Eneas® [Nitrendipine, enalapril]

Pharmacological properties

the active compounds that make up the eneas preparation have a complementary effect. the mechanism of the antihypertensive effect of enalapril maleate is associated with competing inhibition of apf activity, which leads to a decrease in the rate of conversion of angiotensin i to angiotensin ii (which has a pronounced vasoconstrictor effect and stimulates the secretion of aldosterone in the adrenal cortex). as a result of a decrease in the concentration of angiotensin ii, a secondary increase in plasma renin activity occurs due to inhibition of negative feedback upon renin release and a direct decrease in aldosterone secretion. The mechanism by which enalapril reduces hell is primarily associated with the inhibition of the activity of the renin-angiotensin-aldosterone system, which plays a significant role in the regulation of hell, therefore enalapril can also reveal an antihypertensive effect in patients with low-root hypertension. prolonged use of enalapril in patients with primary antigens and renal failure can improve renal function by increasing glomerular filtration rate.

Nitrendipine is a calcium antagonist, a derivative of 1,4-dihydropyridine. The mechanism of antihypertensive action is associated with inhibition of the intake of calcium ions through the cell membranes of smooth muscle cells of the walls of blood vessels. By decreasing the intracellular calcium concentration in the cells, nitrendipine reduces the contractility of the vascular muscles, causes the expansion of peripheral arteries, and reduces the OPSS and pathologically increased blood pressure. Nitrendipine has a moderate natriuretic effect, especially at the beginning of treatment.

Pharmacokinetics After oral administration, enalapril is rapidly absorbed, its presence in the gastrointestinal tract does not affect its absorption. C_max in plasma is reached after 1 hour. Binding to plasma proteins is 50-60%. After absorption, enalapril is rapidly hydrolyzed to enalaprilat. C_max in blood plasma is achieved 3-4 hours after oral administration of the drug. Enalapril is excreted mainly by the kidneys (unchanged and 40% in the form of enaprilat). With the exception of conversion to enaprilat, there are no other signs of significant metabolic transformations of enalapril. The plasma concentration profile of enaprilate is characterized by a prolonged terminal phase, which is associated with ACE binding. In patients with normal renal function, constant concentrations of enaprilat were achieved on the 4th day of taking the drug. Effective T_½ enaprilat after repeated oral administration of enalapril is 11 hours. The degree of absorption and hydrolysis of enalapril is similar in the recommended therapeutic range.

Nitrendipine is rapidly and almost completely (88%) absorbed in the digestive tract. C_max in blood plasma is achieved 1-3 hours after taking the drug. Bioavailability is 20-30%. The binding of nitrendipine to plasma proteins is 96–98%.

Nitrendipine is almost completely metabolized in the liver by oxidation. T_½ is 8–12 hours. No accumulation of the active compound or its metabolites was observed. In patients with chronic impaired liver function, an increase in plasma concentrations of nitrendipine was noted.

Nitrendipine is secreted mainly by the kidneys in the form of inactive metabolites (approximately 77%) and with bile through the digestive tract.

The simultaneous use of enalapril maleate and nitrendipine can slightly increase the bioavailability of these compounds, which does not have clinical significance.

Indications

Treatment of ag in patients in need of combination therapy.

Application

The recommended dose for adults and elderly patients is 1 tablet per day. swallow tablets whole, without breaking or chewing, with plenty of water.

The duration of treatment is determined individually by the doctor, depending on the indications and severity of the disease.

Contraindications

Hypersensitivity to the components of the drug; a history of angioedema caused by any APF inhibitor; hereditary or idiopathic angioedema; ii – iii trimester of pregnancy; a condition with unstable hemodynamics after acute cerebrovascular accident and acute myocardial infarction; renal artery stenosis (bilateral or unilateral); stenosis of the aorta or mitral valve with severe hemodynamic impairment, hypertrophic cardiomyopathy; severe violations of the liver and / or kidneys (creatinine clearance 10 ml / min), during hemodialysis; childhood.

Side effects

Due to the use of the drug Eneas, the following adverse reactions occurred. often (1-10%) - hot flashes, swelling, headache, cough. infrequently (0.1–1%) - dizziness, tachycardia, skin rash, nausea, dyspepsia, arterial hypotension. very rarely (0.01%), including isolated cases, - asthenia, hypothermia, palpitation, peripheral ischemia, hematuria, pharyngitis, tracheitis, dyspnea, bloating, increased levels of liver enzymes, hypokalemia, drowsiness, paresthesia, tremors and convulsions.

The following are the side effects that may occur as a result of monotherapy with one of the active substances

Enalapril

From the cardiovascular system. Infrequently - arterial or orthostatic hypotension with the following symptoms: dizziness, weakness, visual impairment. Rarely, syncope (especially at the beginning of treatment, in patients with heart failure, severe renal failure, and with an increase in dose). Very rarely - in isolated cases in connection with a sudden drop in blood pressure - tachycardia, palpitation, arrhythmia, bradycardia, atrial fibrillation, chest pain, angina pectoris, myocardial infarction, stroke, pulmonary embolism, pulmonary infarction, pulmonary edema.

From the kidneys and urinary system. Infrequently - the occurrence or exacerbation of impaired renal function. Rarely - oliguria, proteinuria, in patients with impaired renal function, pain in the lumbar region can occur. Very rarely - acute renal failure.

From the respiratory system. Infrequently - dry cough, tonsillitis, hoarseness, bronchitis. Rarely - dyspnea, sinusitis, rhinitis. Very rarely - in isolated cases, bronchospasm / asthma, pulmonary infiltrates, stomatitis, glossitis, dry mouth, pneumonia, angioedema involving the pharynx, larynx or tongue, which in some cases can cause obstruction of the respiratory tract (risk group - patients of Negroid race) .

From the digestive tract. Infrequently - nausea, abdominal pain, indigestion. Rarely - vomiting, diarrhea, constipation, dyspepsia, loss of appetite. Very rarely - in isolated cases, impaired liver function, hepatitis, liver failure, bowel obstruction, stomatitis, glossitis, symptoms of cholestatic jaundice with the possibility of progression, up to the development of hepatonecrosis.

From the endocrine system. Very rarely - gynecomastia.

From the nervous system. Infrequently - headache, fatigue. Rarely - dizziness, sleep disturbance, depression, impotence, peripheral neuropathy with paresthesia, imbalance, muscle cramps, nervousness, confusion.

On the part of blood vessels and skin. Infrequently - allergic skin reactions (exanthema). Rarely - itching, skin rash, urticaria, angioedema, spreading to the lips, face and limbs. Very rarely, severe forms of skin reactions (pemphigus, erythema multiforme, exfoliative dermatitis, malignant exudative erythema or toxic epidermal necrosis), photosensitivity, increased sweating, baldness, onycholysis and exacerbation of Raynauds disease. Disturbances from the skin can be accompanied by fever, myalgia, arthritis, vasculitis, serositis, eosinophilia, leukocytosis, an increase in ESR and the level of antinuclear bodies.

From the senses. Rarely - tinnitus, blurred vision, a change in taste or a short-term loss of taste, loss of scent, dry eyes, and tearing.

Changes in laboratory indicators. Infrequently - a decrease in the level of hemoglobin, hematocrit, a decrease in the number of leukocytes and platelets. Rarely, in patients with impaired renal function, collagenosis, or receiving allopurinol, procainamide, or immunosuppressive drugs: anemia, thrombocytopenia, neutropenia, eosinophilia (in isolated cases, agranulocytosis, pancytopenia); in patients with impaired renal function, severe heart failure, renovascular hypertension: an increase in the concentration of urea, creatinine, potassium in the blood plasma, a decrease in the concentration of sodium, hyperkalemia (in patients with diabetes mellitus), increased excretion of albumin in the urine. In isolated cases, hemolytic anemia, an increase in the concentration of liver enzymes and bilirubin, were recorded.

Nitrendipine

From the cardiovascular system. Infrequently - arrhythmia, tachycardia, palpitation, peripheral edema, hot flashes, vasodilation. Very rarely - arterial hypotension, angina pectoris, pain behind the sternum.

From the gastrointestinal tract. Infrequently - nausea, diarrhea. Rarely - abdominal pain, constipation, dyspepsia, vomiting. Very rarely - hypertrophic gingivitis.

From the endocrine system. Very rarely - gynecomastia.

Blood side. Very rarely - leukopenia, agranulocytosis.

From the nervous system. Infrequently - a headache. Rarely - nervousness, paresthesia, tremors, dizziness.

From the respiratory system. Rarely - dyspnea.

From the musculoskeletal system. Rarely - itching, skin rash, urticaria, myalgia.

From the senses. Rarely - visual impairment.

From the urinary system. Very rarely - an increased frequency of urination, polyuria.

Changes in laboratory indicators. In isolated cases, an increase in the concentration of liver enzymes was recorded.

special instructions

During the use of APF inhibitors, especially at the beginning of treatment and with prolonged therapy, in some cases, angioedema may occur. patients urgently need to inform the doctor in case of any symptoms indicating angioedema (swelling of the face, limbs, eyes, lips, tongue, difficulty breathing or swallowing) and immediately stop taking the drug. angioedema, accompanied by laryngeal edema, can be fatal. careful monitoring of the patients condition is necessary in order to control clinical symptoms, stopping the observation only after they disappear. in patients taking APF inhibitors, there have been cases of neutropenia, thrombocytopenia and anemia. patients at risk (renal failure, collagenoses, treatment with immunosuppressants, allopurinol, procainamide) should use the drug with caution and monitor laboratory parameters. persons with renal failure need to control renal function, especially in the first weeks of taking APF inhibitors. patients with moderate renal failure (creatinine clearance 30 ml / min; plasma creatinine 3 mg / ml) do not need dose adjustment. in some patients, arterial hypotension occurs at the beginning of treatment with APF inhibitors, which may further reduce renal function. in these cases attacks of an arrester are observed which usually have a reversible character.

Data on the use of Eneas in patients with a recently transplanted kidney are not available. In individuals with renal failure in rare cases, proteinuria may occur. Patients with proteinuria (1 g / day) should use the drug after a thorough assessment of the benefit / risk ratio and under the supervision of clinical laboratory parameters.

It is necessary to use the drug with caution in patients with mild to moderate liver failure, since there is not enough experience with the combination therapy. Patients with severe hepatic insufficiency are contraindicated. In elderly people, due to a decrease in liver function, the excretion of nitrendipine may slow down, which can lead to arterial hypotension. In case of occurrence of side effects from the liver (cholestatic jaundice, increased liver enzymes), which can lead to hepatonecrosis, it is necessary to stop drug therapy and consult a doctor.

In the treatment of ACE inhibitors in patients with renovascular hypertension and renal artery stenosis (bilateral or unilateral), the risk of arterial hypotension and renal failure is significantly increased, which can lead to impaired renal function.

ACE inhibitors can cause an increase in potassium levels, especially in patients with heart and kidney failure. Combination therapy with potassium-sparing diuretics and dietary supplements containing potassium is not recommended. If necessary, this combination therapy should monitor the concentration of potassium in the blood plasma.

In some cases, Aeneas can cause orthostatic hypotension. Patients should be examined in order to identify and eliminate clinical signs of impaired water-electrolyte balance due to the use of diuretics, low-salt diets, hemodialysis, diarrhea, or vomiting. As with other antihypertensive drugs, some patients may develop symptomatic hypotension that disappears after the patient has taken a horizontal position and corrected blood pressure and bcc levels. Particular care should be taken in treating patients with coronary artery disease or cerebrovascular disease, since an excessive decrease in blood pressure can lead to the development of myocardial infarction or stroke. Rapid arterial hypotension with a restored level of blood pressure and bcc is not a contraindication for treatment with Eneas. ACE inhibitors should be used with caution in patients with obstruction of the outflow pathway from the left ventricle. In case of severe hemodynamic impairment, the drug should not be used (see CONTRAINDICATIONS).

There have been cases of coughing during therapy with ACE inhibitors. Usually a cough is unproductive, permanent and stops after discontinuation of the drug. Patients with primary aldosteronism are usually resistant to therapy with antihypertensive drugs acting on the renin-angiotensin-aldosterone system, and therefore the use of this drug is not recommended.

Due to the increased risk of anaphylactic reactions, the drug should not be prescribed to hemodialysis patients using high-throughput polyacrylonitrile membranes (such as AI 69^®) or plasmapheresis using dextran sulfate, as well as patients during hyposensitization of hymenoptera venom allergen.

During major surgeries or during anesthesia with drugs that increase blood pressure, the drug blocks the formation of angiotensin II for the second time to compensatory release of renin. If arterial hypotension develops in this case, it is corrected by increasing the volume of fluid.

In rare cases, nitrendipine can cause reversible biochemical changes in the sperm head during in vitro fertilization, which can affect the functional state of sperm.

The drug less effectively reduces blood pressure in patients of the Negroid race.Patients with rare hereditary malabsorption of glucose-galactose deficiency of Lapp lactase should not use the drug.

During pregnancy and breastfeeding. Experience with the use of the drug Eneas in the first trimester of pregnancy is limited. During pregnancy, you should stop taking the drug, unless the continuation of the drug is vital for a woman. Acneas is contraindicated in the II and III trimester of pregnancy. The use of ACE inhibitors during this period negatively affects the fetus and newborn, causing renal failure, arterial hypotension, hyperkalemia, hypoplasia of the bones of the skull, and the possible development of oligohydramnios. If the appointment of the drug during pregnancy is unavoidable, it is necessary to monitor the development of the fetus using ultrasound of the kidney and skull bones.

Enaprilat passes into breast milk in trace amounts, therefore, during the period of breast-feeding, a baby is monitored to identify side effects. Mothers should not use the drug during breast-feeding of premature babies and in the first few weeks after the birth of the baby.

Children. Clinical data on the effectiveness and safety of the drug for the treatment of children are not available, therefore, it is not prescribed for this age group of patients.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. In individual cases, at the beginning of treatment and when replacing the drug, as well as when interacting with alcohol, the ability to drive vehicles or work with complex mechanisms may be reduced.

Interactions

The antihypertensive effect of Eneas is enhanced when combined with other antihypertensive drugs, in particular, diuretics, β-adrenergic blockers, α-adrenergic blockers, for example prazosin.

Combinations of enalapril maleate with other agents that must be used with caution

When combined with potassium-sparing diuretics, potassium supplements and drugs that increase the level of potassium in the blood plasma (e.g. heparin), an increase in the concentration of potassium in the blood plasma is possible, especially in patients with impaired renal function. With the combined use of such drugs, it is necessary to control the concentration of potassium in the blood plasma.

When taken simultaneously with lithium preparations, a delay in the removal of lithium from the body and, accordingly, an increase in the risk of its side and toxic effects, are likely. In the case of such a combination, it is necessary to carefully monitor the level of lithium in the blood plasma. Therefore, their combined use is not recommended.

With simultaneous use with NSAIDs, it is possible to weaken the hypotensive effect of ACE inhibitors, an additional increase in the level of potassium in the blood plasma with a decrease in renal function. In some patients with impaired renal function, combined use can lead to further deterioration of renal function. Enalapril can increase the hypoglycemic effect of oral antidiabetic drugs, so it is necessary to control the level of glucose in the blood.

Baclofen, amifostine enhance the hypotensive effect of the drug. Blood pressure monitoring and dose adjustment are required.

Concomitant use with antipsychotics or tricyclic antidepressants can lead to orthostatic arterial hypotension.

When used with allopurinol, cytostatics, immunosuppressants, systemic GCS, procainamide, leukopenia may develop.

Combinations of nitrendipine with other agents that must be used with caution

Nitrendipine can increase the concentration of digoxin in blood plasma with combined use. It is necessary to control the level of digoxin in blood plasma.

Nitrendipine may enhance the effect and duration of muscle relaxants, such as pancuronium bromide.

Grapefruit juice inhibits the oxidative metabolism of nitrendipine, increasing the concentration of the latter in the blood plasma, as a result of which the hypotensive effect of the drug Eneas amplifies. Nitrendipine is metabolized in the mucous membrane of the intestines and liver with the participation of the cytochrome P450 system. Agents that stimulate this system, such as anticonvulsants (phenytoin, phenobarbital, carbamazepine) and rifampicin, can cause a significant decrease in the bioavailability of nitrendipine. Means that suppress this enzyme system, for example, antifungal agents (intraconazole, etc.), increase the concentration of nitrendipine in blood plasma. Nitrendipine and β-adrenergic blockers have a synergistic effect.

Overdose

To date, overdose phenomena as a result of the use of the drug Eneas have not been noted. the most likely symptom of an overdose is arterial hypotension.

Treatment: primary detoxification - gastric lavage, the appointment of sorbents and / or sodium sulfate (during the first 30 minutes). In case of arterial hypotension, the patient must be given a horizontal position and restoration of the water-electrolyte balance. With bradycardia, atropine is prescribed. In case of severe overdose, iv administration of catecholamines, angiotensin II and hemodialysis are possible. It is necessary to carefully monitor the concentration of creatinine and electrolytes in blood plasma.

Storage conditions

At a temperature not exceeding 25 ° C.