Pharmacological properties
Pharmacodynamics. Enalaprilat inhibits ACE, which catalyzes the conversion of angiotensin I to angiotensin II. Inhibition of ACE leads to a decrease in the concentration of angiotensin II, an increase in plasma renin activity and a decrease in aldosterone secretion.
The hypotensive effect and hemodynamic effects of enalaprilat in patients with high blood pressure are the result of dilation of resistance vessels and a decrease in total peripheral resistance, which gradually reduces blood pressure. Systolic and diastolic blood pressure and pulmonary artery pressure decrease, coronary blood flow increases, cardiac index and stroke volume increase (with unchanged heart rate).
After intravenous administration, the effect of the drug occurs after 5-15 minutes, the maximum effect occurs after 1-4 hours, and its action lasts for 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 mellitus, COPD, angina pectoris, congestive heart failure.
Pharmacokinetics. After oral administration, enalaprilat is poorly absorbed and practically inactive, therefore it is administered exclusively intravenously.
After intravenous 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 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 excreted mainly by the kidneys by glomerular filtration and tubular secretion. Elimination occurs in several stages, which is explained by strong binding to ACE in blood plasma. T ½ in the initial stage is approximately 11 hours, and in the final - 35 hours. The clinical effect is observed approximately 15 minutes after intravenous administration of enalaprilat, and the maximum hypotensive effect is 4 hours after administration and lasts for approximately 6 hours.
Indication
Hypertension, hypertensive crisis. Enalaprilat is indicated for the treatment of hypertension when oral enalapril is not possible.
Application
Used in adults.
Enap solution for injection is administered intravenously slowly over at least 5 minutes. It is possible to dilute the drug in 50 ml of 5% glucose solution, 0.9% sodium chloride solution (saline), 5% glucose solution in 0.9% sodium chloride solution or 5% glucose solution in lactated Ringer's solution.
The usual recommended dose for the treatment of hypertension and hypertensive crises is 1.25 mg enalaprilat (1 ampoule) every 6 hours. When switching from enalapril 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 treatment with enalaprilat to oral treatment with enalapril, the recommended initial dose is 5 mg 1 time per day for patients who have already been administered 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 in renal failure. Enalaprilat doses for patients with chronic renal failure depend on creatinine clearance. Patients with creatinine clearance 0.5 ml / s (plasma creatinine - up to 265 μmol / l) are prescribed the usual doses of enalaprilat 1.25 mg (1 ml) every 6 hours. Patients with creatinine clearance 0.5 ml / s (plasma creatinine 265 μmol / l) are prescribed an initial dose of 0.625 mg (0.5 ml). If the clinical effect is unsatisfactory after 1 hour, the same dose should be re-administered. Treatment is continued at a full dose of 1.25 mg every 6 hours.
Dosage in hemodialysis: The recommended dose for patients undergoing hemodialysis is 0.625 mg (0.5 ml) every 6 hours.
Dosage for patients treated with diuretics. For patients treated with diuretics, the recommended initial dose is 0.625 mg (0.5 ml). If the clinical effect is unsatisfactory after 1 hour, a dose of 0.625 mg (0.5 ml) can be repeated. Subsequent doses of 1.25 mg are administered every 6 hours.
Contraindication
Hypersensitivity to enalapril, enalaprilat or any of the ingredients of the drug; history of angioedema associated with previous treatment with ACE inhibitors; hereditary or idiopathic angioedema.
Side effects
Enalaprilat is a metabolite of enalapril. Therefore, during treatment with Enap solution for injection, the same side effects are possible as during treatment with Enap tablets or other ACE inhibitors.
From the blood and lymphatic system: anemia (including aplastic and hemolytic), neutropenia, decreased hemoglobin, decreased hematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, pancytopenia, lymphadenopathy, autoimmune diseases.
Metabolism: hypoglycemia.
On the part of the endocrine system: syndrome of impaired ADH secretion.
Nervous system and mental disorders: headache, depression, confusion, drowsiness, insomnia, nervousness, paresthesia, dizziness, sleep disturbances.
On the part of the organ of vision: blurred vision.
Cardiovascular system: dizziness, hypotension (including orthostatic hypotension), syncope, myocardial infarction or stroke, possibly due to severe hypotension in patients at increased risk, chest pain, cardiac arrhythmias, angina pectoris, tachycardia; infrequently - orthostatic hypotension, tachycardia, Raynaud's syndrome.
Respiratory, thoracic and mediastinal disorders: cough, shortness of breath, rhinorrhea, pharyngitis, dysphonia, bronchospasm/asthma, pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia.
Gastrointestinal tract: nausea, diarrhea, abdominal pain, taste disturbance, intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric mucosal irritation, dry mouth, peptic ulcers, stomatitis/aphthous ulcers, glossitis, angioedema.
From the hepatobiliary system: hepatic failure, hepatocellular or cholestatic hepatitis, hepatonecrosis, cholestasis, including jaundice.
Skin and subcutaneous tissue disorders: rash, hypersensitivity/angioedema, hyperhidrosis, pruritus, urticaria, alopecia, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic dermal necrolysis, pemphigus, erythroderma.
A symptom complex has been reported: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive antinuclear antibodies, increased ESR, eosinophilia and leukocytosis. Rash, photosensitivity and other skin disorders may also occur.
Renal and urinary disorders: renal dysfunction, renal failure, proteinuria, oliguria.
From the reproductive system and mammary glands: impotence, gynecomastia.
General disorders: asthenia, fatigue, muscle cramps, hot flashes, tinnitus, feeling of discomfort, fever.
Laboratory indicators: hyperkalemia, increased creatinine levels in blood plasma, increased urea levels in blood plasma, hyponatremia, increased liver enzyme activity, bilirubin in blood plasma.
If severe side effects occur, treatment should be discontinued.
Special instructions
When administered parenterally, enalaprilat rapidly reduces elevated blood pressure and improves heart function.
Symptomatic hypotension. Patients with hypertension and severe heart failure, hyponatremia and/or hypovolemia due to diuretic therapy, salt-restricted diet, and dialysis, diarrhea, and vomiting constitute a subgroup of patients in whom blood pressure is dependent on renin and activation of the renin-angiotensin system. In these patients, as well as in the elderly and patients with impaired renal function, hypotension with consequent clinical consequences (ranging from dizziness and nausea to acute renal failure, stroke, or myocardial infarction) may occur even several hours after the first dose of enalaprilat.
Arterial hypotension and its severe consequences are rare and reversible. They can be avoided by discontinuing diuretics and following a low-salt diet before starting treatment with Enap, if possible.
Enalaprilat therapy in all these patients, or if it is impossible to discontinue diuretic treatment, is recommended to be started cautiously, with the use of the drug in a lower dose (0.625 mg).
Aortic or mitral valve stenosis/hypertrophic cardiomyopathy. The drug should be used with caution in patients with aortic stenosis or idiopathic hypertrophic subaortic stenosis and generalized atherosclerosis. Arterial hypotension in these patients may lead to hypoperfusion and ischemia of the heart, brain, and kidneys. In patients with peripheral vascular disease or generalized atherosclerosis, latent renal vascular disease may be present, which is not clinically apparent. Enalaprilat therapy should be initiated in these patients with great caution, with a minimum (0.625 mg) dose.
ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction and avoided in cardiogenic shock and hemodynamically significant left ventricular outflow tract obstruction.
Renal impairment: In patients with renal impairment (creatinine clearance 80 ml/min), the dose should be adjusted according to creatinine clearance and then to the response to treatment. Plasma creatinine and potassium levels should be monitored regularly.
In some hypertensive patients with no symptoms of renal disease prior to treatment, enalapril with diuretics has caused, usually minor and transient increases in blood urea and plasma creatinine. In such cases, dose reduction and/or discontinuation of the diuretic may be necessary. This situation raises the possibility of pre-existing renal artery stenosis.
Renovascular hypertension. Patients with bilateral renal artery stenosis and postglomerular efferent arteriole vasodilation may experience transient renal dysfunction or acute renal failure. Patients with renal artery stenosis of a solitary kidney may experience transient renal dysfunction or acute renal failure of the affected kidney. Therefore, evaluation of a patient with hypertension should always include assessment of renal function. Treatment of renovascular hypertension should be undertaken only by an experienced specialist.
Kidney transplantation: There are no adequate data on the treatment of enalapril in patients with a recent kidney transplantation, therefore treatment of this group of patients with enalapril is not recommended.
Hepatic failure: If jaundice or a marked increase in liver enzymes occurs during therapy with ACE inhibitors, treatment should be discontinued immediately, the patient should be closely monitored and treatment should be initiated if necessary.
Neutropenia/agranulocytosis. The possibility of neutropenia or agranulocytosis cannot be completely excluded, therefore regular complete blood counts are recommended. Enalapril should be used with great caution in patients with collagen vascular disease (e.g. systemic lupus erythematosus, scleroderma), concomitantly with antidepressants, allopurinol or procainamide or a combination of these factors, especially in cases of impaired renal function. Some of these patients may develop serious infections, sometimes resistant to intensive antibiotic therapy. When enalapril/enalaprilat is used in these patients, periodic monitoring of the white blood cell count is recommended.
Hypersensitivity/angioedema. In rare cases, angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported with enalaprilat. This may occur at any time during treatment. In such cases, treatment should be discontinued, antihistamines should be administered and the patient should be monitored to ensure that all symptoms of hypersensitivity have resolved. In cases of angioedema of the tongue without respiratory failure, patients may require prolonged observation, as treatment with antihistamines and corticosteroids may be inadequate.
Patients with a history of angioedema associated with ACE inhibitor therapy are at increased risk of developing angioedema while receiving ACE inhibitors. Patients with angioedema of the tongue, glottis and/or larynx are at increased risk of developing airway obstruction, particularly during airway surgery. Angioedema of the tongue, glottis and/or larynx may lead to airway obstruction and should be treated promptly, which may include subcutaneous administration of epinephrine 1:1000 (0.3-0.5 ml) and measures to maintain a patent upper airway.
Angioedema was more common in black patients treated with ACE inhibitors than in patients of other races.
Patients with a history of edema unrelated to ACE inhibitor use may be at increased risk of developing edema while receiving ACE inhibitor therapy.
Anaphylactoid reactions during desensitization. Patients receiving ACE inhibitors during desensitization to wasp or bee venom may rarely experience life-threatening allergic-like reactions (pseudoanaphylactic reactions). Such reactions can be avoided by temporarily withholding ACE inhibitor therapy before each desensitization.
Anaphylactoid reactions during low-density lipoprotein apheresis. Rarely, patients receiving ACE inhibitors during low-density lipoprotein apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. Such reactions can be avoided by temporarily stopping ACE inhibitors before each apheresis.
Patients on hemodialysis. There have been reports of hypersensitivity, allergic-like reactions (pseudoanaphylactic reactions) in patients undergoing dialysis using polyacrylonitrile membranes (e.g. AN 69) and concomitantly taking ACE inhibitors. In such patients, the use of other types of dialysis membranes or a different class of antihypertensive agents should be considered.
Hypoglycemia: In diabetic patients taking oral antidiabetic agents or insulin, careful glycemic control is necessary, especially during the first few months of concomitant treatment with ACE inhibitors.
Surgery/Anesthesia: In patients undergoing major surgery or anesthesia with drugs that produce hypotension, enalapril may block the formation of angiotensin II due to compensatory renin release. If hypotension occurs and is thought to be due to this mechanism, correction should be made by expanding blood volume.
Hyperkalemia. During treatment with ACE inhibitors, including enalapril, increases in blood potassium levels have been observed in some patients. Risk factors for the development of hyperkalemia include renal failure or decreased renal function, age (70 years), diabetes mellitus, intercurrent conditions such as dehydration, acute heart failure, metabolic acidosis and concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride), use of potassium-containing dietary supplements or potassium-containing salt substitutes; or other drugs that cause increases in plasma potassium concentrations (e.g. heparin). The use of potassium-containing dietary supplements or potassium-sparing salt substitutes, especially in patients with impaired renal function, may lead to significant increases in plasma potassium levels. Hyperkalemia may cause serious arrhythmias, sometimes fatal. If concomitant use of these drugs is considered acceptable, regular monitoring of plasma potassium levels is recommended.
Lithium: The combination of lithium and enalapril is generally not recommended.
Ethnicity: As with all ACE inhibitors, enalapril is less effective in lowering blood pressure in black patients than in white patients, possibly because of a higher prevalence of low-renin states in black patients with hypertension.
Special warnings regarding inactive ingredients. Enap contains benzyl alcohol, which may cause toxic and anaphylactoid reactions in infants and children under 3 years of age. The drug is contraindicated in premature infants and newborns. This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially sodium-free.
Children. Enap solution for injection is not used in children due to insufficient data on efficacy and safety.
Pregnancy and breast-feeding. ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, ACE inhibitor treatment should be stopped immediately, and, if possible, alternative therapy should be started.
Ability to influence the reaction rate when driving vehicles or working with other mechanisms. Enalaprilat does not affect the reaction rate when driving vehicles or working with other mechanisms. However, when switching to treatment with enalapril, 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, caution should be exercised when performing these activities.
Interactions
With 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 for the treatment of angina. Combined use with nitroglycerin, other nitrates or other vasoconstrictor drugs may further reduce the risk of angina. Enalapril can be safely administered simultaneously with acetylsalicylic acid (in doses according to cardiac indications) and thrombolytics.
Previous treatment with high doses of diuretics may lead to a decrease in BCC and an increased risk of severe hypotension. The hypotensive 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 insufficient, the possibility of hypotension can be minimized by administering an intravenous infusion of saline solution before starting treatment with enalaprilat. If it is necessary to continue treatment with a diuretic, the patient should be monitored for at least 1 hour after the enalaprilat injection.
ACE inhibitors reduce the potassium loss caused by diuretics. Potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements or salt substitutes containing potassium may lead to hyperkalemia. These combinations should be used with caution. When ACE inhibitors are used concomitantly with potassium-sparing diuretics, regular monitoring of plasma potassium levels is recommended.
Concomitant use of ACE inhibitors and NSAIDs may cause renal dysfunction and/or congestive heart failure and a dry, nonproductive cough. The mechanism of this effect is thought to be via inhibition of prostaglandin action.
Combinations of enalaprilat and cyclosporine should be used with extreme caution, and renal function should be monitored.
Concomitant use of certain anesthetics, tricyclic antidepressants, and neuroleptics with ACE inhibitors may lead to an additional decrease in blood pressure.
There have been reports of anaphylactic-type reactions in patients treated with enalapril and concomitant bee venom immunotherapy (desensitization). Therefore, enalaprilat should be avoided in patients with allergies to wasp and bee venom and undergoing specific desensitization.
In patients undergoing major surgery or during anesthesia with agents that produce hypotension, enalaprilat may block the formation of angiotensin II through compensatory renin release. Hypotension resulting from this mechanism may be reversed by expanding plasma volume.
Concomitant use of ACE inhibitors and antidiabetic agents (insulin or oral antidiabetic agents) may lead to hypoglycemia. 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 cannot be mixed with amphotericin B and phenytoin due to clouding of the solution and formation of a precipitate.
Overdose
Most often manifested by hypotension. If hypotension develops, the patient should be placed on his back and, if necessary, the blood plasma volume should be corrected by intravenous infusion of saline.
During treatment of overdose, the patient's blood pressure, respiratory rate, blood potassium concentration, and diuresis should be monitored.
Transient hypotension is not a contraindication to treatment with enalaprilat. After stabilization of blood pressure and restoration of BCC, further treatment with the drug is usually well tolerated. In severe cases, the use of angiotensin II is recommended. Enalaprilat is removed by hemodialysis. During hemodialysis, the clearance of enalaprilat is 38-62 ml/min; after 4 hours of hemodialysis, the concentration of enalaprilat in blood plasma decreases by 45-57%.
Storage conditions
At a temperature not exceeding 25 °C.
