Enalapril

Enalapril is an antihypertensive agent belonging to ACE inhibitors.

Enalapril is approved for the treatment of heart failure and hypertension.

Enalaprilat is the active metabolite of the oral prodrug enalapril.

It is absorbed in the gastrointestinal tract.

With plasma protein binding of Approx 50% and gets extensively hydrolyzed in the liver into active metabolite enalaprilat and gets excreted via urine (61%; 18% as enalapril, 43% as enalaprilat); feces (33%; 6% as enalapril, 27% as enalaprilat) with an elimination half-life of 2 hours (enalapril); approx 35 hours (enalaprilat).

Enalapril is available in the form of dosage forms such as tablets and injections (enalaprilat).

Enalapril is available in India, France, Japan, and the USA.

Enalapril belonging to ACE inhibitors acts as an Antihypertensive agent. Enalapril works by inhibiting the Angiotensin-converting enzyme (ACE). The beneficial effects of Enalapril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system.

The onset of action is achieved in about 4 to 6 hours.

The Cmax for Enalapril is 313.5+/-139.6 ng/mL.

The Tmax for Enalapril is 0.4 hr.

Enalapril is available in the form of tablets and injections (Enalaprilate).

Enalapril tablets are to be swallowed whole with water.

Enalapril comes as a tablet to be taken by mouth. It is usually taken two times a day.

For injection (enalaprilat):- The starting dose should be no greater than 0.625 mg administered intravenously over a period of no less than five minutes and preferably longer (up to one hour). Patients should be followed closely whenever the dose of enalaprilat injection is adjusted and/or the diuretic is increased.

Enalapril is an antihypertensive agent belonging to ACE inhibitors.

Enalapril is approved for the treatment of heart failure and hypertension.

Angiotensin-converting enzyme (ACE) inhibitors are widely used in the treatment of heart failure. These agents decrease the formation of angiotensin II, thereby decreasing both arteriolar and venous resistance

Enalapril is approved for use in the following clinical indications

• Hypertension

After administration of enalapril antihypertensive effect is achieved in about 1 hour in most of the patients, with peak reductions achieved in 4 to 6 hours.

• Heart failure

In trials, the patients treated with digitalis and diuretics, treatment with Enalapril resulted in decreased systemic vascular resistance, blood pressure, pulmonary capillary wedge pressure, and heart size, and increased cardiac output and exercise tolerance.

Although not approved there has been certain label use documented for Enalapril which includes:

• Non-ST-elevation acute coronary syndrome;
• Posttransplant erythrocytosis,
• Kidney transplant recipients;
• Proteinuric chronic kidney disease,
• Diabetic or nondiabetic;
• Stable coronary artery disease;
• ST-elevation myocardial infarction

Enalapril is available in the form of tablets and injections (Enalaprilate)

Enalapril is available in various dosage strengths as 2.5 mg, 5 mg, 10 mg, and 20 mg.

Enalaprilate injection is available in dosage strength of 1.25 mg/mL (1 mL, 2 mL).

Enalapril is available in the form of tablets and injections (Enalaprilate)

Dose Adjustment in Kidney Patients:

CrCl >30 mL/minute: No dosage adjustment necessary

CrCl ≤30 mL/minute: Initiate with 0.625 mg; if after 1-hour clinical response is unsatisfactory, may repeat. May then administer 1.25 mg every 6 hours.

Intermittent hemodialysis (IHD):

Moderately dialyzable (20% to 50%):

Initial: 0.625 mg IV over a period of 5-60 minutes (60-minute infusion duration preferred)

Conversion from IV enalaprilat to oral enalapril therapy:

CrCl >30 mL/minute: May initiate enalapril 5 mg once daily

CrCl ≤30 mL/minute: May initiate enalapril 2.5 mg once daily.

Dose Adjustment in Hepatic Impairment Patient:

No dose adjustments are needed.

Dose Adjustment in the pediatric patient:

Note: Use lower listed initial dose in patients with hyponatremia, hypovolemia, severe CHF, decreased renal function, or in those receiving diuretics.

• Heart failure:

Infants, Children, and Adolescents:

Oral: Initial: 0.1 mg/kg/day in 1 to 2 divided doses; increase as required over 2 weeks to maximum of 0.5 mg/kg/day; mean dose required for CHF improvement in 39 children (age range: 9 days to 17 years) was 0.36 mg/kg/day; select individuals have been treated with doses up to 0.94 mg/kg/day.

• Hypertension:

Infants, Children, and Adolescents:

Oral: Initial: 0.08 mg/kg/dose once daily (maximum dose: 5 mg); adjust dose according to blood pressure readings; doses >0.58 mg/kg (or >40 mg) have not been studied

• Proteinuria, nephrotic syndrome:

Oral: Fixed dosing: Children ≥7 years and Adolescents: 2.5 to 5 mg/day was reported in a retrospective study in normotensive pediatric patients as either monotherapy (n=17; mean age: 13.7 years; range: 8 to 17 years) or with prednisone (n=11; mean age: 12.6 years; range: 7 to 16 years); a significant decrease in proteinuria (with or without nephrotic syndrome) occurred; no significant change in blood pressure was observed; a case series of three adolescents with sickle anemia nephropathy reported an initial dose of 5 mg/day; one patient required an increase to 7.5 mg/day.

• Weight-directed dosing:

Children and Adolescents: Initial: 0.2 mg/kg/day; titrate to response at 4- to 12-week intervals; range: 0.2 to 0.6 mg/kg/day; maximum daily dose: 20 mg/day; a crossover dose-comparison trial showed effects on proteinuria were dose-dependent ; if combined with other angiotensin blockade (ARB), lower doses have been reported (0.1 to 0.16 mg/kg/day)

Enalapril is approved for the treatment of Hypertension.

Hypertension: It has been observed that the low-salt Dietary Approach to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

The food limitation should be tailored to the patient's needs.

Enalapril may be contraindicated in the following

● Abrupt discontinuation

Abrupt discontinuation of any ACE inhibitor, including Enalapril, can result in the development of myocardial ischemia, myocardial infarction, ventricular arrhythmias, or severe hypertension, particularly in patients with preexisting cardiac disease.

Enalapril is contraindicated in patients who are allergic to the product and in patients with a history of angioedema related to the previous treatment with an ACE inhibitor, and in patients with hereditary or idiopathic angioedema.

The treating doctor must preserve pharmacovigilance as follows and continuously monitor the patient.

• Head and Neck Angioedema

Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported in patients treated with ACE inhibitors, including Enalapril. This may occur at any time during the treatment. In such cases, Enalapril should be discontinued.

• Intestinal angioedema

Intestinal angioedema has been reported in patients treated with Enalapril. These patients presented with abdominal pain with or without nausea and vomiting.

• Hypotension

Excessive hypotension is rare in patients treated with Enalapril. Patients with heart failure experience this side effects.

• Hepatic failure

Rarely ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to hepatic necrosis and sometimes death.

PRECAUTIONS

• Impaired Renal or Hepatic Function

Patients having compromised renal or hepatic function should use ACE inhibitors with care. Enalapril clearance is only marginally impacted by poor renal function, but poor hepatic function may cause blood levels of Enalapril to increase substantially

Drinking alcohol while taking the Enalapril can increase drowsiness and dizziness, which in turn increase the risk of accidental injury.

Enalapril use in breast feeding patient is not recommended.

Potassium Rich Foods: Bananas, sweet potatoes, nuts, and other foods rich in potassium when taken along with Enalapril, can be led to an increase in blood potassium levels.

Pleurisy Root: Pleurisy roots are not recommended with most heart medications due to the cardiac glycoside content of the root.

The adverse reactions related to molecule Enalapril can be categorized as

• Common Adverse effects:

Insomnia, Muscle pain, Dizziness, fatigue etc.

• Less Common adverse effect:

Nervousness, Elevated liver enzymes, joint paint, edema, vivid dreams, abdominal discomfort, nausea, muscle cramps, paresthesias, bradycardia, cold extremities, hypotension, palpitations, syncope, Tachycardia, Anxiety, lethargy, diarrhea, vomiting, Impotence/reduced libido.

• Rare adverse effects:

Heart failure, tachyarrhythmia, bronchospasm, depression, decreased exercise tolerance, Raynaud's phenomenon, etc.

The clinically relevant drug interactions of Enalapril are briefly summarized here

● When used with ACE inhibitors, catecholamine-depleting medications (such as reserpine) may have an additional impact. Therefore, patients using Enalapril together with a catecholamine-depleting medication should be carefully monitored for any signs of hypotension and/or significant bradycardia that might result in vertigo, syncope, or orthostatic hypotension.

● Enalapril has been used with a variety of antihypertensive agents, including hydrochlorothiazide, hydralazine, and guanethidine without unexpected adverse interactions.

● Enalapril has been shown to increase serum thioridazine levels when both drugs are coadministered. Enalapril levels may also be increased with this combination.

The common side of Enalapril include the following

Cold hands or feet, Eye irritation, upset stomach, headache, depression, dizziness, nausea, etc.

The use of Enalapril should be prudent in the following group of special populations:

Pregnancy

Pregnancy Category (FDA): D

The use of the drugs that act on the renin-angiotensin system during the 2 and 3 trimesters of pregnancy reduces the fetal renal function and increases neonatal morbidity and death. When pregnancy is detected, discontinue Enalapril

Nursing Mothers

Since Enalapril is secreted in the human milk, nursing should not be undertaken by the mothers receiving the drug.

Geriatric Use

There is no FDA guidance on the use of Enalapril in geriatric settings.

No specific information on the emergency treatment of overdosage is available. Therefore, on the basis of pharmacologic actions of Enalapril, the following general measures should be employed as appropriate in addition to the gastric lavage:

● Excessive Bradycardia:

Administer atropine; if there is no response to the vagal blockade, administer isoproterenol cautiously.

● Cardiac Failure:

Digitalize the patient and/or administer a diuretic. It has been reported that the glucagon may be useful in this situation.

● Hypotension:

Administer vasopressors like epinephrine or norepinephrine, with serial monitoring of blood pressure. (There is evidence that epinephrine may be the drug of choice.)

● Bronchospasm:

Administration of beta2 stimulating agent like isoproterenol and a theophylline derivative.

A case of an acute overdosage has been reported with an intake of 500 mg of Enalapril by a hypertensive patient. Blood pressure increased, and the heart rate was ≥ 80 beats/min. Recovery was uneventful. In another case, 250 mg of Enalapril was taken with 150 mg diazepam and 50 mg nitrazepam, producing coma and hypotension. The patient recovered in 24 hours.

Pharmacodynamics:

Enalapril is a prodrug which is hydrolysed after the absorption to active angiotensin-converting enzyme (ACE) inhibitor, enalaprilat. Enalapril increases the plasma renin activity and decreases the plasma concentrations of angiotensin II and aldosterone. Most data support the hypothesis that the beneficial haemodynamic effects of Enalapril are caused by the ACE inhibition and the consequent reduction in the angiotensin II, which either directly or indirectly results in the dilatation of peripheral vessels and reduced vascular resistance. Cumulating evidence suggests tissue ACE, particularly in the vasculature, rather than circulating ACE, is primary target determining the haemodynamic effects. A few studies have implicated kallikrein-kinin-prostaglandin systems and sympathetic nervous system in the mechanism of action of Enalapril.

In healthy subjects, and patients with hypertension or congestive heart failure with the normal renal function, Enalapril generally increases the renal blood flow and decreases the renal vascular resistance without changing the glomerular filtration rate. In patients with unilateral renal artery stenosis, a reduction in renal blood flow in the stenotic kidney is counterbalanced by an increase in the unaffected kidney. Plasma volume is unaffected. Shortly after onset of enalapril therapy modest natriuresis is indicated by an increase in fractional excretion of sodium. This negative sodium balance is maintained during the prolonged treatment as exchangeable sodium is reduced. Serum sodium concentration is unaffected by long term treatment. The fractional excretion of potassium is not affected by treatment with Enalapril, although sufficient retention occurs to cause a marginal increase in serum potassium concentration. Enalapril blunts the hyperaldosteronism associated with hydrochlorothiazide and also attenuates the ensuing hypokalaemia

Pharmacokinetics:

• Absorption

Following oral administration of enalapril peak serum concentrations of the occur within an hour after taking Enalapril. Enalapril is absorbed to a degree of around 60%, according to urine recovery..

• Distribution

The volume of distribution in the healthy subjects is about 2 /kg. Enalapril undergoes extensive metabolism in animals and man. In man, 94% of the dose is recovered in the urine and feces as enalaprilat or Enalapril.

• Metabolism

There is no proof that Enalapril has any additional metabolites except Enalapril. Enalapril has an 11-hour effective half-life for accumulation.

• Elimination

About 94% of Enalapril is excreted via urine or feces.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/018998s076lbl.pdf
• Arafat T, Awad R, Hamad M, Azzam R, Al-Nasan A, Jehanli A, Matalka K. Pharmacokinetics and pharmacodynamics profiles of enalapril maleate in healthy volunteers following determination of Enalapril and enalaprilat by two specific enzyme immunoassays. J Clin Pharm Ther. 2005 Aug;30(4):319-28. DOI: 10.1111/j.1365-2710.2005.00646.x. PMID: 15985045.
• https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-depth/ace-inhibitors/art-20047480