Enalapril

Summary

Synopsis

Enalapril provides significant haemodynamic, symptomatic and clinical improvement when added to maintenance therapy with digitalis and diuretics in patients with congestive heart failure [itNYHA (New York Heart Association) classes II to IV]. These effects are not attenuated during long term therapy. More significantly, a clinical study demonstrated that enalapril reduces mortality when added to established therapy in patients with severe congestive heart failure (NYHA class IV) refractory to digitalis, diuretics and other vasodilators. Thus, ACE inhibitors such as enalapril off er a significant advance in the treatment of congestive heart failure. Because these drugs improve symptoms in patients with classes II to IV failure, and reduce mortality in patients with severe heart failure, they should be considered as first choice adjuvant therapy when a vasodilator is needed in addition to conventional treatment with digitalis and diuretics.

Pharmacological Properties

When administered orally to patients with congestive heart failure, enalapril effectively inhibits ACE activity. As a consequence, angiotensin II and aldosterone levels are decreased, and those of renin and angiotensin I are increased. Most evidence suggests that inhibition of angiotensin II is the key mechanism whereby enalapril exerts its haemodynamic effects. Enalapril may also inhibit bradykinin and prostaglandin degradation. While this is unlikely to be involved in the mechanism of action of the drug, it is postulated to be involved in the aetiology of certain ACE inhibitor-induced adverse effects (e.g. cough, rash, angio-oedema), although definitive evidence is lacking. Sympathetic tone assessed by plasma adrenaline (epinephrine) and noradrenaline (norepinephrine) levels appears unaffected by enalapril, but reductions in plasma adrenaline levels may be seen in patients with initially elevated pretreatment levels. The acute haemodynamic effects of enalapril indicate a balanced effect on preload and afterload (reduced systemic vascular resistance and pulmonary capillary wedge pressure, and increased cardiac output), accompanied by a decrease in blood pressure without an increase in heart rate. Myocardial metabolism and coronary haemodynamics are improved. Abrupt hypotension may occasionally occur when initiating enalapril administration.

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 humans. About 60% of an oral dose of enalapril is absorbed in healthy subjects, and peak plasma concentrations of enalapril are reached in about 1 hour. Absorption is unaffected by food. Enalapril undergoes de-esterification primarily in the liver to the active form, enalaprilat, which reaches peak plasma concentrations in about 3 to 4 hours. The maximum plasma concentration of enalaprilat is linearly related to dose, and the absolute bioavailability of enalapril as enalaprilat is about 40%. Steady-state concentrations are reached after about 3 or 4 doses. Enalaprilat is about 50% protein bound. No further metabolism occurs and unchanged enalapril and enalaprilat are excreted in the urine and faeces. The primary route of elimination is renal: the respective renal clearances of enalapril and enalaprilat are about 18 L/h and 9 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. Drug accumulation occurs in patients with moderate and severe renal impairment (GFR < 30 ml/min), and haemodialysis removes enalaprilat from circulation. Lower dosages should therefore be used in renally impaired patients. Peak plasma concentrations of enalaprilat may be delayed in patients with hepatic dysfunction or congestive heart failure.

Therapeutic Trials

Non-comparative and placebo-controlled studies have shown that the addition of enalapril to established digitalis and diuretic treatment in patients with congestive heart failure (NYHA classes II to IV) produces a sustained haemodynamic improvement, as assessed by invasive and non-invasive methods, which is paralleled by improvements in exercise performance, NYHA classification and symptoms. The clinical improvement is not attenuated during long term therapy as may occur with conventionally acting vasodilators. The maximal effective dosages of enalapril have ranged from 2.5 to 40mg daily, being administered either once or twice daily: most patients received 10 to 20mg daily. The therapeutic efficacy of enalapril and captopril appears to be similar, although direct comparisons are few.

No known biochemical or haemodynamic characteristics reliably predict a favourable clinical response to enalapril. Favourable results may be achieved regardless of the aetiology of heart failure: idiopathic dilated cardiomyopathy, ischaemic or hypertensive heart disease, and valvular regurgitation. On an individual basis a few patients do not respond to enalapril either in the short or long term. Also, some patients may fail to show short term haemodynamic benefit and yet gain delayed clinical benefit. Conversely, others may show a marked haemodynamic response which is not translated into long term clinical benefit. However, the majority of patients do benefit, and initiation of enalapril therapy is therefore justified with long term clinical response being used as a measure of efficacy.

Retrospective analysis of data from a number of studies has indicated that the addition of enalapril or another ACE inhibitor to established therapy with digitalis and diuretics in patients with congestive heart failure (NYHA classes II to IV) offers greater potential than other drug therapy in improving survival. More importantly, a prospective double-blind trial (the CONSENSUS trial) has shown that the addition of enalapril to established therapy in patients with severe congestive heart failure (NYHA class IV) refractory to digitalis, diuretics and other vasodilators produces a significant reduction in mortality compared with placebo.

Adverse Effects

The most significant clinical adverse effect during treatment with enalapril in patients with congestive heart failure is hypotension. This usually occurs after introduction of the first dose of enalapril and may be associated with symptoms of dizziness and syncope. The frequency of hypotension can be reduced by introducing low initial doses of enalapril and by the temporary withdrawal or reduction in high dosages of diuretics. Other clinical effects which may cause problems during therapy include rash (although this is generally mild), cough and angio-oedema, which occurs infrequently. The remaining significant effects are generally metabolic. Serum creatinine levels may increase with enalapril but only rarely does this progress to renal failure. Hyperkalaemia may develop, almost exclusively in patients receiving potassium-sparing diuretics or potassium supplements, or in patients with existing renal insufficiency. Withdrawal or restriction of these agents rapidly reverses the condition. Hypokalaemia, hyponatraemia and elevations in hepatic enzymes occur less frequently during enalapril treatment compared with placebo.

Dosage and Administration

The initial dose of enalapril in patients with congestive heart failure is 2.5mg. The patient should be closely observed for at least 2 hours after the dose and until blood pressure has been stabilised for an additional hour. Established therapy with digitalis and diuretics should be continued, although diuretics should be temporarily withdrawn if possible and high dosages should certainly be reduced at the initiation of enalapril therapy. The dosage should be gradually titrated according to clinical response to a maximum of 40mg daily administered either once or twice daily. The usual maintenance dosage is 10 to 20mg daily, although lower dosages should be used in patients with renal impairment. Potassium-sparing diuretics and potassium supplements should be avoided or, if necessary, used minimally with careful monitoring.