Enalapril

Enalapril is a widely used antihypertensive agent that belongs to the angiotensin-converting enzyme (ACE) inhibitors class. It is a prodrug that is metabolized in the liver to its active form, enalaprilat, which inhibits the conversion of angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor that also stimulates aldosterone secretion; thus, inhibiting its production leads to vasodilation, reduced sodium and water retention, and decreased blood pressure. Enalapril is commonly used in hypertension, heart failure, left ventricular dysfunction, and diabetic nephropathy.

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Pharmacological Classification

• Therapeutic class: Antihypertensive

• Pharmacologic class: Angiotensin-converting enzyme inhibitor (ACE inhibitor)

• ATC code: C09AA02

• Drug class: RAAS-modifying agents

• Available forms: Oral tablets, oral solution, intravenous injection (enalaprilat)

• Brand names: Renitec, Vasotec, Enapril, Epaned (solution)

• Legal status: Prescription only (Rx)

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Mechanism of Action

Enalapril is a prodrug that is converted by hepatic esterases into enalaprilat, its active metabolite. Enalaprilat competitively inhibits ACE, an enzyme responsible for converting angiotensin I to angiotensin II. Angiotensin II mediates vasoconstriction, aldosterone secretion, and sympathetic activation.

By blocking ACE, enalapril:

• Reduces peripheral vascular resistance (vasodilation)

• Lowers aldosterone secretion, reducing sodium and water retention

• Decreases blood pressure

• Decreases afterload and preload, benefiting heart failure patients

• Slows progression of kidney disease, particularly in diabetic nephropathy

It also reduces degradation of bradykinin, a vasodilator, which may contribute to its antihypertensive effect but is also responsible for its common adverse effect: dry cough.

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Therapeutic Indications

1. Essential hypertension

   • Alone or in combination with other antihypertensives (e.g., thiazide diuretics)

2. Congestive heart failure

   • Improves survival, reduces hospitalization, and relieves symptoms in patients with reduced ejection fraction (HFrEF)

3. Asymptomatic left ventricular dysfunction

   • Delays the development of symptomatic heart failure and reduces hospitalizations

4. Diabetic nephropathy and chronic kidney disease (off-label)

   • Particularly in patients with proteinuria

5. Post-myocardial infarction (off-label)

   • Used to prevent remodeling in patients with left ventricular dysfunction

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Dosage and Administration

Hypertension

• Initial dose: 5 mg once daily

• Maintenance dose: 10–20 mg once daily or in two divided doses

• Elderly or volume-depleted patients: start at 2.5 mg once daily

Heart failure

• Initial dose: 2.5 mg twice daily

• Target dose: 10–20 mg twice daily, titrated over weeks

Asymptomatic LV dysfunction

• Initial dose: 2.5 mg twice daily

• Target dose: 10 mg twice daily

Pediatric hypertension (off-label in many regions)

• Children ≥1 month: 0.08 mg/kg/day once daily (max 5 mg/day); titrate to effect

Renal impairment

• If creatinine clearance <30 mL/min:

  • Initial dose: 2.5 mg/day

  • Maintenance dose: adjust to avoid accumulation

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Pharmacokinetics

• Absorption: ~60% orally bioavailable

• Onset of action: 1 hour; peak effect at 4–6 hours

• Half-life: 11 hours for enalaprilat

• Duration: 24 hours (allows once-daily dosing)

• Metabolism: Hepatic (prodrug to enalaprilat)

• Excretion: Primarily renal (60–70% as enalaprilat)

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Contraindications

• History of angioedema associated with previous ACE inhibitor use

• Bilateral renal artery stenosis or severe unilateral stenosis in a solitary kidney

• Pregnancy (Category D): fetal toxicity

• Concomitant use with aliskiren in patients with diabetes or renal impairment

• Hypersensitivity to enalapril or any ACE inhibitor

• Primary hyperaldosteronism (ineffective and contraindicated)

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Warnings and Precautions

Angioedema

• Can be life-threatening

• May occur at any time during treatment, even after months of use

• Discontinue permanently if it occurs

Hyperkalemia

• Especially in patients with renal impairment, diabetes, or those using potassium-sparing diuretics or supplements

Hypotension

• Risk in volume-depleted or salt-depleted individuals

• Initiate cautiously in heart failure or diuretic users

Renal impairment

• May cause reversible increase in serum creatinine

• Monitor renal function closely, especially in the elderly or those with renal artery stenosis

Cough

• Persistent dry cough is common

• Resolves within weeks after discontinuation

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Adverse Effects

Very Common (≥10%)

• Dry persistent cough

• Dizziness

• Headache

• Fatigue

• Hypotension (especially first dose)

Common (1–10%)

• Hyperkalemia

• Increased serum creatinine or urea

• Nausea, vomiting, diarrhea

• Rash, pruritus

• Taste disturbance

Uncommon to Rare (<1%)

• Angioedema (face, tongue, airway)

• Neutropenia/agranulocytosis (especially in renal impairment or collagen vascular disease)

• Hepatotoxicity, cholestatic jaundice

• Gynecomastia (very rare)

• Acute kidney injury

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Drug Interactions

1. Diuretics (thiazides, loop)

   • May cause excessive hypotension on initiation; volume status should be optimized

2. Potassium supplements or potassium-sparing diuretics (e.g., spironolactone, eplerenone)

   • Increased risk of hyperkalemia

3. NSAIDs

   • Can blunt the antihypertensive effect and reduce renal perfusion, especially in volume-depleted patients

4. Lithium

   • Risk of lithium toxicity due to reduced renal clearance

5. Aliskiren

   • Concomitant use is contraindicated in diabetics and patients with renal impairment

6. Antihypertensive agents

   • Additive effects with beta blockers, calcium channel blockers, ARBs

7. Gold salts (e.g., sodium aurothiomalate)

   • Risk of nitritoid reactions (facial flushing, nausea, hypotension)

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Use in Special Populations

Pregnancy

• Contraindicated

• Causes fetal toxicity (renal dysplasia, hypotension, skull hypoplasia)

• Discontinue immediately upon confirmation of pregnancy

Lactation

• Excreted in breast milk in low amounts

• Consider alternatives, particularly for preterm neonates

Elderly

• Increased risk of hypotension and renal impairment

• Start with lower doses and titrate cautiously

Pediatrics

• Off-label in many countries, but may be used in children ≥1 month for hypertension

• Dose based on weight

Renal impairment

• Adjust dose according to eGFR

• Closely monitor potassium and creatinine

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Monitoring Parameters

• Blood pressure: Regularly to assess efficacy

• Serum potassium: At baseline, within 1 week of initiation, and periodically

• Renal function (serum creatinine, eGFR): At baseline and routinely

• Signs of angioedema: Particularly after initial doses

• CBC (in select patients): For leukopenia in patients with autoimmune disease

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Clinical Trial Evidence

• CONSENSUS Trial: Enalapril reduced mortality in severe congestive heart failure

• SOLVD Treatment Trial: Reduced risk of death and hospitalizations in heart failure with reduced ejection fraction

• SOLVD Prevention Trial: Delayed onset of symptomatic heart failure in patients with asymptomatic LV dysfunction

• RENAAL and IDNT Trials (related to RAAS inhibition): Indirect evidence supporting use in diabetic nephropathy

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Comparison with Other ACE Inhibitors

• Ramipril: Similar effects; ramipril may have more outcome data in cardiovascular protection (HOPE trial)

• Lisinopril: Longer half-life, no hepatic activation needed

• Perindopril: Preferred in stroke prevention (PROGRESS trial)

• Captopril: Shorter half-life, requires more frequent dosing

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Patient Counseling Points

• Take at the same time every day, with or without food

• Avoid salt substitutes containing potassium unless prescribed

• Rise slowly from sitting/lying positions to avoid dizziness

• Report persistent dry cough, swelling of lips/tongue/face, or urinary changes

• Regular blood tests are necessary to monitor potassium and kidney function

• Do not use during pregnancy

• Do not stop suddenly unless instructed