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Enalapril


Category:

Antihypertensive, Vasodilator congestive heart failure,  Angiotensin – Converting enzyme (ACE) inhibitor  (USP DI 2007)

Composition:

Each tablet contains enalapril maleate 5 mg and 20 mg.

Chemistry:

Enalapril Maleate is the maleate salt of enalapril, the ethyl ester of a long – acting angiotensin converting ezyme inhibitor. Enalapril maleate is chemically described as (S) – 1-  N- (ethoxycarbonyl) – 3 – phenylpropyl  - Lalanyl  - L – praline, (Z) – 2 – butenedioate salt (1:1), and it's structural formula is:
(C20 H28 N2 O5 . C4 H4 O4 )
Molecular weight = 492.53 (Martindale 35)

Mechanism of Action:

Enalapril, after hydrolysis to enalaprilat, inhibits angiotensin- converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of enalapril in hypertension and heart failure appear to result primarily from suppression of the rennin- angiotensin- aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and aldosterone secretion.
Although the latter decrease in small, it results in small increases of serum potassium. While the mechanism through which enalapril lowers blood pressure is believed to be primarily suppression of the rennin – angiotensin- aldosterone system, it is antihypertensive even in patients with low – rennin hypertension. (Martindale 35)

Pharmacokinetics:

Following oral administration of enalapril, peak serum concentrations of enalapril occur within about one hour. Based on urinary recovery the extent of absorption of enalapril is approximately 60 percent. Enalapril absorption is not influenced by the presence of food in the gastrointestinal tract. Following absorption enalapril is hydrolyzed to enalaprilat, which is a more potent angiotensin converting enzyme inhibitor than enalapril. Enalaprilat is poorly absorbed when administered orally. Peak serum concentrations of enalaprilat occur three to four hours after an oral dose of enalapril maleate. Excretion of enalapril is primarily renal. Approximately 94 percent of the dose is recovered in the urine and feces as enalaprilat or enalapril. The principal components in urine are enalaprilat, accounting for about 40 precent of the dose, and intact enalapril. Hemodialysis reduces serum enalaprilat concentrations by approximately 35% Onset of action of enalapril is 1 hours after oral administration. (USPDI 2007)

Indications:

1) Hypertension: Enalapril is indicated for the treatment of hypertension. Enalapril is effective alone or in combination with other antihypertensive agents, especially a thiazide diuretic. The blood pressure lowering effects of enalapril and thiazides are approximately additive. Enalapril also used for renovascular hypertension (except in patients with bilateral renal artery stenosis).
2) Heart Failure: Enalapril is indicated for the treatment of symptomatic congestive heart failure, usually in combination with diuretics and digitalis therapy , for treatments of congestive heart failure not responding to other measures.
3) Asymptomatic left ventricular dysfunction:
In clinically stable asymptomatic patients with left ventricular dysfunction (ejection fraction ≤ 35 percent), enalapril decreases the rate of development of overt heart failure and decreases the frequency of hospitalization for heart failure. (USPDI 2007)

Contraindications:

Enalapril is contraindicated in patients who are hypersensitive to any components of this product and in patients with a history of medical problems especially angioedema related to previous treatment with an ACE-inhibitor, hepatic function impairment, hyperkalemina, renal artery stenosis, renal transplant, renal function impairment or sodium and volume depletion. (USPDI 2007)

Warnings:

  • Anaphylactoid and possibly related reactions: Presumably because Angiotensin – converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients reciving ACE inhibitors may be subject to a variety of adverse reactions, some of them serious. (Martindale 35)
  • Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and / or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalapril. This may occur at any time during treatment. In such cases enalapril should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 ml to 0.5 ml) and / Checking patient airway, should be promptly provided.
    (Martindale 35)
  • Other possibly and rare reactions: Anaphylactoid reactions during desensitization, anaphylactoid reactions during membrane exposure, hypotension, neutropenia and agranulocytosis, hepatic failure, fetal / neonatal morbidity and mortality. (USPDI 2007)

Precautions:

  • Aortic stenosis / Hypertrophic cardiomiopathy: Enalapril should be given with caution to patients with obstruction in the outflow of the left ventricle.
  • Surgery / Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, enalapril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism it can be corrected by volume expansion. (Martindale 35)

Usage in pregnancy:

Pregnancy categories: C. (first trimester) and D . (second and third trimester). When pregnancy is detected, enalapril should be discontinued as soon as possible. (USPDI 2007)

Nursing Mothers:

Enalapril and Enalaprilat are detected in human milk in trace amounts. Caution should be made when enalapril is given to a nursing mother. (USPDI 2007)

Pediatric use:

Safety and effectiveness in children have not been established.

Drug Interactions:

  • ●Diuretics, may occasionally experience an excessive reduction of blood pressure with enalapril. The possibility of hypotensive effects with enalapril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril. If it is necessary to continue the diuretic, therapy close medical supervision after the initial dose for at least two hours and until blood pressure has stabilized for at least an additional hour is recommended.
  • ●Agents causing rennin release: The antihypertensive effect of enalapril is augmented by antihypertensive agents that cause renin release (e.g.diuretics).
  • ●Non – steroidal anti – inflammatory agents:>
    In some patients with compromised renal function who are being treated with non – steroidal anti – inflammatory drugs, the co – administration of enalapril may result in a further deterioration of renal function. These effects are usually reversible.
  • ●Agents increasing serum potassium:
    Enalapril attenuates potassium loss caused by thiazide – type diuretics. Potassium sparing diuretics (e.g. spironolactone, triamteren, or amiloride) , potassium supplements or potassium – containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium. Potassium sparing agents should generally not be used in patients with heart failure receiving enalapril.
  • ●Lithium : Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium , including ACE inhibitors. It is recommended that serum lithium levels be monitored frequently if enalparil is administered concomitantly with lithium. (USPDI 2007)

Adverse Reactions:

Enalapril has been found to be generally tolerated in controlled clinical trials. Adverse experiences were mild and transient in nature. In clinical trials discontinuation of therapy due to clinical adverse experiences was required in 3.3 percent of patients with hypertension and in 5.7 percent of patients with heart failure. The frequency of adverse experiences was not related to total daily dosage within the usual dosage ranges. In patients with hypertension. the overall percentage of patients treated with enalapril, reporting adverse experiences was comparable to placebo.
- Incidence more frequent (more than 1 percent) : Fatigue, headache, dizziness, rash, hypotension, diarrhea, cough.
- Incidence rare (less than 1 percent) : Renal dysfunction, decreased hemoglobin and hematocrit, pemphigus, bradycardia, hepatic failure, peripheral neuropathy, pneumonia. (USPDI 2007)

Overdosage:

The most likely manifestation of overdosage would be hypotension. For which the usual treatment would be intravenous infusion of normal saline solution. (Martindale 35)

Dosage and Administration:

- Usual adult and adolescent dose:
  • ● Antihypertensive:
    * Initial: Oral , 5mg once a day, the dosage being adjusted after one or two weeks according to clinical response.
    * Maintenace: Oral , 10 to 40 mg per day, as a single dose or in two divided doses. (USPDI 2007)
    Note:
    An initial dose of 2.5 mg should be used in patients who are sodium – and water – depleted as a result of prior diuretic therapy, patients continuing to receive diuretic therapy, or patients with renal failure (creatinine clearance less than 30ml per minute). Such patients should be kept under medical supervision for at least two hours after this initial dose (and for an additional hour after blood pressure has stabilized), to watch for excessive hypotension effect. (USP DI 2007)
  • ● Congestive heart failure , vasodilator:
    * Initial: Oral, 2.5mg once or twice a day, the dosage being adjusted after a few days or weeks according to clinical response.
    * Maintenance: Oral, 5 to 40mg per day, as a single dose or in two divided doses. (USPDI 2007)
  • ● Asymptomatic left ventricular dysfunction:
    Oral , 2.5mg two times a day titrated as tolerated up to a target dose of 20mg a day in divided doses. Note: patients should be kept under medical supervision for at least two hours and until blood pressure has stabilized for an additional hour after the initial dose. In patients with hyponatremia (serum sodium concentration less than 130mEq per liter) or serum creatinine greater than 1.6mg per deciliter, an initial dose of 2.5mg once a day is recommended. If possible, the dose of the diuretic should be reduced to decrease the likelihood of hypotension effect.

-Usual adult prescribing limits: 40mg per day.
-Usual pediatric dose: Safety and efficacy have not been established. (USPDI 2007)

Dosage in renal insufficiency:

Generally, the intervals between the administration of Enalapril should be prolonged and /or the dosage reduced. Initial dose in mild impairment With creatinine clearance between 30 and 80 ml/min is 5mg.
In moderate to severe impairment with creatinine clearance lower than 30ml/min is 2.5 mg.
In dialysis patients is 2.5 mg on dialysis days. (Martindale 35 , Fact and comparison 2007)

Storage:

Store below 25˚C, preferably between 15 and 30˚C, in a well – closed container. (USPDI 2007)

How Supplied:

Enalapril maleate 5mg is oblong shaped, white, scored tablets.
Enalapril maleate 20mg is oblong shaped, scored, light brown tablets.
There are blister of 10's, box of 100's.

References:

1- Martindale 35
2- USP DI 2007
3- Fact and Comparison 2007
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