Continuing Education Activity

Enalapril maleate is a prominent angiotensin-converting enzyme inhibitor approved by the US Food and Drug Administration (FDA) for the treatment of heart failure, chronic hypertension, and asymptomatic left ventricular dysfunction. The FDA has approved a fixed-dose combination of enalapril with hydrochlorothiazide. Enalapril is utilized in asymptomatic left ventricular dysfunction as it mitigates progression to symptomatic heart failure and reduces mortality.

This activity focuses on various aspects of enalapril, including its indications, mechanism of action, adverse event profile, dosing considerations, monitoring strategies, and potential drug interactions, specifically emphasizing its crucial role as an effective agent in managing hypertension and associated disorders. This activity also highlights the significance of a collaborative approach involving an interprofessional healthcare team in effectively utilizing and managing enalapril, ensuring shared decision-making and patient safety while delivering optimal care to patients with hypertension and related conditions.

Objectives:

• Identify patients who would benefit from enalapril therapy based on indications such as heart failure, chronic hypertension, and asymptomatic left ventricular dysfunction.

• Screen patients for potential contraindications and risk factors associated with enalapril therapy, including age-related considerations and drug interactions.

• Assess patient response to enalapril therapy by regularly monitoring renal function as well as blood pressure and electrolyte levels in patients.

• Collaborate with interprofessional healthcare teams to coordinate follow-up care and monitoring for patients receiving enalapril therapy, thereby optimizing treatment outcomes and safety.

Indications

Enalapril maleate is a prominent angiotensin-converting enzyme (ACE) inhibitor approved by the US Food and Drug Administration (FDA) for the treatment of heart failure, chronic hypertension, and asymptomatic left ventricular (LV) dysfunction.

FDA Approved Indications

The FDA-approved indications of enalapril are heart failure, chronic hypertension, and asymptomatic LV dysfunction, with ejection fraction (EF) ≤35%.[1][2] As per the American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Failure Society of America (HFSA) 2022 guideline, ACE inhibitors, such as enalapril, are part of guideline-directed medical therapy. Enalapril is specifically indicated for the treatment of heart failure with reduced EF of <40%.[3]

According to the ACC/AHA clinical practice guideline for hypertension, ACE inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers, and thiazides are the preferred pharmacotherapy choices.[4] The International Society of Hypertension (ISH) guidelines recommend single-pill combination therapy or fixed-dose combination (FDC) due to increased adherence. The FDA has approved a FDC of enalapril with hydrochlorothiazide.[5] Enalapril is utilized in asymptomatic LV dysfunction as it mitigates progression to symptomatic heart failure and reduces mortality.[6]

Off-Label Uses

Adults with ST-elevated myocardial infarction, non-ST–elevated acute coronary syndrome, stable coronary artery disease, post-transplant erythrocytosis, and proteinuric chronic kidney disease are candidates for off-label use of enalapril. In addition, enalapril has been found to prevent diabetic nephropathy in normotensive patients.[7] 

According to the joint American Diabetes Association (ADA)/Kidney Disease Improving Global Outcomes (KDIGO) guideline, treatment with ACE inhibitors, such as enalapril, is recommended for patients with diabetes and hypertension, particularly those with an increased urine albumin-to-creatinine ratio (ACR) of 30 to 299 mg/g. Treatment is strongly suggested for those with a urinary ACR ≥300 mg/g or an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m².[8]

Mechanism of Action

Chemically enalapril is (S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline. The active form of enalapril is enalaprilat, which inhibits the ACE, thereby reducing the level of angiotensin-II. This action leads to a decrease in total peripheral resistance without an increase in cardiac oxygen demand. Consequently, a decrease in aldosterone and an increase in serum renin levels are observed.[9] 

Activation of the renin-angiotensin-aldosterone system (RAAS) leads to maladaptive mechanisms, resulting in cardiac remodeling. ACE inhibitors prevent maladaptive cardiac cell hypertrophy, facilitate salt and water excretion, and increase bradykinin levels by reducing the breakdown, resulting in vasodilation. Comprehensive modulation of RAAS by ACE inhibitor enhances LV function and cardiac remodeling.[10][11]

Pharmacokinetics

Absorption: Enalapril exhibits good oral absorption, with peak concentration achieved in approximately 1 hour.[12]

Distribution: The volume of distribution for enalapril is 1 to 2.4 L/kg, and according to a recent meta-analysis, it poorly crosses the blood-brain barrier.[13]

Metabolism: Organic anion transporting polypeptide-1B1 (OATP1B1) transports enalapril into hepatocytes. Within the hepatocytes, enalapril undergoes metabolism by carboxylesterase 1 (CES1) to enalaprilat, which is its active metabolite.[14][15]

Excretion: Approximately two-thirds of enalapril is excreted unchanged in the urine and as enalaprilat. The remaining portion is excreted in the feces via the bile. Renal excretion of enalaprilat involves both glomerular filtration and tubular secretion.[16]

Administration

Available Dosage Forms and Strengths

The absorption and metabolism of enalapril remain unaffected by food, making administration independent of food intake. The oral solution is available in a concentration of 1 mg/mL, whereas tablets come in strengths of 2.5 mg, 5 mg, 10 mg, or 20 mg.

Typical adult dosing regimens range from once to twice daily, depending on the indication. The fixed-dose combination is available as enalapril 5 mg/hydrochlorothiazide 12.5 mg and enalapril 10 mg/hydrochlorothiazide 25 mg.

Adult Dosage

Hypertension: Managing hypertension effectively with enalapril requires tailored treatment approaches, as mentioned below.

• Patients not on diuretics: The recommended initial dosage of enalapril for patients not on diuretics is 5 mg daily, with dosage adjustments based on the patient's blood pressure. The typical dosage range is 10 to 40 mg/d. For patients on daily enalapril treatment, the antihypertensive effect may diminish near the end of the dosing interval. In such cases, it is advisable to consider twice-daily administration or an increase in the total once-daily dosage.[4]

• Patients on concomitant diuretics: If blood pressure remains uncontrolled with enalapril maleate alone, adding a diuretic may be necessary. Patients currently on diuretic therapy may experience symptomatic hypotension following the first dose of enalapril maleate. Notably, it is advisable to discontinue diuretic medication for 2 to 3 days before initiating enalapril treatment. If blood pressure remains uncontrolled with enalapril alone after this period, diuretic therapy can be resumed. If discontinuing the diuretic is not feasible, an initial enalapril dose of 2.5 mg should be administered to patients under medical supervision. This should be continued for at least 2 hours, with additional monitoring until blood pressure stabilizes for at least another hour. 

• Patients on concomitant potassium supplements, potassium salt substitutes, or potassium-sparing diuretics: Patients coadministering enalapril with all these compounds may experience an elevation in serum potassium levels.

Heart failure with reduced ejection fraction: Enalapril is usually used in combination with diuretics and digitalis for managing symptomatic heart failure. Monitoring patients for at least 2 hours for symptomatic hypotension following the first dose is crucial. The recommended initial dosage of enalapril for heart failure with reduced ejection fraction (HFrEF) is 2.5 mg twice daily. Prescribers are advised to gradually titrate the dosage up to the target range of 10 to 20 mg twice daily, as tolerated by the patient, over several days to weeks.[3] 

For patients with heart failure whose serum creatinine exceeds 1.6 mg/dL or who have serum sodium levels below 130 mEq/L, enalapril should be initiated at 2.5 mg daily under close medical supervision. The dosage can be escalated to 2.5 mg twice daily, then to 5 mg twice daily, and further increased as necessary, typically every fourth day or longer intervals. Dosage adjustments should be made cautiously, increasing only if excessive hypotension or significant deterioration of renal function is not observed. The maximum daily dosage permitted is 40 mg.

Asymptomatic left ventricular dysfunction: In the clinical trial, patients were initiated on a dosage of 2.5 mg twice daily, with gradual titration to the targeted maximum daily dose of 20 mg, administered in divided daily doses as tolerated. 

Specific Patient Populations

Renal impairment: Enalapril should be started at 2.5 mg/d for patients with creatinine clearance less than 30 mL/min and serum creatinine greater than 3 mg/dL. The dosage can be gradually increased, if necessary, until blood pressure is adequately controlled or to a maximum of 40 mg/d.

Hepatic impairment: Due to limited available data, enalapril should be used with caution in patients with hepatic impairment.

Pregnancy considerations: Enalapril should be discontinued immediately if a patient becomes pregnant, as its use during pregnancy can result in fetal injury and death. Furthermore, there have been reports linking ACE inhibitors to renal dysplasia and oligohydramnios during the second and third trimesters.[17][18]

Breastfeeding considerations: Although enalapril's concentration in breastmilk is low, the amount ingested by the infant is minimal. However, considering the potential adverse reactions in breastfed infants, it is advisable to either discontinue breastfeeding or discontinue enalapril, weighing the risks and benefits carefully.[19]

Pediatric patients: According to the American Academy of Pediatrics (AAP) guidelines, the recommended initial dosage for patients 1 month or older is 0.08 mg/kg. However, due to insufficient data, enalapril is not recommended for neonates and pediatric patients with a GFR of less than 30 mL/min/1.73m².[20]

Older patients: Caution is warranted when using enalapril in older patients, as they may be at an increased risk of drug interactions due to polypharmacy.[21]

Adverse Effects

The most commonly encountered adverse drug reaction with ACE inhibitors is cough.[22] The cough is characteristically nonproductive and resolves upon discontinuation of the drug. If dry cough persists after ruling out other potential causes, switching to ARBs is recommended.[23] Other adverse effects associated with enalapril include hypotension, hyperkalemia, angioedema, cholestatic jaundice, and hypersensitivity reactions.

Vasodilation induced by enalapril, which diminishes the heart's afterload and lowers total peripheral resistance, can lead to hypotension. Initially, patients may experience symptoms such as light-headedness upon standing (orthostatic hypotension), which may progress to fainting spells over time. 

Aldosterone, the end product of the RAAS, promotes sodium and water reabsorption while facilitating potassium excretion in the kidneys. However, the use of enalapril can interfere with potassium excretion, leading to an accumulation of potassium in the blood, known as hyperkalemia. Hyperkalemia may be asymptomatic if mild or moderate. Chronic hyperkalemia can be entirely asymptomatic, with an electrocardiogram (ECG) showing normal patterns. However, ECG changes indicative of hyperkalemia may include a small or absent P wave, prolonged PR interval, augmented R wave, widened QRS complex, and peaked T waves.[24] 

Angioedema is a rare but possible adverse effect associated with the use of ACE inhibitors. Notably, its incidence is higher among individuals of African-American descent.[25][26][27] In severe cases, angioedema involving the head and neck regions can pose a risk to the airway. Gastrointestinal involvement may manifest as abdominal pain.[28][29] Furthermore, an important drug interaction to be mindful of is the combination of mammalian target of rapamycin (mTOR) inhibitors and neprilysin inhibitors with ACE inhibitors, as this combination may heighten the risk of angioedema.[30][31]

In rare instances, ACE inhibitors may impact the hepatobiliary system, leading to conditions such as cholestatic jaundice and fulminant hepatic necrosis.[32] Elevated hepatic transaminase levels may serve as early indicators, warranting discontinuation of ACE inhibitors in such cases. In addition, clinicians should promptly discontinue the drug if any signs of anaphylaxis or anaphylactoid reactions become evident.

A recent case report highlights unilateral tongue edema (angioedema) attributed to enalapril.[33]

Drug-Drug Interactions

ACE inhibitors interact with numerous drugs and can cause adverse effects, therapeutic failures, and toxicities. Therefore, it is crucial to consider the following interactions when prescribing enalapril:

• Drugs that enhance the hypotensive activity of ACE inhibitors include alfuzosin, amifostine, antipsychotic agents, barbiturates, benperidol, brimonidine, dapoxetine, diazoxide, duloxetine, levodopa, loop diuretics, lormetazepam, molsidomine, naftopidil, nicergoline, nitroprusside, obinutuzumab, pholcodine, phosphodiesterase-5 inhibitors, prostacyclin analogs, thiazide and thiazide-like diuretics, and tizanidine.[34][35]

• Drugs that reduce the antihypertensive effect of ACE inhibitors include amphetamines, aprotinin, brigatinib, bromperidol, dexmethylphenidate, icatibant, lanthanum, methylphenidate, yohimbine, and nonsteroidal anti-inflammatory drugs (NSAIDs).[5]

• Drugs that enhance the adverse effects of ACE inhibitors include ARBs, dipeptidyl peptidase IV inhibitors, everolimus, racecadotril, ranolazine, salicylates, and sirolimus.[36]

• Drugs that enhance the incidence of hyperkalemia when given concomitantly with ACE inhibitors include aliskiren, drospirenone, eplerenone, heparin, low-molecular-weight heparin, nicorandil, potassium salts, potassium-sparing diuretics, tacrolimus, tolvaptan, and trimethoprim.[22]

• Drugs that ACE inhibitors can enhance the adverse effects of include allopurinol, alteplase, azathioprine, ferric gluconate, ferric hydroxide poly-maltose complex, gelatin (succinylated), gold sodium thiomalate, iron dextran complex, lithium, pregabalin, sacubitril, and sodium phosphate.[37]

Contraindications

Box Warning

Enalapril has a boxed warning for fetal toxicity. Exposure to ACE inhibitors during pregnancy is associated with adverse pregnancy outcomes, including fetal lung hypoplasia, skeletal malformations, skull hypoplasia, renal agenesis, and oligohydramnios. ACE inhibitors are also associated with congenital malformations and miscarriages. If pregnancy is detected, clinicians should promptly discontinue enalapril.[38][39]

Contraindications Associated With Enalapril

Absolute contraindications: Enalapril is contraindicated in patients with idiopathic angioedema, hereditary angioedema, or a previous history of angioedema associated with ACE inhibitor use.[40] In addition, the drug is contraindicated in patients with a history of hypersensitivity reactions to ACE inhibitors. Dual blockade of RAAS with enalapril and aliskiren should be avoided, as their concomitant use increases the risk of hyperkalemia, hypotension, and acute renal failure in diabetic patients. Furthermore, using neprilysin inhibitors, such as sacubitril, with ACE inhibitors heightens the risk of angioedema. Therefore, enalapril should not be administered within 36 hours of transitioning to or from sacubitril/valsartan.[30][31]

Relative contraindications: Relative contraindications to enalapril use include aortic stenosis, myocardial infarction, stroke, hypertrophic cardiomyopathy, collagen vascular disease such as SLE, bilateral renal artery stenosis, and renal impairment.[41] Thus, clinicians should exercise caution when prescribing enalapril in these patients, and its use should be avoided if possible

Monitoring

When administering enalapril to patients with relative contraindications, it is essential to prioritize monitoring vital signs, renal function, and cardiac activity. Clinicians should consider the following tests:

• The ISH recommends monitoring serum creatinine and eGFR, conducting a dipstick urine test, and obtaining a 12-lead ECG.[5]

• Serum potassium levels should be regularly monitored.

• A complete blood count with a differential should be obtained if agranulocytosis is suspected.[42]

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (hepatic transaminases) should be monitored in patients with hepatic impairment due to the risk of hepatotoxicity.[43]

• In heart failure patients, monitoring should include assessing volume status, body weight (simultaneously each day), and clinical signs of congestion and hypoperfusion.[3]

• For diabetic nephropathy, monitoring the ACR is recommended.[8]

Toxicity

Enalapril toxicity is rare, with hypotension being a major complication. Management typically involves symptomatic treatment, while fluid resuscitation can be utilized to increase intravascular volume. In neonates, peritoneal dialysis can remove enalapril from circulation, while hemodialysis is effective in general cases.

A recent case report demonstrated the successful use of naloxone for ACE inhibitor overdose, suggesting a potential mechanism involving the endogenous opioid system and accumulation of enkephalins. However, due to the opioid epidemic, concomitant opioid intoxication cannot be excluded. Further research is warranted to explore the use of naloxone in ACE inhibitor poisoning.[44][45]

Enhancing Healthcare Team Outcomes

Enalapril is a frequently prescribed medication by clinicians for treating chronic hypertension, heart failure, asymptomatic LV dysfunction, and diabetic nephropathy. Today, approximately 66% of the older population suffers from hypertension.[46] According to The Centers for Disease Control and Prevention (CDC), approximately 6.2 million adults in the United States were diagnosed with heart failure in 2020, with ACE inhibitors commonly used in treatment.[47] 

Healthcare providers should be mindful during routine checkups that patients using ACE inhibitors and those aged 70 or older are at a higher risk of developing hyperkalemia.[48] In contrast, patients younger than 70 and on ACE inhibitors typically develop only mild-to-moderate hyperkalemia. Patients taking ACE inhibitors with blood urea nitrogen (BUN) higher than 8.9 mmol/L are at an increased risk of developing hyperkalemia.[48] As severe hyperkalemia can precipitate life-threatening complications, healthcare providers should provide adequate counseling to such patients about these risks. Chronic hyperkalemia can manifest as entirely asymptomatic, with no discernible ECG changes. Thus, relying solely on ECG for diagnosing hyperkalemia may be insufficient. Timely diagnosis of severe hyperkalemia is imperative, as it can lead to life-threatening complications such as cardiac arrest.[49] 

Although enalapril is a widely used and generally well-tolerated medication, its proper utilization and management necessitate the collaboration of an interprofessional healthcare team comprising clinicians, specialists, nurses, and pharmacists. This collaboration facilitates shared decision-making and ensures patient safety. Participating clinicians can deliver optimal care to patients with hypertension and related conditions through effective communication and essential information obtained from this activity.