Enalaprilat

Pharmacological properties

enalaprilat suppresses APF, which catalyzes the conversion of angiotensin i to angiotensin ii. inhibition of apf leads to a decrease in the concentration of angiotensin ii, an increase in the activity of renin in blood plasma and a decrease in the secretion of aldosterone.

The antihypertensive effect and hemodynamic effects of enalaprilat in patients with high blood pressure are the result of the expansion of resistant vessels and a decrease in total peripheral resistance, which gradually reduces blood pressure. Systolic and diastolic blood pressure and pulmonary artery pressure decrease, coronary circulation increases, cardiac index and stroke volume increase (with constant heart rate).

After iv administration, the effect of the drug occurs after 5-15 minutes, the maximum effect after 1-4 hours, and its effect lasts approximately 6 hours.

Enalaprilat does not affect the metabolism of glucose, lipoproteins, uric acid and cholesterol. The drug can be prescribed to patients with diabetes, COPD, angina pectoris, congestive heart failure.

Pharmacokinetics After oral administration, enalaprilat is weakly absorbed and practically inactive, therefore it is administered exclusively iv.

After iv injection, the drug is rapidly distributed in most body tissues, with the highest concentrations in the lungs, kidneys and blood vessels, observed in blood plasma for 96 hours. T_½ - 4 hours C_max in the blood plasma is observed after 3-5 hours. 50-60% of enalaprilat binds to blood plasma proteins.

Enalaprilat is not metabolized; 100% of enalaprilat is excreted in the urine.

Enalaprilat is secreted mainly through the kidneys using glomerular filtration and tubular secretion. Excretion occurs in several stages, which is explained by strong binding to ACE in blood plasma. T_½ at the initial stage, it is approximately 11 hours, and at the last, 35 hours. The clinical effect is observed approximately 15 minutes after iv administration of enalaprilat, and the maximum antihypertensive effect is 4 hours after administration and lasts for approximately 6 hours.

Indications

Ar, hypertensive crisis. enalaprilat is indicated for the treatment of ag if enalapril cannot be taken orally.

Application

Used in adults.

Enap rr for injection is administered iv in a jet slowly over a period of at least 5 minutes. It is possible to dilute the drug in 50 ml of 5% glucose solution, 0.9% sodium chloride solution (physiological solution), 5% glucose solution in 0.9% sodium chloride solution or 5% solution glucose in Ringers lactate.

The usual recommended dose for the treatment of hypertension and hypertensive crises is 1.25 mg of enalaprilat (1 ampoule) every 6 hours. When switching from enalapril treatment to enalaprilat treatment, the usual dose is 1 ampoule (1.25 mg) every 6 hours.

As a rule, treatment with enalaprilat lasts 48 hours. After this, the patient is transferred to therapy with enalapril tablets. When switching from parenteral enalaprilate treatment to oral enalapril treatment, the recommended initial dose is 5 mg once a day for patients who have already received 1 ampoule (1.25 mg) of enalaprilat every 6 hours. If necessary, the dose can be increased. For patients who were initially treated with half the usual dose of enalaprilat (0.625 mg), the recommended dose when switching to oral treatment is 2.5 mg of enalapril per day.

Dosage for renal failure. Doses of enalaprilat for patients with chronic renal failure depend on creatinine clearance. Patients with a creatinine clearance of 0.5 ml / s (plasma creatinine - up to 265 μmol / L) are prescribed the usual doses of enalaprilat at 1.25 mg (1 ml) every 6 hours. Patients with a creatinine clearance of 0.5 ml / s (creatinine blood plasma 265 μmol / l) prescribe an initial dose of 0.625 mg (0.5 ml). If the clinical effect after 1 h is unsatisfactory, you must re-enter the same dose.Treatment is continued in a full dose of 1.25 mg every 6 hours.

Dosage for hemodialysis. The recommended dose for patients on hemodialysis is 0.625 mg (0.5 ml) every 6 hours.

Dosage for patients who are treated with diuretics. For patients who are treated with diuretics, the recommended starting dose is 0.625 mg (0.5 ml). If the clinical effect after 1 h is unsatisfactory, a dose of 0.625 mg (0.5 ml) can be repeated. The following doses of 1.25 mg are prescribed every 6 hours.

Contraindications

• Hypersensitivity to enalapril, enalaprilat or to any ingredients of the drug; the presence of a history of angioedema associated with previous treatment with APF inhibitors; hereditary or idiopathic angioedema.

Side effects

Enalaprilat is a metabolite of enalapril. therefore, during treatment with Enap rr for injection, the same side effects are possible as during treatment with Enap tablets or other APF inhibitors.

In controlled clinical trials of enalaprilat, the most common side effect in patients with hypersensitivity was arterial hypotension (1.8%). Side effects observed in 1% of patients also included headache (2.9%) and nausea (1.1%). Less frequent side effects that occurred in 0.5–1% of patients were myocardial infarction, fatigue, dizziness, fever, skin rashes, and constipation.

From the blood and lymphatic systems: anemia (including aplastic and hemolytic), neutropenia, decreased hemoglobin, decreased hematocrit, thrombocytopenia, agranulocytosis, inhibition of bone marrow function, pancytopenia, lymphadenopathy, autoimmune diseases.

From the side of metabolism: hypoglycemia.

From the endocrine system: ADH secretion disorder syndrome.

From the nervous system and mental disorders: headache, depression, confusion, drowsiness, insomnia, nervousness, paresthesia, dizziness, sleep disturbance.

From the side of the organ of vision: blurred vision.

On the part of the cardiovascular system: dizziness, arterial hypotension (including orthostatic hypotension), syncope, myocardial infarction or stroke, possibly due to severe arterial hypotension in patients at increased risk, chest pain, heart rhythm disturbance, angina pectoris, tachycardia; infrequently - orthostatic hypotension, tachycardia, Raynauds syndrome.

On the part of the respiratory system, chest and mediastinum: cough, shortness of breath, rhinorrhea, pharyngitis, dysphonia, bronchospasm / asthma, lung infiltrate, rhinitis, allergic alveolitis / eosinophilic pneumonia.

From the digestive tract: nausea, diarrhea, abdominal pain, taste disturbance, bowel obstruction, pancreatitis, vomiting, dyspepsia, constipation, anorexia, irritation of the gastric mucosa, dry mouth, peptic ulcers, stomatitis / aphthous ulcers, glossitis, angioedema .

From the hepatobiliary system: liver failure, hepatocellular or cholestatic hepatitis, hepatonecrosis, cholestasis, including jaundice.

From the skin and subcutaneous tissues: rash, hypersensitivity / angioedema, hyperhidrosis, pruritus, urticaria, alopecia, polymorphic erythema, Stevens-Johnson syndrome, exfoliative dermatitis, toxicodermal necrolysis, pemphigus, erythroderma.

A set of symptoms has been reported: fever, serositis, vasculitis, myalgia / myositis, arthralgia / arthritis, a positive result for antinuclear antibodies, increased ESR, eosinophilia and leukocytosis. Exanthema, photosensitivity and other skin disorders are also possible.

From the side of the kidneys and urinary tract: impaired renal function, renal failure, proteinuria, oliguria.

From the reproductive system and mammary glands: impotence, gynecomastia.

Common disorders: asthenia, fatigue, muscle cramps, hot flashes, tinnitus, discomfort, fever.

Laboratory indicators: hyperkalemia, increased creatinine in plasma, increased urea in blood plasma, hyponatremia, increased activity of liver enzymes, bilirubin in blood plasma.

If severe side effects occur, treatment should be discontinued.

special instructions

With parenteral administration, enalaprilat quickly reduces elevated hell and improves heart function.

Symptomatic hypotension. Patients with hypertension and severe heart failure, hyponatremia and / or hypovolemia due to diuretic therapy, a salt-free diet and dialysis, diarrhea and vomiting are a subgroup of patients in whom blood pressure depends on renin and the activation of the renin-angiotensin system. In these patients, as well as in the elderly and patients with impaired renal function, arterial hypotension may occur with the following clinical consequences (from dizziness and nausea to acute renal failure, stroke or myocardial infarction) even several hours after taking the first dose of enalaprilat.

Arterial hypotension and its grave consequences are single and reversible phenomena. They can be avoided by discontinuing diuretics and eating a low-salt diet before starting Enap treatment, if possible.

Enalaprilat therapy of all these patients, or if it is impossible to stop treatment with a diuretic, is recommended to be started carefully with the use of the drug in a low dose (0.625 mg).

Stenosis of the aorta or mitral valve of the heart / hypertrophic cardiomyopathy. The drug is used with caution in patients with aortic stenosis or idiopathic hypertrophic subaortic stenosis and generalized atherosclerosis. Arterial hypotension in these patients can lead to hypoperfusion and ischemia of the heart, brain, and kidneys. Persons with peripheral vascular disease or generalized atherosclerosis may have a latent renal vascular disease that is not clinically apparent. Enalaprilat should begin therapy in these patients very carefully, with a minimum (0.625 mg) dose.

ACE inhibitors are used with caution in patients with left ventricular outflow tract obstruction and avoid use in cardiogenic shock and hemodynamically significant left ventricular outflow tract obstruction.

Impaired renal function. In patients with impaired renal function (creatinine clearance of 80 ml / min), it is necessary to adjust the dose of the drug according to creatinine clearance, and then according to the reaction in response to treatment. It is necessary to regularly monitor the level of creatinine and potassium in the blood plasma.

In some patients, in the absence of clear symptoms of kidney disease, a slight and transient increase in the level of urea and creatinine in blood plasma may occur if enalapril was administered simultaneously with diuretics. A dose reduction of an ACE inhibitor and / or diuretic withdrawal may be necessary. This situation should indicate the likelihood of stenosis of the renal arteries.

In some patients with hypertension who did not show symptoms of kidney disease before treatment, enalapril, combined with diuretics, usually caused a slight and transient increase in blood urea and creatinine in blood plasma. In such cases, a dose reduction and / or diuretic withdrawal may be required. This situation increases the likelihood of renal artery stenosis.

Renovascular hypertension. In patients with bilateral renal artery stenosis, vasodilation of postglomerular efferent arterioles, there may be transient renal failure or acute renal failure.In individuals with renal artery stenosis of a single kidney, transient dysfunction of the kidney or acute renal failure of the affected kidney may be observed. Therefore, the assessment of the patient with hypertension should always include an assessment of renal function. Renovascular hypertension should only be treated by an experienced specialist.

Kidney transplantation. There is insufficient data on the treatment of enalapril in patients with recent kidney transplantation; therefore, treatment with enalapril in patients of this group is not recommended.

Liver failure. If jaundice or a marked increase in the level of liver enzymes occurs during therapy with ACE inhibitors, treatment should be stopped immediately, the patient should be carefully monitored and treatment should be prescribed if necessary.

Neutropenia / agranulocytosis. The possibility of the development of neutropenia or agranulocytosis cannot be completely excluded, therefore it is recommended that a general blood test be performed regularly. Enalapril is used with extreme caution in patients with vascular collagenosis (for example, systemic lupus erythematosus, scleroderma), simultaneously with antidepressants, allopurinol or procainamide, or with a combination of these factors, especially when there is impaired renal function. Some of these patients may develop a severe infection that is sometimes resistant to intensive antibiotic therapy. When enalapril / enalaprilat is used in these patients, it is recommended to conduct a periodic analysis of the number of leukocytes in the blood.

Hypersensitivity / angioedema. In rare cases, treatment with enalaprilat develops angioedema of the face, limbs, lips, tongue, glottis and / or larynx. This can happen at any time during the treatment process. In such cases, you should stop treatment, prescribe antihistamines and conduct appropriate monitoring of the patient in order to make sure that all symptoms of hypersensitivity have completely disappeared. With angioedema of the tongue, without respiratory failure, patients may require prolonged observation, since treatment with antihistamines and corticosteroids may be insufficient.

Patients who have had a history of angioedema associated with ACE inhibitor therapy have an increased risk of developing angioedema while taking ACE inhibitors. Patients with angioedema of the tongue, glottis and / or larynx have an increased risk of airway obstruction, especially during surgery on the airways. Angioedema of the tongue, glottis and / or larynx can lead to airway obstruction, so it is necessary to conduct appropriate therapy as soon as possible, which may include sc administration of 1: 1000 epinephrine solution (0.3-0.5 ml) , and measures to ensure patency of the upper respiratory tract.

Representatives of the black race who took ACE inhibitors more often had angioedema compared with patients of other races.

In patients with a history of angioedema that is not associated with the use of ACE inhibitors, there may be an increased risk of its occurrence in the treatment with an ACE inhibitor.

Anaphylactoid reactions during desensitization. In patients taking ACE inhibitors during desensitization to aspen or bee venom, reactions similar to allergic (pseudo-anaphylactic), which are life-threatening, rarely occur. Such reactions can be avoided by temporarily stopping ACE inhibitor therapy before each desensitization.

Anaphylactoid reactions during apheresis of LDL. Rarely, patients taking ACE inhibitors during LDL apheresis with dextran sulfate experienced anaphylactoid reactions that posed a life threat.Such reactions can be avoided by temporarily stopping the use of ACE inhibitors before each apheresis.

Patients on hemodialysis. There have been reports of hypersensitivity, similar to allergic (pseudo-anaphylactic) reactions, in patients undergoing dialysis using polyacrylonitrile membranes (e.g. AN 69) and concomitant use of ACE inhibitors. For such patients, it is necessary to consider the use of other types of dialysis membranes or another class of antihypertensive agents.

Hypoglycemia. In patients with diabetes taking oral antidiabetic drugs or insulin, careful glycemic control is necessary, especially during the first few months of concomitant treatment with ACE inhibitors.

Cough. A continuous, dry, unproductive cough that stops after discontinuation of treatment may occur during treatment with ACE inhibitors. This should be considered as part of a differential diagnosis of cough.

Surgery / anesthesia. In patients undergoing major surgery or anesthesia with hypotension medications, enalapril may block the formation of angiotensin II due to compensatory renin release. If hypotension occurs and it is believed that it has developed due to such a mechanism, it is necessary to carry out a correction using an increase in blood volume.

Hyperkalemia During treatment with ACE inhibitors, including enalapril, an increase in potassium levels in the blood was noted in some patients. Risk factors for hyperkalemia include kidney failure or decreased kidney function, age (70 years), diabetes mellitus, intercurrent conditions such as dehydration, acute heart failure, metabolic acidosis, and the simultaneous use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, or amiloride) , the use of food additives containing potassium, or salt substitutes with potassium; or other drugs that cause an increase in the concentration of potassium in the blood plasma (e.g. heparin). The use of potassium supplements, potassium-sparing diuretics or potassium salt substitutes, especially in patients with impaired renal function, can lead to a significant increase in plasma potassium levels. Hyperkalemia can cause severe arrhythmias, sometimes fatal. If the simultaneous use of these drugs is considered acceptable, it is recommended to regularly check the level of potassium in the blood plasma.

Lithium. Typically, a combination of lithium and enalapril is not recommended.

Ethnic features. Like all ACE inhibitors, enalapril is less effective in lowering blood pressure in patients of the Negroid race than in the Caucasoid, possibly due to the greater prevalence of conditions with low levels of renin among patients of the Negroid race with AH.

Special warnings regarding inactive ingredients. Enap contains benzyl alcohol, which can cause toxic and anaphylactoid reactions in infants and children under 3 years of age. The drug is contraindicated in premature infants and newborns. This medicine contains less than 1 mmol of sodium (23 mg) in a dose, that is, in fact, is free of sodium.

Children. Enap solution for injection is not used in children due to insufficient data on the effectiveness and safety of use.

During pregnancy and breastfeeding. ACE inhibitors should not be started during pregnancy. If continued therapy with ACE inhibitors is considered important, patients planning a pregnancy should be transferred to alternative antihypertensive treatment, which has an approved safety profile for use during pregnancy.If pregnancy is established, treatment with ACE inhibitors should be stopped immediately and, if possible, start alternative therapy.

The ability to influence the reaction rate when driving vehicles and working with other mechanisms. Enalaprilat does not affect the reaction rate when driving vehicles and working with other mechanisms. However, when switching to enalapril treatment, it should be remembered that some patients may experience dizziness and fatigue, which may affect the ability to drive vehicles and work with other mechanisms. If these or similar side effects occur, use caution when performing these activities.

Interactions

With the simultaneous use of enalaprilat with digitalis, β-adrenergic blockers, methyldopa, nitrates, calcium channel blockers, hydralazine and prazosin, a slight synergistic effect is observed. thus, enalaprilat can be used simultaneously with any other drug to treat ag. combined use with nitroglycerin, other nitrates or other vasoconstrictor drugs can further reduce hell. enalapril can be safely administered simultaneously with acetylsalicylic acid (in doses according to cardiological indications) and thrombolytics.

Previous treatment with diuretics in high doses can lead to a decrease in bcc and an increased risk of developing severe arterial hypotension. The antihypertensive effect can be reduced by stopping the diuretic or starting therapy with a lower dose (0.625 mg) of enalaprilat. If such a dose reduction is not enough, the possibility of developing hypotension can be minimized by the use of iv infusion of physiological saline sodium chloride solution before treatment with enalaprilat. If it is necessary to continue treatment with a diuretic, the patient should be monitored for at least 1 hour after enalaprilat injection.

ACE inhibitors reduce potassium loss caused by diuretics. Potassium-sparing diuretics (e.g. spironolactone, triamteren, or amiloride), potassium supplements, or salt substitutes containing potassium can lead to hyperkalemia. These combinations are used with extreme caution. With the combined use of ACE inhibitors and potassium-sparing diuretics, it is necessary to regularly monitor the concentration of potassium in the blood plasma.

The simultaneous use of ACE inhibitors and lithium can lead to a transient increase in plasma lithium levels and lithium intoxication. With the combined use of ACE inhibitors and thiazide diuretics, plasma lithium levels and the risk of lithium intoxication may additionally increase.

The simultaneous use of ACE inhibitors and NSAIDs can cause impaired renal function and / or congestive heart failure and dry unproductive cough. It is believed that the mechanism by which this effect occurs is the inhibition of the action of prostaglandins.

Combinations of enalaprilat and cyclosporin are used with extreme caution, and kidney function monitoring is required.

The simultaneous use of certain anesthetics, tricyclic antidepressants and antipsychotics with ACE inhibitors can lead to an additional decrease in blood pressure.

There are reports of anaphylactic type reactions in patients treated with enalapril and the simultaneous use of bee venom immunotherapy (desensitization). Therefore, the use of enalaprilat should be avoided in patients allergic to wasp venom and bees and in whom specific desensitization is performed.

In patients during extensive operations or during anesthesia using drugs that cause arterial hypotension, enalaprilat can block the formation of angiotensin II due to the compensatory release of renin. Arterial hypotension arising from this mechanism can be stopped by increasing the volume of blood plasma.

The simultaneous use of ACE inhibitors and antidiabetic drugs (insulin or antidiabetic oral drugs) can lead to hypoglycemia.The appearance of this phenomenon is possible during the first weeks of combined treatment and in patients with impaired renal function.

Alcohol enhances the hypotensive effect of ACE inhibitors.

Incompatibility. The drug should not be mixed with amphotericin B and phenytoin due to clouding of the solution and the formation of sediment.

Overdose

Most often manifested arterial hypotension. if hypotension develops, the patient should be placed on his back and, if necessary, corrected blood plasma volume by iv infusion of isotonic sodium chloride solution.

During treatment of an overdose, the patient should control blood pressure, respiratory rate, blood potassium concentration and diuresis.

Transient hypotension is not a contraindication for treatment with enalaprilat. After stabilization of blood pressure and replenishment of BCC, further treatment with the drug is usually well tolerated. In severe cases, the use of angiotensin II is recommended. Enalaprilat is excreted by hemodialysis. With hemodialysis, the clearance of enalaprilat is 38–62 ml / min; after 4-hour hemodialysis, enalaprilat plasma concentrations are reduced by 45–57%.

Storage conditions

At a temperature not exceeding 25 ° c.