, Volume 31, Issue 3, pp 198-248
Date: 03 Nov 2012

Enalapril

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Summary

Synopsis: Enalapril maleate1 is an orally active angiotensin-converting enzyme inhibitor. It lowers peripheral vascular resistance without causing an increase in heart rate. Enalapril 10 to 40 mg/day administered either once or twice daily is effective in lowering blood pressure in all grades of essential and renovascular hypertension, and shows similar efficacy to usual therapeutic dosages of hydrochlorothiazide, β-blockers (propranolol, atenolol and metoprolol) and captopril. Most patients achieve adequate blood pressure control on enalapril alone or with hydrochlorothiazide. In patients with severe congestive heart failure resistant to conventional therapy, enalapril improves cardiac performance by a reduction in both preload and afterload, and improves clinical status long term. Enalapril appears to be well tolerated, with few serious adverse effects being reported. It does not induce the bradycardia associated with β-blockers or the adverse effects of diuretics on some laboratory values. In fact, the hypokalaemic effect of hydrochlorothiazide is attenuated by the addition of enalapril. The incidence of the main (but rare) side effects of hypotension in hypovolaemic patients and reduced renal function in certain patients with renovascular hypertension, which are also seen with captopril, might be reduced by careful dosage titration, discontinuation of diuretics, and monitoring of at-risk patients.

Thus, enalapril is a particularly worthwhile addition to the antihypertensive armamentarium, as an alternative for treatment of all grades of essential and renovascular hypertension. It also shows promise in the treatment of congestive heart failure.

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

Enalapril is effective in lowering blood pressure in animal models of hypertension which are believed to be primarily dependent on (e.g. 2-kidney hypertension) and independent of (e.g. spontaneous hypertension, 1-kidney hypertension) the renin-angiotensin-aldosterone system, although its effects are more pronounced in the former. Prophylactic administration of enalapril to young spontaneously hypertensive rats completely prevented the development of hypertension. In patients with hypertension, single oral doses of enalapril 5 to 40mg reduce blood pressure maximally by 15 to 20% after 6 to 8 hours. The magnitude of the acute blood pressure lowering effect is dependent on the initial severity of hypertension and is dose-dependent up to about 10mg, with higher doses increasing the duration of effect up to 24 to 36 hours.

During long term treatment of hypertension with enalapril 10 to 40mg daily, total peripheral resistance is reduced (21 to 36%) by dilation of resistance vessels as well as large arteries, without any significant change in heart rate or cardiac output. The lack of reflex tachycardia does not appear related to a reduction in baroreceptor sensitivity. In hypertensive patients with left ventricular hypertrophy prolonged treatment with enalapril causes a reversal of the cardiac hypertrophy without any deterioration of pump function.

In patients with severe congestive heart failure maintained on digitalis and/or diuretics, acute administration of enalapril 2.5 to 20mg reduces mean arterial pressure (about 15%) which is associated with beneficial cardiovascular changes; for example reduced systemic vascular resistance (about 35%), pulmonary capillary wedge pressure (about 25 to 40%) and right atrial pressure (about 25 to 40%), and increased cardiac output (about 25%). As in patients with hypertension, heart rate is not altered significantly.

In healthy subjects, and patients with hypertension or congestive heart failure with normal renal function, enalapril generally increases renal blood flow and decreases renal vascular resistance without changing glomerular filtration rate. In patients with unilateral renal artery stenosis, a reduction in renal blood flow in the stenotic kidney is counter-balanced by an increase in the unaffected kidney. Plasma volume is unaffected. Shortly after the onset of enalapril therapy modest natriuresis is indicated by an increase in the fractional excretion of sodium. This negative sodium balance is maintained during 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.

Pharmacokinetic Studies: Enalapril, administered as the maleate salt, was designed as a prodrug to improve the systemic availability of the active ACE inhibitor enalaprilat, which is poorly absorbed in man. About 60% of an oral dose of enalapril is absorbed in healthy subjects, and peak serum concentrations of enalapril are reached in about 1 hour. Absorption is unaffected by food. Enalapril undergoes de-esterification primarily in the liver to form enalaprilat, which reaches peak serum concentrations about 3 to 4 hours after enalapril administration. The maximum serum concentration of enalaprilat is linearly related to dose, and the bioavailability of oral enalapril as enalaprilat is about 40%. Enalaprilat is less than 50% protein bound. No further metabolism of enalaprilat occurs in man, and unchanged enalapril and enalaprilat are excreted in the urine and faeces. The primary route of elimination appears to be renal: the respective renal clearances of enalapril and enalaprilat are 18 L/h and 8.1 to 9.5 L/h. Enalaprilat has polyphasic elimination kinetics, with drug persistence during the terminal phase representing the strong binding of enalaprilat to serum ACE. The terminal half-life is 30 to 35 hours. Steady-state is reached after 3 or 4 oral doses of enalapril 10mg every 24 hours. Drug accumulation can occur in patients with moderate to severe renal impairment. The drug is removed by haemodialysis. In patients with hepatic dysfunction conversion of enalapril to enalaprilat may be delayed However, steady-state plasma concentrations of enalaprilat appear similar in patients with congestive heart failure and those with hypertension after repeated doses of enalapril.

Therapeutic Trials: In open and placebo-controlled studies in patients with mild to severe essential or renovascular hypertension, enalapril 10 to 40 mg/day reduces both systolic and diastolic blood pressure by about 15 to 20%, with adequate pressure control being achieved in about 50 to 75% of patients on enalapril alone. Addition of hydrochlorothiazide usually provided adequate control in the remainder. Once daily administration of enalapril appears to be as effective as twice daily administration in controlling blood pressure in most patients.

In mild to moderate essential hypertension enalapril (up to 40 mg/day) is as effective as hydrochlorothiazide (up to 100 mg/day). Lower than usual therapeutic dosages of hydrochlorothiazide (as low as 6.25 mg/day) may be effective in combination with enalapril. Black patients respond better to hydrochlorothiazide and worse to enalapril than non-Black patients although both racial groups respond similarly to the drugs given in combination.

Enalapril (up to 40 mg/day) appears as effective as propranolol (up to 240 mg/day) and metoprolol (up to 400 mg/day) in mild to moderate essential hypertension, and as effective as atenolol (up to 100 mg/day) and captopril (up to 300 mg/day) in moderate to severe essential hypertension. For a similar reduction in diastolic pressure, enalapril seems more effective than β-blockers in reducing systolic pressure. Enalapril ‘triple therapy’ (enalapril 20 mg/day plus hydrochlorothiazide 50 mg/day plus α-methyldopa 1000 mg/ day) is as effective as standard ‘triple therapy’ (hydrochlorothiazide 50 mg/day plus propranolol 240 mg/day plus hydralazine 200 mg/day) in lowering blood pressure in moderate to severe essential hypertension. In patients with renovascular hypertension, enalapril (up to 40 mg/day) plus hydrochlorothiazide (up to 100 mg/day) appears to be more effective than ‘triple therapy’ using hydrochlorothiazide (up to 100 mg/day) plus timolol (up to 60 mg/day) plus hydralazine (up to 300 mg/day) in controlling diastolic blood pressure.

Open and placebo-controlled studies in severe congestive heart failure resistant to digitalis and/or diuretics have shown encouraging improvement in indices of cardiac function (increased cardiac output, stroke work index and ejection fraction; and decreased pulmonary capillary wedge pressure). Patients also showed improvement in exercise performance, New York Heart Association functional classification and associated symptomatology after receiving enalapril (usually 10 to 20 mg/day) for up to 3 months. Clinical improvement is not attenuated during long term therapy and has been sustained for several years in some patients.

Side Effects: The most frequently reported side effects during clinical trials with enalapril include headache, dizziness, fatigue, diarrhoea, nausea, rash, cough, hypotension and angioneurotic oedema. The majority of these effects were mild, transient, and probably unrelated to treatment as they were often seen with similar frequencies in patients receiving placebo. Serious adverse effects with enalapril have been rare. Reversible deterioration of renal function has been reported in a few patients and appears more frequently if hydrochlorothiazide is given concurrently with enalapril. In 1 patient it was associated with glycosuria. A sudden, reversible deterioration of renal function has been seen in some patients with bilateral renal artery stenosis or stenosis of a single kidney, and appears more likely in those patients made hypovolaemic by the concurrent use of diuretics or with pre-existing renal insufficiency. These renal effects appear related to the haemodynamic changes induced by AGE inhibition and not a direct nephrotoxic effect. Symptomatic hypotension, also related to the haemodynamic effects of ACE inhibition, has been rarely reported, occurring most often in hypovolaemic patients.

Rash and taste disturbances have been rarely associated with enalapril, and proteinuria and leucopenia have not been definitely associated with the drug. More experience is required with both enalapril and captopril at therapeutically similar dosages in similar populations to determine the relative risk of these adverse effects. However, about 90% of patients who were withdrawn from captopril because of adverse effects did not have a recurrence when switched to enalapril.

Dosage and Administration: The initial dosage in patients with normal renal function is 5 mg/day, and 2.5 mg/day in patients with renal impairment (creatinine clearance less than 30 ml/min). Dosage can be doubled at intervals of 1 to 2 weeks depending on individual response, to a maximum of 40 mg/day. A thiazide diuretic can be added in hypertensive patients responding inadequately to enalapril alone, and a third agent, such as a β-blocker, may be required occasionally. In patients with congestive heart failure, digitalis and/or diuretics should be continued and the dosage of enalapril gradually titrated, most patients responding optimally with 10 to 20 mg/day. Dosages should be carefully titrated in patients with renal impairment with a prolonged dosage interval to prevent accumulation. Haemodialysis patients can receive normal dosages on dialysis days.

Hypotension, especially after initial doses, can occur rarely in patients treated with enalapril. It is more likely to occur if a patient is volume-depleted (by prior diuretic therapy, salt restriction, dialysis, diarrhoea or vomiting) and in patients undergoing major j surgery or during anaesthesia with agents that cause hypotension. Initial doses of enalapril should be reduced, diuretics temporarily withdrawn prior to introducing enalapril, and adequate rehydration undertaken in patients considered at risk. Renal function should be monitored in patients with renal impairment, and dosage titration should start with very low doses of enalapril in patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney. As enalapril may cause a marginal increase in serum potassium concentrations, potassium supplements or potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride) should be used with caution, especially in patients with decreased renal function.

Various sections of the manuscript reviewed by: J. Biollaz, Département de Médecine Interne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; P.G. Fernandez, Faculty of Medicine, Memorial University of Newfoundland, St Johns, Newfoundland, Canada; M.A. Fitzpatrick, Princess Margaret Hospital, Christchurch, New Zealand; B. Jackson, Department of Medicine, Prince Henry’s Hospital, Melbourne, Victoria, Australia; C.I. Johnston, Department of Medicine, Prince Henry’s Hospital, Melbourne, Victoria, Australia; W.P. Leary, Department of Pharmacology, Natal University, Durban, South Africa; JA, Millar, University of Otago Medical School, Dunedin, New Zealand; M. Safar, Hôpital Broussais, Paris, France; G.S. Thind, Division of Cardiology, Department of Medicine, University of Louisville, Louisville, Kentucky, USA; T. Unger, German Institute for High Blood Pressure Research, University of Heidelberg, Heidelberg, West Germany; D.G. Vidt, Department of Hypertension and Nephrology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA; P.H. Vlasses, Division of Clinical Pharmacology, Thomas Jefferson University Hospital, Philadelphia, USA.
‘Enapren’, ‘Innovace’, ‘Renitec’, ‘Reniten’, ‘Vasotec’, ‘Xanef’ (Merck Sharp & Dohme).