Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1. Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin-converting enzyme inhibitors, ATC Code: C09A A02

Enalapril (enalapril maleate) is the maleate salt of enalapril, a derivative of two amino acids; L-alanine and L-proline. Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to the pressor substance angiotensin II. After absorption, Enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to removal of negative feedback of renin release) and decreased aldosterone secretion.

ACE is identical to kinase II. Thus Enalapril may also block the degradation of bradykinin, a potent vasodepressor peptide. However the role that this plays in the therapeutic effects of Enalapril remains to be elucidated.

Mechanism of action
While the mechanism through which Enalapril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, Enalapril is antihypertensive even in patients with low-renin hypertension.

Pharmacodynamic effects
Administration of Enalapril to patients with hypertension results in a reduction of both supine and standing blood pressure without a significant increase in heart rate.

Symptomatic postural hypotension is infrequent. In some patients the development of optimal blood pressure reduction may require several weeks of therapy. Abrupt withdrawal of Enalapril has not been associated with rapid increase in blood pressure.

Effective inhibition of ACE activity usually occurs 2 to 4 hours after oral administration of an individual dose of Enalapril. Onset of antihypertensive activity was usually seen at one hour, with peak reduction of blood pressure achieved by 4 to 6 hours after administration. The duration of effect is dose- related. However, at recommended doses, antihypertensive and haemodynamic effects have been shown to be maintained for at least 24 hours.

In haemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of Enalapril there was an increase in renal blood flow; glomerular filtration rate was unchanged. There was no evidence of sodium or water retention. However, in patients with low pre-treatment glomerular filtration rates, the rates were usually increased.

In short-term clinical studies in diabetic and non-diabetic patients with renal disease, decreases in albuminuria and urinary excretion of IgG and total urinary protein were seen after the administration of Enalapril.

When given together with thiazide-type diuretics, the blood pressure-lowering effects of Enalapril are at least additive. Enalapril may reduce or prevent the development of thiazide-induced hypokalaemia.

In patients with heart failure on therapy with digitalis and diuretics, treatment with oral or injection Enalapril was associated with decreases in peripheral resistance and blood pressure. Cardiac output increased, while heart rate (usually elevated in patients with heart failure) decreased. Pulmonary capillary wedge pressure was also reduced. Exercise tolerance and severity of heart failure, as measured by New York Heart Association criteria, improved. These actions continued during chronic therapy.

In patients with mild to moderate heart failure, Enalapril retarded progressive cardiac dilatation/enlargement and failure, as evidenced by reduced left ventricular end diastolic and systolic volumes and improved ejection fraction.

Dual Blockage of the renin-angiotensin-aldosterone system (RAAS) Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes) have examined the use of combination of an ACE-inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed.
Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. CV death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

Clinical efficacy and safety
A multicentre, randomised, double-blind, placebo-controlled trial (SOLVD Prevention trial) examined a population with asymptomatic left ventricular dysfunction (LVEF<35%). 4228 patients were randomised to receive either placebo (n=2117) or Enalapril (n=2111). In the placebo group, 818 patients had heart failure or died (38.6%) as compared with 630 in the Enalapril group (29.8%) (risk reduction: 29%; 95% CI; 21 - 36%; p<0.001). 518 patients in the placebo group (24.5%) and 434 in the Enalapril group (20.6%) died or were hospitalized for new or worsening heart failure (risk reduction 20%; 95% CI; 9-30%; p<0.001).

A multicentre, randomised, double-blind, placebo-controlled trial (SOLVD treatment trial) examined a population with symptomatic congestive heart failure due to systolic dysfunction (ejection fraction <35%). 2569 patients receiving conventional treatment for heart failure were randomly assigned to receive either placebo (n=1284) or Enalapril (n=1285). There were 510 deaths in the placebo group (39.7%) as compared with 452 in the Enalapril group (35.2%) (reduction in risk, 16%; 95% CI, 5 - 26%; p=0.0036). There were 461 cardiovascular deaths in the placebo group as compared with 399 in the Enalapril group (risk reduction 18%, 95% CI, 6 - 28%, p<0.002), mainly due to a decrease of deaths due to progressive heart failure (251 in the placebo group vs 209 in the Enalapril group, risk reduction 22%, 95% CI, 6 - 35%). Fewer patients died or were hospitalised for worsening heart failure (736 in the placebo group and 613 in the Enalapril group; risk reduction, 26%; 95% CI, 18 - 34%; p<0.0001). Overall in SOLVD study, in patients with left ventricular dysfunction, Enalapril reduced the risk of myocardial infarction by 23% (95% CI, 11 – 34%; p<0.001) and reduced the risk of hospitalisation for unstable angina pectoris by 20% (95% CI, 9 – 29%; p<0.001).


Paediatric population
There is limited experience of the use in hypertensive paediatric patients >6 years. In a clinical study involving 110 hypertensive paediatric patients 6 to 16 years of age with a body weight ≥20 kg and a glomerular filtration rate>30 ml/min/1.73 m2, patients who weighed <50 kg received either 0.625, 2.5 or 20 mg of Enalapril daily and patients who weighed ≥50 kg received either 1.25, 5 or 40 mg of Enalapril daily. Enalapril administration once daily lowered trough blood pressure in a dose-dependent manner. The dose-dependent antihypertensive efficacy of Enalapril was consistent across all subgroups (age, Tanner stage, gender, race). However, the lowest doses studied, 0.625 mg and 1.25 mg, corresponding to an average of 0.02 mg/kg once daily, did not appear to offer consistent antihypertensive efficacy. The maximum dose studied was 0.58 mg/kg (up to 40 mg) once daily. The adverse experience profile for paediatric patients is not different from that seen in adult patients.

Pharmacokinetic Properties

5.2. Pharmacokinetic properties
Absorption
Oral Enalapril is rapidly absorbed, with peak serum concentrations of Enalapril occurring within one hour. Based on urinary recovery, the extent of absorption of Enalapril from oral Enalapril tablet is approximately 60%. The absorption of oral Enalapril is not influenced by the presence of food in the gastro-intestinal tract.

Following absorption, oral Enalapril is rapidly and extensively hydrolysed to enalaprilat, a potent angiotensin-converting enzyme inhibitor. Peak serum concentrations of enalaprilat occur about 4 hours after an oral dose of Enalapril. The effective half-life for accumulation of enalaprilat following multiple doses of oral Enalapril is 11 hours. In subjects with normal renal function, steady-state serum concentrations of enalaprilat were reached after 4 days of treatment.

Distribution
Over the range of concentrations which are therapeutically relevant, enalaprilat binding to human plasma proteins does not exceed 60%.

Biotransformation
Except for conversion to enalaprilat, there is no evidence for significant metabolism of Enalapril.
Elimination
Excretion of enalaprilat is primarily renal. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact Enalapril (about 20%).

Renal impairment
The exposure of Enalapril and enalaprilat is increased in patients with renal insufficiency. In patients with mild to moderate renal insufficiency (creatinine clearance 40-60 ml/min) steady state AUC of enalaprilat was approximately two-fold higher than in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (creatinine clearance ≤30 ml/min), AUC was increased approximately 8-fold. The effective half-life of enalaprilat following multiple doses of Enalapril is prolonged at this level of renal insufficiency and time to steady state is delayed. (See section 4.2).
Enalaprilat may be removed from the general circulation by haemodialysis.
The dialysis clearance is 62 ml/min.

Children and adolescents
A multiple dose pharmacokinetic study was conducted in 40 hypertensive male and female paediatric patients aged 2 months to ≤16 years following daily oral administration of 0.07 to 0.14 mg/kg Enalapril. There were no major differences in the pharmacokinetics of enalaprilat in children compared with historic data in adults. The data indicate an increase in AUC (normalised to dose per body weight) with increased age; however, an increase in AUC is not observed when data are normalised by body surface area. At steady state, the mean effective half-life for accumulation of enalaprilat was 14 hours.

Lactation
After a single 20 mg oral dose in five postpartum women, the average peak Enalapril milk level was 1.7 µg/L (range 0.54 to 5.9 µg/L) at 4 to 6 hours after the dose. The average peak enalaprilat level was 1.7 µg/L (range 1.2 to 2.3 µg/L); peaks occurred at various times over the 24-hour period. Using the peak milk level data, the estimated maximum intake of an exclusively breastfed infant would be about 0.16% of the maternal weight-adjusted dosage. A women who had been taking oral Enalapril 10 mg daily for 11 months had peak Enalapril milk levels of 2 µg/L 4 hours after a dose and peak enalaprilat levels of 0.75 µg/L about 9 hours after the dose. The total amount of Enalapril and enalaprilat measured in milk during the 24 hour period was 1.44 µg/L and 0.63 µg/L of milk respectively. Enalaprilat milk levels were undetectable (<0.2 µg/L) 4 hours after a single dose of Enalapril 5 mg in one mother and 10 mg in two mothers; Enalapril levels were not determined.