Enalapril

Article Author:
Arjumand Faruqi
Article Editor:
Ashish Jain
Updated:
5/13/2020 5:09:18 PM
PubMed Link:
Enalapril

Indications

The most important labeled indications of enalapril are heart failure and 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 the 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 so that administration can be irrespective of food intake. Oral solution available is of 1 mg/ml concentration and tablets are of 2.5 mg, 5 mg, 10 mg, or 20 mg.

Adverse Effects

The side effect most commonly encountered with the use of 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 heart and decrease the total peripheral resistance is also responsible for hypotension. The patient may at first 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 absorption of sodium and water and excretion of potassium ion. The use of enalapril can reduce potassium excretion from the kidney leading to build up 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 normal ECG pattern. The following ECG changes are suggestive of hyperkalemia: small or absent P wave, prolonged PR interval, augmented R wave, wide QRS complex, and peaked T waves.[7]

Angioedema may rarely occur with the use of ACE inhibitors. The incidence of angioedema is higher in African-American individuals.[8][9][10] The involvement of the head and neck can potentially compromise the airway. When the intestines are involved, the patient usually presents with abdominal pain.[11][12] An important drug interaction to remember is that of mTOR inhibitors and neprilysin inhibitor with ACE inhibitors. The use of these drugs, along with ACE inhibitors, can increase the risk of angioedema.[13][14]

On rare occasions, ACE inhibitors can affect the hepatobiliary system causing cholestatic jaundice and fulminant hepatic necrosis.[15] 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 
  • or 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 (eg., 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 (hundred times the normal dose) and 225 mg oxazepam.[16] In 1986, another woman tried the same by ingesting 440 mg of enalapril with 42 mg warfarin.[17] 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.

Enhancing Healthcare Team Outcomes

Today, about 66% of the geriatric population is hypertensive.[18] Clinicians prescribe ACE inhibitors in large part 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.[19] Healthcare providers should counsel the patient adequately about the same. Patients, less than 70 years of age, on ACE inhibitors usually develop mild to moderate hyperkalemia only. Even patients on ACE inhibitors with blood urea nitrogen (BUN) greater than 8.9mmol/L  have a higher risk of developing hyperkalemia.[19] 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.[20]


References

[1] Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The New England journal of medicine. 1987 Jun 4;     [PubMed PMID: 2883575]
[2] Swedberg K,Kjekshus J, Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The American journal of cardiology. 1988 Jul 11;     [PubMed PMID: 2839019]
[3] Yusuf S,Pitt B,Davis CE,Hood WB,Cohn JN, Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The New England journal of medicine. 1991 Aug 1;     [PubMed PMID: 2057034]
[4] Kjekshus J,Swedberg K, Enalapril for congestive heart failure. The American journal of cardiology. 1989 Feb 21;     [PubMed PMID: 2537563]
[5] Marre M,Chatellier G,Leblanc H,Guyene TT,Menard J,Passa P, Prevention of diabetic nephropathy with enalapril in normotensive diabetics with microalbuminuria. BMJ (Clinical research ed.). 1988 Oct 29;     [PubMed PMID: 2848604]
[6] Todd PA,Goa KL, Enalapril. A reappraisal of its pharmacology and therapeutic use in hypertension. Drugs. 1992 Mar;     [PubMed PMID: 1374319]
[7] Simon LV,Hashmi MF,Farrell MW, Hyperkalemia 2020 Jan;     [PubMed PMID: 29261936]
[8] Gibbs CR,Lip GY,Beevers DG, Angioedema due to ACE inhibitors: increased risk in patients of African origin. British journal of clinical pharmacology. 1999 Dec;     [PubMed PMID: 10594491]
[9] Brown NJ,Ray WA,Snowden M,Griffin MR, Black Americans have an increased rate of angiotensin converting enzyme inhibitor-associated angioedema. Clinical pharmacology and therapeutics. 1996 Jul;     [PubMed PMID: 8689816]
[10] Kostis JB,Kim HJ,Rusnak J,Casale T,Kaplan A,Corren J,Levy E, Incidence and characteristics of angioedema associated with enalapril. Archives of internal medicine. 2005 Jul 25;     [PubMed PMID: 16043683]
[11] Schmidt TD,McGrath KM, Angiotensin-converting enzyme inhibitor angioedema of the intestine: a case report and review of the literature. The American journal of the medical sciences. 2002 Aug;     [PubMed PMID: 12186104]
[12] Oudit G,Girgrah N,Allard J, ACE inhibitor-induced angioedema of the intestine: Case report, incidence, pathophysiology, diagnosis and management. Canadian journal of gastroenterology = Journal canadien de gastroenterologie. 2001 Dec;     [PubMed PMID: 11773949]
[13] Duerr M,Glander P,Diekmann F,Dragun D,Neumayer HH,Budde K, Increased incidence of angioedema with ACE inhibitors in combination with mTOR inhibitors in kidney transplant recipients. Clinical journal of the American Society of Nephrology : CJASN. 2010 Apr;     [PubMed PMID: 20093343]
[14] Charmillon A,Deibener J,Kaminsky P,Louis G, Angioedema induced by angiotensin converting enzyme inhibitors, potentiated by m-TOR inhibitors: successful treatment with icatibant. Intensive care medicine. 2014 Jun;     [PubMed PMID: 24737261]
[15] Todd P,Levison D,Farthing MJ, Enalapril-related cholestatic jaundice. Journal of the Royal Society of Medicine. 1990 Apr;     [PubMed PMID: 2342045]
[16] Waeber B,Nussberger J,Brunner HR, Self poisoning with enalapril. British medical journal (Clinical research ed.). 1984 Jan 28;     [PubMed PMID: 6318878]
[17] Lau CP, Attempted suicide with enalapril. The New England journal of medicine. 1986 Jul 17;     [PubMed PMID: 3014333]
[18] Nguyen QT,Anderson SR,Sanders L,Nguyen LD, Managing hypertension in the elderly: a common chronic disease with increasing age. American health     [PubMed PMID: 24991317]
[19] Reardon LC,Macpherson DS, Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors. How much should we worry? Archives of internal medicine. 1998 Jan 12;     [PubMed PMID: 9437375]
[20] Raebel MA, Hyperkalemia associated with use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Cardiovascular therapeutics. 2012 Jun;     [PubMed PMID: 21883995]