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.
- 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.
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. 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.
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.
- 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
Food does not affect the absorption and metabolism of enalapril; therefore, 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. Typical adult dosing regimens are once or twice daily, depending on the indication.
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 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 absorption of sodium and water and excretion of potassium ions. 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 a 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.
Angioedema may rarely occur with the use of ACE inhibitors. The incidence of angioedema is higher in African-American individuals. The involvement of the head and neck can potentially compromise the airway. When the intestines are involved, the patient usually presents with abdominal pain. An important drug interaction to remember is that of mTOR inhibitors and neprilysin inhibitors with ACE inhibitors. The use of these drugs, along with ACE inhibitors, can increase the risk of angioedema.
On rare occasions, ACE inhibitors can affect the hepatobiliary system causing cholestatic jaundice and fulminant hepatic necrosis. 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.
- 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 (e.g., SLE), renal artery stenosis, and renal impairment.
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:
- Antipsychotic agents
- Loop diuretics
- Phosphodiesterase-5 inhibitors
- Prostacyclin analogs
- Thiazide and thiazide-like diuretics
2. Drugs that diminish the antihypertensive effect of ACE inhibitors are:
3. Drugs that enhance the adverse effects of ACE inhibitors are:
- Angiotensin receptor blockers (ARBs)
- Dipeptidyl peptidase IV inhibitors
4. Drugs that enhance the incidence of hyperkalemia ( when given concomitantly with ACE inhibitors)
- Low molecular weight heparin
- Potassium salts
- Potassium-sparing diuretics
5. ACE inhibitors can enhance the adverse effects of the following drugs:
- Ferric gluconate
- Ferric hydroxide polymaltose complex
- Gelatin (succinylated)
- Gold sodium thiomalate
- Iron dextran complex
- Non-steroidal anti-inflammatory drugs (NSAIDs)
- Sodium phosphate
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
- Complete blood count
- SGOT and SGPT (hepatic transaminases)
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. In 1986, another woman tried the same by ingesting 440 mg of enalapril with 42 mg warfarin. 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. 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. Healthcare providers should counsel the patient adequately about the same. Patients under 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. 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.
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]