 94% recovered in urine and feces as enalaprilat or enalapril 1
Clinical Effects
The inhibition of ACE by enalapril results in several beneficial effects:
- Reduced peripheral vascular resistance: This occurs without increasing heart rate or cardiac output 3
- Balanced vasodilation: Effects on both arterial and venous beds 4
- Antihypertensive effect: Onset typically seen at one hour with peak reduction at four to six hours 1
- Natriuresis: Mild increase in sodium excretion 5
- Positive potassium balance: Due to decreased aldosterone production 5
Unique Characteristics of Enalapril
- Nonsulfhydryl structure: Unlike captopril, enalapril does not contain a sulfhydryl group, which may account for its different side effect profile 6
- Once-daily dosing: Due to its pharmacokinetic profile, enalapril can typically be administered once daily for hypertension 3
- More complete inhibition: At conventional doses, enalapril more completely prevents posture-induced increases in aldosterone than captopril, suggesting more complete inhibition of angiotensin II formation 5
Clinical Applications
Enalapril's mechanism of action makes it effective for:
- Hypertension: All grades of essential and renovascular hypertension 3
- Heart failure: Beneficial hemodynamic effects through reduction of both cardiac preload and afterload 6
- Diabetic nephropathy: Reduces progression of kidney disease 2
Pitfalls and Considerations
- Renal function: In patients with impaired renal function (GFR ≤30 mL/min), enalaprilat levels increase and half-life is prolonged 1
- First-dose hypotension: Can occur, especially in volume-depleted patients 1
- Hyperkalemia risk: Increases when combined with potassium-sparing diuretics or aldosterone antagonists 7
- Cough: Most frequent adverse effect limiting ACE inhibitor therapy, related to bradykinin accumulation 3
- Angioedema: Rare but serious side effect 7
Understanding enalapril's mechanism of action is crucial for optimizing its use in cardiovascular and renal diseases, as well as anticipating and managing potential adverse effects.