Continuing Education Activity

Enalapril is a medication used in the management of hypertension and congestive heart failure. It is an angiotensin-converting enzyme inhibitor. This activity outlines the indications, action, and contraindications for enalapril as a valuable agent in managing hypertension and other disorders. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the healthcare team in the care of patients with hypertension and related conditions.

Objectives:

• Identify the mechanism of action of enalapril.
• Describe the potential adverse effects of enalapril.
• Review the appropriate monitoring and toxicity of enalapril.
• Outline interprofessional team strategies for improving care coordination and communication to advance enalapril and improve outcomes.

Indications

The most important labeled indications of enalapril are heart failure and chronic hypertension. Clinicians give enalapril for both symptomatic and asymptomatic congestive heart failure to decrease mortality and morbidity.[1][2][3][4] It is also used for the treatment of hypertensive emergency and hypertensive urgency. 

Off-labeled indications for adults are ST-elevated myocardial infarction, non-ST-elevated acute coronary syndrome, stable coronary artery disease, post-transplant erythrocytosis, and proteinuric chronic kidney disease. Enalapril also prevents diabetic nephropathy in normotensive patients.[5]

Mechanism of Action

Chemically enalapril is (S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-l-alanyl]-l-proline. The active form of enalapril is enalaprilat. It inhibits angiotensin-converting enzyme (ACE), thereby reducing the level of angiotensin-II. This action causes a decrease in total peripheral resistance without an increase in cardiac oxygen demand. There is a decrease in aldosterone and an increase in serum renin levels.[6]

Pharmacokinetics

• Absorption: Good oral absorption 
• Distribution: Volume of distribution is 1 to 2.4 L/kg
• Metabolism: De-esterified into enalaprilat in the liver
• Excretion: Excreted into the bile and urine

Administration

Food does not affect the absorption and metabolism of enalapril; therefore, administration can be irrespective of food intake. The oral solution is available in 1 mg/ml concentration, and tablets are available in 2.5 mg, 5 mg, 10 mg, or 20 mg strength. Typical adult dosing regimens are once or twice daily, depending on the indication.

Hypertension

• The recommended initial dose of enalapril in patients not on diuretics is 5 mg once a day, and the dose needs to be adjusted according to the patient's blood pressure. The normal dosage range is 10 to 40 mg per day. When patients are treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval, then twice-daily administration, or an increase in total once-daily dosage. 
• Concomitant diuretic: If blood pressure is uncontrolled with enalapril maleate alone, a diuretic may be added. In patients currently being treated with a diuretic, symptomatic hypotension may occur following the first dose of enalapril maleate.
• Before beginning treatment with enalapril, consider discontinuing diuretic medicine for two to three days. After that, if the patient's blood pressure is not controlled with enalapril alone, diuretic therapy can be resumed.
• If the diuretic cannot be discontinued, an initial dose of 2.5 mg should be used under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour. 
• Concomitant potassium supplements, potassium salt substitutes, or potassium-sparing diuretics: Co-administration of enalapril may increase serum potassium levels.

Heart Failure

• Enalapril is usually used in combination with diuretics and digitalis to treat symptomatic heart failure. The recommended initial dose of enalapril maleate is 2.5 mg, and observe the patient for at least 2 hours for symptomatic hypotension. Then, taper up to a maximum of 20 mg twice a day as tolerated by the patient over a few days or weeks. 

Asymptomatic Left Ventricular Dysfunction

• In the clinical trial, patients were started on 2.5 mg twice daily and titrated as tolerated to the targeted maximum daily dose of 20 mg in divided daily doses.

Speicific Patient Population

Pregnant Women: When a patient is pregnant, discontinue enalapril right away. Using enalapril in pregnancy can cause fetal injury and/or death. There are reports of ACE inhibitors causing severe renal and other problems during the second and third trimesters.

Breastfeeding Women: Enalapril maleate and enalaprilat are detected in human breast milk. Because of the potential serious adverse reactions in breastfed infants, discontinue breastfeeding or discontinue enalapril maleate, taking into account the risk-benefit of using enalapril.[7]

Pediatric Hypertensive Patients: Enalapril is not recommended in neonates and pediatric patients with GFR <30 mL/min/1.73m2, as no data are available.

Patients with Hypertension and Renal Impairment: If creatinine clearance <30 mL/min (SeCr>3 mg/dL), start at dose 2.5 mg once a day. If needed, titrate upward until blood pressure is under control or to the maximum of a total of 40 mg per day.

Patients with Heart Failure and Renal Impairment or Hyponatremia: Patients with heart failure whose serum creatinine is more than 1.6 mg/dl or have serum sodium LT 130 mEq/L, enalapril should be started at 2.5 mg daily under close medical supervision. The dose can be increased to 2.5 mg twice per day, then 5 mg twice per day, and higher as needed, usually after every fourth day or more. The dose is increased only if there is no excessive hypotension or significant deterioration of renal function when adjusting. The allowed maximum daily dose is 40 mg.

Adverse Effects

• The side effect most commonly encountered with ACE inhibitors is cough. The cough is characteristically non-productive and stops with the discontinuation of the drug.
• Other adverse effects of enalapril are hypotension, hyperkalemia, angioedema, cholestatic jaundice, and hypersensitivity reaction.
• Vasodilation caused by enalapril to reduce the afterload of the heart and decrease the total peripheral resistance is also responsible for hypotension. At first, the patient may only complain of a feeling of light-headedness on standing (orthostatic hypotension), which may later progress to fainting spells. 
• Aldosterone, the end product of renin-angiotensin-aldosterone-system (RAAS), causes sodium and water absorption and potassium ions' excretion. The use of enalapril can reduce potassium excretion from the kidney, leading to the buildup of potassium in the blood: a condition known as hyperkalemia. Hyperkalemia, if only mild or moderate, may be asymptomatic. Even chronic hyperkalemia can be completely asymptomatic with a normal ECG pattern. The following ECG changes suggest hyperkalemia: small or absent P wave, prolonged PR interval, augmented R wave, wide QRS complex, and peaked T waves.[8]
• Angioedema may rarely occur with the use of ACE inhibitors. The incidence of angioedema is higher in African-American individuals.[9][10][11] The involvement of the head and neck can potentially compromise the airway. When the intestines are involved, the patient usually presents with abdominal pain.[12][13] An important drug interaction to remember is mTOR inhibitors and neprilysin inhibitors with ACE inhibitors. The use of these drugs, along with ACE inhibitors, can increase the risk of angioedema.[14][15]
• On rare occasions, ACE inhibitors can affect the hepatobiliary system causing cholestatic jaundice and fulminant hepatic necrosis.[16] The earliest evidence could be the elevation of hepatic transaminases, and such cases merit discontinuation of ACE inhibitors. The clinician should also discontinue the drug if there is any indication of anaphylaxis or anaphylactoid reaction.

Contraindications

Absolute Contraindications 

1. Use of enalapril is contraindicated in patients with:

• Idiopathic angioedema 
• Hereditary angioedema 
• Previous history of  angioedema associated with ACE inhibitors

     2. History of hypersensitivity reaction with the use of ACE inhibitors

     3. Pregnancy and lactation

Relative Contraindications: Clinicians should avoid using enalapril or, if necessary, use it with caution in patients with aortic stenosis, myocardial infarction, stroke, hypertrophic cardiomyopathy, collagen vascular disease (e.g., SLE), renal artery stenosis, and renal impairment. 

Drug Interaction: ACE inhibitors interact with numerous drugs and can cause adverse effects, therapeutic failures, and toxicities. Thus these interactions are important to take under consideration when prescribing enalapril:

1. Drugs that enhance the hypotensive activity of  ACE inhibitors are:

• 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
• Tizanidine

2. Drugs that diminish the antihypertensive effect of  ACE inhibitors are:

• Amphetamines
• Aprotinin
• Brigantinib 
• Bromperidol
• Dexmethylphenidate
• Icatibant 
• Lanthanum
• Methylphenidate 
• Yohimbine

3. Drugs that enhance the adverse effects of ACE inhibitors are: 

• Angiotensin receptor blockers (ARBs)
• Dipeptidyl peptidase IV inhibitors 
• Everolimus
• Racecadotril 
• Ranolazine
• Salicylates
• Sirolimus
• Temsirolimus
• Urokinase

4. Drugs that enhance the incidence of hyperkalemia ( when given concomitantly with  ACE inhibitors)

• Aliskiren
• Drospirenone
• Eplerenone
• Heparin
• Low molecular weight heparin
• Nicorandil
• Potassium salts
• Potassium-sparing diuretics
• Tacrolimus
• Tolvaptan
• Trimethoprim

5. ACE inhibitors can enhance the adverse effects of the following drugs:

• Allopurinol
• Alteplase 
• Azathioprine
• Ferric gluconate
• Ferric hydroxide polymaltose complex
• Gelatin (succinylated)
• Gold sodium thiomalate 
• Iron dextran complex
• Lithium
• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Pregabalin
• Sacubitril
• Sodium phosphate

Monitoring

Monitoring the vital signs, renal function, and cardiac activity is of the utmost importance when administering enalapril in patients with relative contraindications. The clinician should consider the following tests:

• Renal function
• Serum potassium
• Serum creatinine
• BUN
• Complete blood count
• SGOT and SGPT (hepatic transaminases)

Toxicity

The occurrence of enalapril toxicity is rare. A single such case of toxicity came into light in 1984 when a woman tried to commit suicide by ingesting 300 mg of enalapril (a hundred times the normal dose) and 225 mg oxazepam.[17] In 1986, another woman tried the same by ingesting 440 mg of enalapril with 42 mg warfarin.[18] Fortunately, both recovered from acute intoxication of enalapril. Fluid resuscitation played a major role in increasing intravascular volume as hypotension was the major complication. The second patient died forty days later due to intractable heart failure. Hence enalapril toxicity can be managed by giving symptomatic treatment. Enalaprilat is removed from neonatal circulation by peritoneal dialysis and can be removed from general circulation via hemodialysis.

Enhancing Healthcare Team Outcomes

Today, about 66% of the geriatric population is hypertensive.[19] Clinicians prescribe ACE inhibitors in a large segment of this population as the first-line treatment of hypertension. During a routine examination of such patients, physicians and other healthcare providers (especially nurses and nurse practitioners) should keep in mind that patients more than 70 years of age are at greater risk of hyperkalemia due to ACE inhibitors.[20] Healthcare providers should counsel the patient adequately about the same. Patients under 70 years of age on ACE inhibitors usually only develop mild to moderate hyperkalemia. Even patients on ACE inhibitors with blood urea nitrogen (BUN) greater than 8.9mmol/L  have a higher risk of developing hyperkalemia.[20] Chronic hyperkalemia can be completely asymptomatic, and even ECG changes can be absent in such patients. For the same reason, ECG cannot serve as a diagnostic modality for hyperkalemia. It is crucial to diagnose severe hyperkalemia in time as it can cause life-threatening complications such as cardiac arrest.[21]

While enalapril is a common and well-tolerated medication, but its use and management still require the efforts of an interprofessional healthcare team that includes clinicians, specialists, mid-level practitioners, nurses, and pharmacists, all working collaboratively and sharing open communication to direct patient care and achieve the nest outcomes with minimal adverse events. [Level 5]