Enalapril

Pharmacological properties

berlipril (enalapril maleate) is a maleic acid salt of enalapril, which is a derivative of two amino acids, l-alanine and l-proline.

Angiotensin-converting enzyme (ACE) is a peptidyldipetidase, which catalyzes the conversion of angiotensin I to angiotensin II and has a vasoconstrictive effect. After absorption, enalapril undergoes hydrolysis with the formation of enalaprilat, an ACE inhibitor. As a result of this inhibition of ACE, the concentration of angiotensin II in the blood plasma decreases, which, in turn, leads to an increase in renin activity in blood plasma (due to the blocking of the negative feedback mechanism of renin release) and to a decrease in aldosterone secretion.

The structure of ACE is identical to the structure of kinase II. Thus, Berlipril can also block the breakdown of bradykinin, a peptide that is a powerful vasodilator. However, the role this effect plays in the therapeutic effect of the drug remains unexplored.

Mechanism of action. The mechanism of the antihypertensive effect of the drug Berlipril is primarily associated with inhibition of the renin-angiotensin-aldosterone system (RAAS); enalapril can lower blood pressure even in patients with a low-root form of hypertension.

Pharmacodynamic effects. The use of Berlipril in patients with hypertension leads to a decrease in blood pressure in both horizontal and vertical positions, without a significant increase in heart rate.

In rare cases, symptomatic orthostatic hypotension occurs. In some patients, an optimal decrease in blood pressure occurs only after a few weeks of therapy. A sharp cessation of therapy with Berlipril is not associated with a sharp increase in blood pressure.

Effective suppression of ACE activity usually occurs 2–4 hours after oral administration of an individual dose of enalapril maleate. The antihypertensive effect, as a rule, is noted already 1 hour after use, and the maximum decrease in blood pressure is achieved 4-6 hours after taking the drug. The duration of action depends on the dose. However, at recommended doses, the antihypertensive and hemodynamic effects last for at least 24 hours.

A study of hemodynamics in patients with essential arterial hypertension proved that a decrease in blood pressure was accompanied by a decrease in peripheral resistance in the arteries and an increase in IOC, but heart rate was almost unchanged. After applying Berlipril, blood circulation in the kidneys increased; the degree of glomerular filtration remained unchanged. No signs of salt and fluid retention were noted. However, in patients whose glomerular filtration rate was low prior to initiation of therapy, this indicator tended to increase.

In short-term clinical studies in patients with and without diabetes mellitus, as well as with kidney diseases, enalapril maleate decreased albuminuria as well as decreased urinary IgG and total protein.

With the simultaneous use of diuretics of the thiazide group, the antihypertensive effect of Berlipril is additive in nature. Burlipril can prevent or reduce thiazide-induced hypokalemia.

In patients with heart failure taking drugs of the cardiac glycoside and diuretic group, a decrease in peripheral resistance and a decrease in blood pressure were observed after oral or iv administration of enalapril maleate. IOC increased, while heart rate (which is usually increased in patients with heart failure), on the contrary, decreased. The pressure in the final pulmonary capillaries also decreased. Physical exercise tolerance and the degree of heart failure, as determined by the NYHA criteria, have improved. With prolonged treatment, these effects persist.

In patients with mild to moderate heart failure, enalapril slowed the progression of dilatation / enlargement of the heart and heart failure, determined by a decrease in the final diastolic and systolic volume in the left ventricle and an increase in the ejection fraction.

Clinical efficacy and safety. A multicenter, randomized, double-blind, placebo-controlled study (SOLVD, prevention study) studied a population of patients with asymptomatic left ventricular dysfunction (ejection fraction of 35%). 4228 patients were randomized to placebo (n = 2117) or enalapril maleate (n = 2111). In the placebo group, 818 individuals developed heart failure or death (38.6%) compared with 630 patients in the enalapril group (29.8%) (risk reduction: 29%; 95% confidence interval (CI) 21–36% ; p0.001).

518 patients in the placebo group (24.5%) and 434 in the enalapril group (20.6%) died or were hospitalized due to the development of heart failure or complications of an existing disease (20% risk reduction; 95% CI: 9-30 %; p0.001).

A multicenter, randomized, double-blind, placebo-controlled study (SOLVD, therapeutic study) studied a population of patients with clinical manifestations of congestive heart failure due to systolic dysfunction (ejection fraction of 35%). 2569 patients receiving conventional treatment for heart failure were randomly assigned to placebo (n = 1284) or enalapril maleate (n = 1285). In the placebo group, 510 (39.7%) deaths were recorded compared to 452 (35.2%) in the enalapril group (risk reduction: 16%; 95% CI: 5–26%; p = 0.0036). In the placebo group, 461 patients died due to cardiovascular disease, compared with 399 in the enalapril group (risk reduction: 18%; 95% CI: 6–28%; p0.002), mainly due to a decrease in mortality from progressive heart failure ( 251 cases in the placebo group compared with 209 in the enalapril group; risk reduction: 22%; 95% CI: 6–35%). Several patients died or were hospitalized due to progression of heart failure (736 patients in the placebo group and 613 in the enalapril group; risk reduction: 26%; 95% CI: 18–34%; p0,0001). In general, in patients with left ventricular dysfunction in the SOLVD study, enalapril reduced the risk of myocardial infarction by 23% (95% CI: 11–34%; p0.001), as well as the risk of hospitalization for unstable angina by 20% (95% CI: 9–29%; p0.001).

In two large-scale randomized controlled trials (ONTARGET - ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial / Current international study on telmisartan use alone and in combination with ramipril and VA NEPHRON-D - The Veterans Affairs Nephropathy in Diabetes / Diabetic Nephropathy Treatment Study) studied the use of an ACE inhibitor in combination with angiotensin II receptor blockers.

The ONTARGET study was conducted among patients with a history of cardiovascular or cerebrovascular disease or type II diabetes mellitus, which was accompanied by signs of target organ damage. The VA NEPHRON-D study included patients with type II diabetes mellitus and diabetic nephropathy. In the course of these studies, a slight beneficial effect was found with respect to renal and / or cardiovascular disorders and a decrease in mortality, while there was an increased risk of hyperkalemia, acute kidney damage, and / or hypotension compared with monotherapy. Given the similar pharmacodynamic properties, these results also apply to other ACE inhibitors and angiotensin II receptor blockers.

That is why patients with diabetic nephropathy should not be prescribed ACE inhibitors and angiotensin II receptor blockers at the same time.

The aim of the ALTITUDE study (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was to determine the benefits of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor blockers in patients with sugar type II diabetes and chronic kidney disease or cardiovascular disease, or both at the same time. The study was prematurely terminated due to an increased risk of adverse events. Death due to cardiovascular disease and stroke more often occurred in the aliskiren group than in the placebo group, as well as serious adverse events that are the subject of research (hyperkalemia, hypotension and renal dysfunction).

Children. There is some evidence on the use of the drug in children with hypertension at the age of 6 years. In clinical studies involving 110 children with hypertension aged 6–16 years, whose body weight was ≥20 kg and glomerular filtration rate was 30 ml / min / 1.73 m², patients with a body weight of 50 kg received 0.625 mg, 2.5 mg or 20 mg of enalapril maleate daily, and patients with a body weight of ≥50 kg received 1.25 mg, 5 mg or 40 mg of enalapril maleate daily. When taken once a day, enalapril maleate reduced blood pressure, depending on the dose. A dose-dependent antihypertensive effect was noted in all subgroups (by age, Tanner stage, gender, race). However, when applying the lowest studied doses of 0.625 and 1.25 mg, which corresponds to an average of 0.02 mg / kg of body weight 1 time per day, no corresponding antihypertensive effectiveness was revealed. The maximum dose of the drug that was studied during the study was 0.58 mg / kg body weight (up to 40 mg) 1 time daily. The profile of adverse events in children was similar to that observed in adult patients.

Pharmacokinetics Suction. After oral administration of enalapril, maleate is rapidly absorbed and its C_max in blood plasma is achieved after 1 hour. After oral administration of enalapril maleate tablets, absorption, determined by the degree of re-determination in urine, is about 60%. The presence of food in the digestive tract does not affect the absorption of Berlipril when taken orally. After absorption, enalapril maleate taken internally undergoes rapid and full-scale hydrolysis to enalaprilat, a potent ACE inhibitor. The peak concentration of enalaprilat in blood plasma is reached 4 hours after oral administration of enalapril tablets.

Effective T_½ enalaprilat after repeated oral administration is 11 hours. In individuals with normal renal function, a stable concentration of enalaprilat in blood plasma was achieved after 4 days of treatment.

Distribution. In the range of therapeutically significant concentrations in humans, binding to plasma proteins does not exceed 60%.

Biotransformation. In addition to conversion to enalaprilat, there is no data on further significant metabolism of enalapril maleate.

Breeding. Enalaprilat is excreted mainly by the kidneys. The main component in the urine are enalaprilat, the amount of which is 40% of the dose taken, and unchanged enalapril maleate (about 20%).

Impaired renal function. In patients with renal failure, the exposure of enalapril maleate and enalaprilat in the body is increased. In patients with mild or moderate renal failure (creatinine clearance of 40-60 ml / min), the AUC value (area under the curve) of enalaprilat with continuous use of 5 mg / day was approximately 2 times higher than in patients with normal renal function. In severe renal failure (creatinine clearance ≤30 ml / min), the AUC value was approximately 8 times higher. At this stage of renal failure, effective T_½ enalaprilat after prolonged use of enalapril maleate lengthens, and the achievement of a stationary level slows down (see APPLICATION).

Enalaprilat can be eliminated from the body via hemodialysis. The degree of dialysis is 62 ml / min.

Children. Studies of pharmacokinetics using multiple doses in 40 children with hypertension in the age of 2 months to 16 years who took enalapril maleate orally at a dose of 0.07-0.14 mg / kg / day. In the pharmacokinetics of enalaprilat, no significant differences were found between children and adults. The results indicate an increase in AUC (with dose normalization based on body weight) with age, however, such an increase in AUC was not observed if the doses were normalized based on body area. In steady state, average effective T_½ enalaprilat was 14 hours

Lactation. 4-6 hours after taking a single oral dose of 20 mg in 5 women after childbirth, average C_max enalapril in breast milk is 1.7 μg / L (range 0.54–5.9 μg / L).

Average c_max enalaprilat in breast milk was 1.7 mcg / l (range 1.2–2.3 mcg / l); peak concentrations were observed at different times of the day. Based on the values ​​of C_max in breast milk, the maximum amount consumed by a child who is exclusively breastfed is 0.16% of the mothers dose.

C_max enalapril in breast milk of a woman who orally took enalapril at a dose of 10 mg / day for 11 months was 2 μg / l 4 hours after the dose, and C_max enalaprilat - 0.75 mcg / l about 9 hours after taking the dose. The total amount of enalapril and enalaprilat in milk was measured during the day and amounted to 1.44 and 0.63 μg / L, respectively.

It was impossible to determine the concentration of enalaprilat in milk (0.2 μg / l) 4 hours after taking a single dose of enalapril 5 mg in one mother and a dose of 10 mg in two mothers; enalapril concentrations not determined.

Indications

Ag treatment; treatment of heart failure with severe symptoms; prevention of symptomatic heart failure in patients with asymptomatic left ventricular dysfunction (ejection fraction ≤35%).

Application

Eating does not affect the absorption of berlipril.

The dose of the drug should be selected individually, depending on the condition of the patient (see SPECIAL INSTRUCTIONS) and on the effect of the drug on blood pressure.

AH. The initial dose of Berlipril is 5–20 mg, depending on the severity of hypertension and the patients condition (see below). The drug Berlipril is taken 1 time per day.

In mild hypertension, the recommended initial dose of the drug is 5-10 mg.

In patients with pronounced activation of RAAS (for example, with renovascular hypertension, lack of salts and / or fluid in the body, cardiac decompensation, or severe hypertension), a significant decrease in blood pressure may occur after taking the initial dose. In such patients, treatment should be started with a dose of 5 mg or a lower dose and under close medical supervision.

With preliminary treatment with diuretics in high doses, hypovolemia may develop and there is a risk of developing hypotension at the beginning of enalapril treatment. Therefore, it is recommended that such patients begin treatment with Berlipril at a dose of 5 mg or at a lower dose and, if possible, cancel diuretics 2–3 days before the start of therapy. Monitoring of renal function and plasma potassium levels is also recommended.

The usual maintenance dose is 20 mg enalapril per day, and the maximum is 40 mg / day.

Heart failure / asymptomatic left ventricular dysfunction. In the treatment of heart failure, Berlipril is prescribed in addition to diuretics, digitalis drugs or β-adrenergic blockers. The initial dose for patients with heart failure or asymptomatic left ventricular dysfunction is 2.5 mg. In order to determine the effect of the drug on blood pressure, therapy should be started under close medical supervision. If, after starting treatment with Berlipril in case of heart failure, symptomatic arterial hypotension does not occur or is eliminated, the dose should be gradually increased to a generally accepted maintenance dose of 20 mg, which is taken once or divided into 2 doses depending on patient tolerance. Such dose titration is recommended during the first 2–4 weeks of therapy. The maximum dose is 40 mg of enalapril per day, which should be divided into 2 doses.

Recommended dose titration of Burlipril in patients with heart failure / asymptomatic left ventricular dysfunction

* Special care should be taken with patients with impaired renal function and patients taking diuretics (see SPECIAL INSTRUCTIONS).

Before and after the start of therapy with Berlipril, careful monitoring of blood pressure and renal function should be carried out (see SPECIAL INSTRUCTIONS), since there have been reports of the development of arterial hypotension and (less often) renal failure. Before starting treatment with Berlipril, if possible, reduce the dose of diuretics that patients use. The antihypertensive reaction at the beginning of treatment with Berlipril is not a sign of its development with prolonged treatment and does not exclude its further use. Plasma potassium levels and kidney function should also be monitored.

Renal failure. As a rule, you should increase the intervals between doses of the drug and / or reduce the dose.

*Cm. SPECIAL INSTRUCTIONS: patients who receive hemodialysis treatment.

Enalaprilat undergoes dialysis. The dose on days on which dialysis is not performed is adjusted depending on the degree of reduction in blood pressure.

Elderly patients. The dose should be selected in accordance with the condition of the patients kidneys (see SPECIAL INSTRUCTIONS).

Children with hypertension at the age of 6 years. Clinical data on the use of Berlipril in patients with a pediatric profile with hypertension are limited (see SPECIAL INSTRUCTIONS, PHARMACOLOGICAL PROPERTIES).

If the patient is able to swallow tablets, the dose should be selected individually, depending on his condition, degree of decrease in blood pressure and body weight. For children with a body weight of 20 to 50 kg, the recommended initial dose is 2.5 mg, and for patients with a body weight of ≥50 kg, 5 mg. Berlipril is prescribed 1 time per day. The dose should be selected depending on the needs of the patient. Do not exceed the maximum daily dose of 20 mg for patients with body weight from 20 to 50 kg and 40 mg for patients with body weight ≥50 kg (see SPECIAL INSTRUCTIONS: children).

Berlipril is not recommended for children with a glomerular filtration rate of 30 ml / min / 1.73 m² due to lack of relevant information.

Contraindications

Hypersensitivity to enalapril maleate, one of the components of the drug or other APF inhibitors. the presence in the history of angioedema, which developed as a result of the use of inhibitors of apf. hereditary or idiopathic angioedema. contraindicated in pregnant women and women planning a pregnancy (see use during pregnancy and lactation).

It is contraindicated to prescribe Berlipril simultaneously with drugs containing aliskiren for patients with diabetes mellitus and impaired renal function (glomerular filtration rate of 60 ml / min / 1.73 m²).

Side effects

To assess the incidence of side effects that developed with enalapril, the following classification is used: very often (≥1 / 10); often (≥1 / 100 and 1/10); infrequently (≥1 / 1000 and 1/100); rarely (≥1 / 10,000 and 1/1000); very rarely (1/10 000); unknown (assessment cannot be made according to available data).

On the part of the blood system and lymphatic system: infrequently - anemia (including aplastic and hemolytic); rarely - neutropenia, decreased hemoglobin and hematocrit, thrombocytopenia