Continuing Education Activity

Enalaprilat injection is used in the management of hypertension when oral therapy is not practical. Enalaprilat is the active metabolite of the oral prodrug enalapril maleate. Enalaprilat is poorly absorbed orally and requires intravenous administration. It inhibits angiotensin I to angiotensin II conversion via competitive inhibition of the angiotensin-converting enzyme (ACE). This activity will highlight the mechanism of action, adverse event profile, pharmacology, dosing, contraindications, warning and precautions, monitoring, toxicity, and relevant interactions of enalaprilat, pertinent for members of the interprofessional team in the treatment of patients with conditions where this agent is indicated.

Objectives:

• Review the mechanism of action of enalaprilat and its conversion to enalapril.
• Discuss the contraindication for enalaprilat therapy.
• Review the adverse event profile for enalaprilat.
• Review interprofessional team strategies for improving care coordination and communication to advance enalaprilat and improve outcomes in hypertensive care.

Indications

Enalaprilat injection is used in the management of hypertension when oral therapy is not practical.[1] Enalaprilat injection is studied with only one other antihypertensive diuretic, furosemide, which reports approximately additive effects on blood pressure. Enalapril, the pro-drug of enalaprilat, is used extensively with various antihypertensive medicines without apparent adverse reactions except for occasional hypotension.

While considering enalaprilat injection, clinicians should pay attention to the fact that another angiotensin-converting enzyme inhibitor drug, captopril, is reported to cause agranulocytosis, particularly in patients with collagen vascular disease or renal impairment, and that available data are not sufficient to conclude if enalaprilat injection does have a similar risk. In considering the administration of enalaprilat injection, healthcare providers should note that ACE inhibitors affect blood pressure less in African American patients than in other races in controlled clinical trials. In addition, it should be taken into account that African American patients receiving ACE inhibitor medicines have been reported to have higher chances of angioedema than other patients.[2]

Mechanism of Action

Enalaprilat is the active metabolite of the oral prodrug enalapril maleate. Enalaprilat is poorly absorbed orally and must be administered intravenously. It inhibits angiotensin I to angiotensin II conversion via competitive inhibition of the angiotensin-converting enzyme (ACE).[3] This inhibition disrupts the renin-angiotensin-aldosterone system. Angiotensin II binds to AT1 receptors on smooth muscles to produce vasoconstriction and increased blood pressure. Additionally, angiotensin II  stimulates the adrenal cortex to secrete aldosterone. Aldosterone causes the distal tubules and collecting ducts of the kidneys to reabsorb water and sodium in exchange for potassium, which results in an expansion in extracellular volume and an increase in blood pressure. ACE inhibition leads to decreased plasma angiotensin II, leading to vasodilation and decreased aldosterone secretion. Angiotensin II also causes vasoconstriction of the afferent and efferent arterioles of the kidney, exerting a more significant effect on the efferent arterioles. Enalaprilat administration in the presence of hypovolemia can cause renal injury due to inadequate renal perfusion.[4] ACE breaks down bradykinin, a peptide that causes vasodilation. ACE inhibitors impede the breakdown of bradykinin, resulting in vasodilation and a bradykinin cough.[5]

Pharmacokinetics

Following intravenous administration of an enalaprilat, a small fraction is bound to ACE. The amount bound does not increase with a higher dose, indicating a saturable binding site for enalaprilat. The effective half-life for enalaprilat is around 11 hours. Enalaprilat is poorly absorbed following oral administration. Enalaprilat is primarily excreted via the kidneys, and more than 90 percent of a given dose is eliminated in the urine as an unchanged drug within 24 hours. Drug disposition remains unchanged for patients with creatinine clearance of more than 30 ml per minute. In patients with creatinine clearance less than 30 ml per minute, the time for Cmax, Tmax, and steady-state may be altered. Animal studies in dogs show that enalapril does not cross the blood-brain barrier and is found in the brain at very low concentrations. Studies conducted in rats show minimal tissue accumulation after multiple doses of enalapril maleate.

Administration

Heart Failure

• Avoid administration in patients with unstable heart failure or acute myocardial infarction.

Hypertension

• Intravenous (IV): 1.25 mg/dose given over 5 minutes every 6 hours. A clinical response typically occurs within 15 minutes.
• Concomitant diuretic therapy: start with 0.625 mg IV over 5 minutes.

  • If the effect is inadequate after 1 hour: repeat the dose and administer 1.25 mg at 6-hour intervals
  • If the effect is adequate after 1 hour: administer 0.625 mg IV every 6 hours
• Conversion from IV enalaprilat to enalapril:

  • No concomitant diuretic therapy: initiate enalapril 5 mg once daily
  • Concomitant diuretic therapy: initiate enalapril 2.5 mg once daily and titrate as needed

Patients with Renal Impairment

• Creatinine Clearance (CrCl) > 30 mL/minute: No dosage adjustment necessary
• CrCl ≤ 30 mL/minute: initiate 0.625 mg; if after 1 hour clinical response is unsatisfactory, repeat and then administer 1.25 mg every 6 hours
• Intermittent hemodialysis (IHD): 20 to 50% dialyzable (moderate)

  • Initial: 0.625 mg IV over 5 to 60 minutes
• Conversion from IV enalaprilat to enalapril:

  • CrCl > 30 mL/minute: initiate enalapril 5 mg once daily
  • CrCl ≤ 30 mL/minute: initiate enalapril 2.5 mg once daily

Enalaprilat administration should be via IV push undiluted over at least 5 minutes or as an infusion diluted in up to 50 milliliters of D5W or 0.9% NaCl. Avoid salt substitutes or a potassium-rich diet. A dose no greater than 0.625 mg over 5 minutes should be administered in patients with heart failure or hyponatremia and patients undergoing intensive diuresis, an increase in diuretic dose, or renal dialysis.[6]

Adverse Effects

• Hypotension (2-5%) is the most common manifestation of overdose, but the incidence of excessive hypotension remains relatively rare. Incidence increases with use in severely salt or volume-depleted persons, such as patients treated with diuretics or patients on dialysis. Before initiating therapy with enalaprilat, consider eliminating or reducing the diuretic dose. In the event of hypotension, place the patient in the supine position and infuse IV normal saline.
• Headache (3%)
• Nausea (1%)
• Myocardial infarction (< 1%)
• Cough (< 1%)
• Constipation (< 1%)
• Rash (< 1%)
• Fever (< 1%)
• Hypersensitivity reactions or anaphylactoid reactions

These adverse reactions may also be associated with enalapril because enalapril undergoes biotransformation to enalaprilat.

Warnings and Precautions

Pregnancy/Breastfeeding Considerations: Enalaprilat is pregnancy Category C in the first trimester and Category D in the second and third trimesters. All ACE inhibitors can cause injury and even death to the fetus when used in pregnancy during the second and third trimesters. Hypotension, neonatal skull hypoplasia, anuria, and renal failure can also occur with use in pregnancy.[7] If pregnancy is detected, discontinuing enalaprilat should be done as soon as possible. Enalaprilat is also detectable in human breast milk, which creates a potential for adverse events in nursing infants.[8] The safety and effectiveness of enalaprilat use in children have not been established.[9] 

Geriatric Considerations: In elderly patients, dose selection should be modest and initiated at a low dose. Enalaprilat undergoes substantial excretion by the kidney, and the risk of toxic reactions may be higher in elderly patients with impaired renal function. For patients with severe heart failure whose renal function depends on the renin-angiotensin-aldosterone system activity, ACE inhibitor therapy may be associated with oliguria, progressive azotemia, acute renal failure, or death. In the absence of pre-existing renal vascular disease, it is still possible to develop increases in blood urea and serum creatinine.

Hyperkalemia: In some hypertensive patients, hyperkalemia or elevated serum potassium greater than 5.7 mEq/L may occur. Additional risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium supplements or potassium-sparing agents.[10] In patients undergoing major surgery or anesthesia with agents that may cause hypotension, enalaprilat may block angiotensin II formation, and hypotension may result. This hypotension is correctable by volume expansion.[11]

Contraindications

• Hypersensitivity to enalapril, enalaprilat, or any component of the formulation
• Patients with a history of angioedema resulting from previous treatment with an ACE inhibitor
• Idiopathic or hereditary angioedema
• Concomitant aliskiren use in patients with diabetes mellitus
• Pregnancy[7]
• Breastfeeding[8]

Monitoring

Monitoring parameters include blood pressure, BUN, serum creatinine, and potassium. Blood pressure needs to be closely monitored with first dose administration or change in dose. If the patient has collagen vascular disease or renal impairment, complete blood count with differential is also a periodic monitoring requirement. Each patient should have an assessment for the presence of potential interactions with other medications that may impact their fluid balance or cardiac status. Monitoring for anaphylactic reactions, hypovolemia, angioedema, and postural hypotension is also necessary.[6]

Toxicity

Cholestatic jaundice progressing to fulminant hepatic necrosis may occur. Enalaprilat should be discontinued if a marked elevation of hepatic transaminases or jaundice occurs. Following the first dose or at any time during treatment, angioedema can occur.[12] Angioedema of the face, extremities, lips, tongue, glottis, or larynx can lead to airway compromise. African Americans may be at an increased risk of developing angioedema.[13] If angioedema occurs, immediately discontinue enalaprilat and initiate appropriate therapy with antihistamines and monitoring as needed. When the tongue, glottis, or larynx is involved, subcutaneous epinephrine 1:1000 may be administered to reverse airway obstruction. A persistent, dry, hacking, nonproductive cough that occurs within the first few months of treatment can also occur with enalaprilat therapy. ACE inhibitor-induced cough is the result of the inhibition of the degradation of bradykinin and generally resolves within 1 to 4 weeks after discontinuation.[5] Symptomatic hypotension, including syncope, can occur with ACE inhibitor therapy. Close monitoring and correction of volume depletion are necessary before initiating treatment. If hypotension occurs, consider reducing the enalaprilat dose, but do not abruptly discontinue therapy.

Enhancing Healthcare Team Outcomes

Enalaprilat is a widely used drug in the ICU for the management of hypertension. It is often prescribed by nurse practitioners, intensivists, cardiologists, and internists. The drug is effective with a rapid onset of action. However, nurses need to monitor the patient as hypotension can develop quickly. It is preferable to have an arterial line for continuous blood pressure monitoring while using enalaprilat. Nursing should verify the dose before administering the dose to patients and also inform the patients of potential adverse reactions. Pharmacists need to perform medication reconciliation and inform clinicians of any issues. Open communication and collaborative work among health care providers can result in the successful treatment of patients needing treatment with enalaprilat while in hospital. Clinicians need to verify that patient is converted to an equivalent oral dose of enalapril before discharge if needed to continue anti hypertensive treatment with it. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

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Papademetriou V, Narayan P, Kokkinos P. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in African-American patients with hypertension. J Clin Hypertens (Greenwich). 2004 Jun;6(6):310-4. [PMC free article: PMC8109657] [PubMed: 15187493]

3.

Verbeeck RK, Kanfer I, Löbenberg R, Abrahamsson B, Cristofoletti R, Groot DW, Langguth P, Polli JE, Parr A, Shah VP, Mehta M, Dressman JB. Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Enalapril. J Pharm Sci. 2017 Aug;106(8):1933-1943. [PubMed: 28435140]

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Wolf S, Risler T. [Are all antihypertensive drugs renoprotective?]. Herz. 2004 May;29(3):248-54. [PubMed: 15167950]

5.

Sachs B, Meier T, Nöthen MM, Stieber C, Stingl J. [Drug-induced angioedema : Focus on bradykinin]. Hautarzt. 2018 Apr;69(4):298-305. [PubMed: 29392343]

6.

Tabacova SA, Kimmel CA. Enalapril: pharmacokinetic/dynamic inferences for comparative developmental toxicity. A review. Reprod Toxicol. 2001 Sep-Oct;15(5):467-78. [PubMed: 11780954]

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Schubiger G, Flury G, Nussberger J. Enalapril for pregnancy-induced hypertension: acute renal failure in a neonate. Ann Intern Med. 1988 Feb;108(2):215-6. [PubMed: 2829674]

8.

Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, Hall K, Ray WA. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med. 2006 Jun 08;354(23):2443-51. [PubMed: 16760444]

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"Inactive" ingredients in pharmaceutical products: update (subject review). American Academy of Pediatrics Committee on Drugs. Pediatrics. 1997 Feb;99(2):268-78. [PubMed: 9024461]

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Santoro A, Mandreoli M. [Hyperkalemia as a limiting factor in the use of drugs that block the Renin Angiotensin Aldosterone System (RAAS)]. G Ital Nefrol. 2018 May;35(3) [PubMed: 29786183]

11.

Walker SLM, Abbott TEF, Brown K, Pearse RM, Ackland GL. Perioperative management of angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers: a survey of perioperative medicine practitioners. PeerJ. 2018;6:e5061. [PMC free article: PMC6055831] [PubMed: 30042876]

12.

Forner D, Kulai T, Arnason T, E Gruchy S, MacLeod M. Ramipril-associated cholestasis in the setting of recurrent drug-induced liver injury. Gastroenterol Hepatol Bed Bench. 2017 Spring;10(2):143-146. [PMC free article: PMC5495903] [PubMed: 28702139]

13.

Brown T, Gonzalez J, Monteleone C. Angiotensin-converting enzyme inhibitor-induced angioedema: A review of the literature. J Clin Hypertens (Greenwich). 2017 Dec;19(12):1377-1382. [PMC free article: PMC8031276] [PubMed: 28994183]

Disclosure: Francheska Marte declares no relevant financial relationships with ineligible companies.

Disclosure: Graham Dersnah declares no relevant financial relationships with ineligible companies.

Disclosure: Manouchkathe Cassagnol declares no relevant financial relationships with ineligible companies.