Monograph of Enalapril

Introduction/Overview

Enalapril is an orally active angiotensin‑converting enzyme (ACE) inhibitor that has been widely employed in the management of arterial hypertension, chronic heart failure, and post‑myocardial infarction syndrome. Its development in the early 1980s marked a significant advance in cardiovascular pharmacotherapy, providing a therapeutic option with improved tolerability compared to earlier ACE inhibitors. Clinical relevance stems from its proven efficacy in reducing morbidity and mortality associated with cardiovascular disease, as well as its role in renal protection for patients with diabetic nephropathy and chronic kidney disease. The following chapter aims to equip medical and pharmacy students with a comprehensive understanding of enalapril’s pharmacological profile, facilitating informed clinical decision‑making.

Learning objectives

• Describe the chemical classification and generic structure of enalapril.
• Explain the pharmacodynamic mechanisms underlying ACE inhibition and downstream physiological effects.
• Summarize key pharmacokinetic parameters, including absorption, distribution, metabolism, and elimination.
• Identify approved therapeutic indications as well as common off‑label applications.
• Recognize typical adverse reactions, serious complications, and contraindications.
• Discuss drug interactions and special patient populations requiring dose adjustment or monitoring.

Classification

Drug Class and Category

Enalapril belongs to the class of ACE inhibitors, which exert their primary action by inhibiting the catalytic conversion of angiotensin I to angiotensin II. Within the cardiovascular drug taxonomy, it is categorized under the subclass of antihypertensives and diuretics.

Chemical Classification

Structurally, enalapril is a prodrug that contains a carbamate functional group and a β‑hydroxy‑α‑amino acid moiety. The active metabolite, enalaprilat, possesses a carboxylate and a primary amine, enabling high affinity binding to the catalytic zinc ion within the ACE active site. Enalapril is also classified as a low‑molecular‑weight, lipophilic agent with a molecular formula of C₁₅H₂₈N₂O₅.

Mechanism of Action

Pharmacodynamics

The principal pharmacodynamic effect of enalapril is the attenuation of the renin‑angiotensin‑aldosterone system (RAAS). By competitively inhibiting ACE, the conversion of angiotensin I to angiotensin II is markedly reduced, resulting in decreased vasoconstriction, aldosterone release, and sympathetic activation. The downstream consequence is a sustained reduction in systemic vascular resistance and plasma volume, thereby lowering arterial blood pressure.Receptor Interactions

Angiotensin II, the main effector peptide, exerts its actions through AT₁ receptors located on vascular smooth muscle, cardiac myocytes, and adrenal cortical cells. Enalapril’s suppression of angiotensin II synthesis diminishes AT₁ receptor stimulation, which translates into vasodilation and anti‑remodeling effects on the myocardium. Additionally, decreased angiotensin II levels reduce the activation of AT₂ receptors, which are implicated in counter‑regulatory mechanisms but are less influential in the therapeutic context of enalapril.

Molecular/Cellular Mechanisms

At the cellular level, enalaprilat binds to the active site of ACE, coordinating with a zinc ion through its carboxylate group. This interaction prevents the C–N bond cleavage that normally generates angiotensin II. The inhibition of ACE also leads to increased bradykinin concentrations, a vasodilatory peptide degraded by ACE. Elevated bradykinin contributes to the antihypertensive effect and, in some patients, may underlie the incidence of cough and angioedema. The cumulative impact of ACE inhibition and bradykinin accumulation is a reduction in afterload and preload on the heart, promoting favorable remodeling in heart failure settings.

Pharmacokinetics

Absorption

Oral enalapril is rapidly absorbed from the gastrointestinal tract, achieving peak plasma concentrations (C_max) within 1–3 hours post‑dose. The bioavailability of the parent prodrug is approximately 30 %, largely due to first‑pass metabolism to enalaprilat. Food intake may modestly delay absorption but does not significantly diminish overall exposure.

Distribution

Enalaprilat is moderately lipophilic, allowing distribution into various tissues, including the myocardium and kidneys. The volume of distribution (V_d) is estimated at 0.5–1.0 L kg^-1, indicating a distribution largely confined to the extracellular fluid space. Plasma protein binding is relatively low (~20 %), facilitating rapid equilibration between plasma and interstitial compartments.

Metabolism

The pharmacologically active metabolite, enalaprilat, is generated by hydrolysis of the prodrug via non‑specific esterases. No significant hepatic biotransformation occurs; thus, hepatic impairment has limited impact on systemic exposure. The metabolism pathway involves hydrolysis rather than oxidative biotransformation, resulting in a negligible formation of reactive metabolites.

Excretion

Renal excretion predominates, with approximately 70–80 % of the administered dose eliminated unchanged in the urine. The renal clearance of enalaprilat approximates the glomerular filtration rate (GFR), rendering dose adjustments necessary in patients with reduced renal function. No enterohepatic recirculation has been observed.

Half‑Life and Dosing Considerations

Enalapril’s terminal half‑life (t_1/2) for the active metabolite ranges from 11 to 17 hours, supporting once‑daily dosing in most therapeutic contexts. In patients with severe renal impairment (Cr_Cl < 30 mL min^-1 1.73 m^-2), a reduction to 5 mg twice daily or 10 mg once daily may be considered, depending on the clinical scenario. The standard adult starting dose is 5 mg twice daily, titrated to 20 mg twice daily based on tolerability and blood pressure response. Pediatric dosing follows a weight‑based approach, typically 0.1 mg kg^-1 once daily for hypertension and 0.02–0.04 mg kg^-1 for heart failure, with close monitoring for hypotension and renal function.

Therapeutic Uses/Clinical Applications

Approved Indications

• Essential hypertension: effective as monotherapy or in combination with diuretics, calcium‑channel blockers, or beta‑blockers.
• Chronic heart failure: reduces mortality and hospitalization when used in conjunction with diuretics and beta‑blockers.
• Post‑myocardial infarction: improves left ventricular function and survival when started within 24 hours of reperfusion therapy.
• Diabetic nephropathy: slows progression of albuminuria and preserves glomerular filtration rate in patients with type 1 or type 2 diabetes and micro‑albuminuria.

Common Off‑Label Uses

• Pre‑conditioning for elective coronary artery bypass graft surgery to mitigate ischemia‑reperfusion injury.
• Management of resistant hypertension in patients with concomitant hyperaldosteronism, where ACE inhibition synergizes with mineralocorticoid antagonists.
• Adjunctive therapy in chronic obstructive pulmonary disease (COPD) with concomitant heart failure to ameliorate pulmonary hypertension.

Adverse Effects

Common Side Effects

• Dry cough: affecting approximately 10–20 % of patients, attributed to bradykinin accumulation.
• Hypotension: especially after the initial dose or in volume‑depleted states.
• Hyperkalemia: occurs in patients with renal impairment or concomitant potassium‑sparing diuretics.
• Azotemia: mild elevations in serum creatinine due to reduced glomerular filtration.

Serious or Rare Adverse Reactions

• Angioedema: rare but potentially life‑threatening, typically within the first few weeks of therapy; requires immediate discontinuation.
• Severe renal dysfunction: can develop in patients with pre‑existing renal disease or in the setting of hypovolemia.
• Rhabdomyolysis: very uncommon but reported when combined with statins; monitoring of creatine kinase levels is advised.

Black Box Warnings

• Pregnancy Category X: teratogenic effects, particularly fetal renal dysgenesis and oligohydramnios; contraindicated at all gestational ages.
• Potential for acute kidney injury in patients with bilateral renal artery stenosis or severe atherosclerotic disease of the renal arteries.

Drug Interactions

Major Drug‑Drug Interactions

• Potassium‑sparing diuretics (spironolactone, triamterene): synergistic hyperkalemia; serum potassium should be monitored.
• Non‑steroidal anti‑inflammatory drugs (NSAIDs): potential attenuation of ACE inhibition and reduced renal perfusion; caution in patients with renal impairment.
• Diuretics (thiazide, loop): increased risk of hypotension and electrolyte imbalance; dosage adjustments may be required.
• Statins (especially simvastatin): increased risk of rhabdomyolysis; recommend using lower statin doses or alternative agents.

Contraindications

• History of angioedema related to prior ACE inhibitor or ARB therapy.
• Pregnancy and lactation due to teratogenicity.
• Severe bilateral renal artery stenosis.
• Hypersensitivity to any constituent of the formulation.

Special Considerations

Use in Pregnancy/Lactation

Enalapril is strictly contraindicated in pregnancy owing to its high risk of fetal renal damage and oligohydramnios. During lactation, excretion into breast milk is minimal; however, the drug is not recommended for nursing mothers due to the potential for infant hypotension and bradycardia.

Pediatric/Geriatric Considerations

In pediatric patients, dosing is weight-based, and careful monitoring of blood pressure, renal function, and serum potassium is required. In geriatric patients, the decreased renal clearance necessitates dosage adjustment and vigilant monitoring for hypotension and electrolyte disturbances.

Renal/Hepatic Impairment

Renal impairment leads to accumulation of enalaprilat; dose reduction is mandatory when Cr_Cl < 30 mL min^-1 1.73 m^-2. Hepatic impairment has minimal influence on pharmacokinetics due to non‑hepatic metabolism, yet mild hepatic dysfunction may still affect drug efficacy and safety.

Summary/Key Points

• Enalapril is a well‑established ACE inhibitor with proven benefits in hypertension, heart failure, and diabetic nephropathy.
• Its pharmacodynamic profile hinges on the inhibition of ACE, resulting in lowered angiotensin II and elevated bradykinin levels.
• Renal excretion dominates elimination; therefore, dose adjustments are essential in impaired renal function.
• Common adverse effects include cough, hypotension, and hyperkalemia, while angioedema and renal dysfunction represent serious concerns.
• Drug interactions with potassium‑sparing diuretics, NSAIDs, and statins necessitate careful monitoring and potential dose modifications.
• Contraindications encompass pregnancy, lactation, and prior ACE‑inhibitor‑induced angioedema.
• Special populations—pregnant women, nursing mothers, the elderly, and patients with renal or hepatic impairment—require particular attention to dosing and safety.

Incorporating these considerations into clinical practice enhances therapeutic efficacy while mitigating risk, thereby aligning patient care with evidence‑based pharmacological principles.

References

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7. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
8. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.