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Active ingredients
Enalapril + Hydrochlorothiazide
Release form
Pills
Composition
enalapril maleate 20 mg hydrochlorothiazide 12.5 mg Auxiliary substances: sodium bicarbonate, lactose monohydrate, corn starch, pregelatinized starch, talc, magnesium stearate.
Pharmacological effect
Combined antihypertensive drug action is due to the components belonging to it sostav.Enalapril inhibits ACE, promotes conversion of angiotensin I into angiotensin II, reduces the concentration of aldosterone in blood increases renin release, improves the functioning of the kallikrein-kinin system, it stimulates the release of prostaglandins and endothelial relaxing factor depresses the sympathetic nervous system. Together, these effects eliminate spasm and dilate the peripheral arteries, reduce the total peripheral vascular resistance, systolic and diastolic blood pressure, post- and preload on the myocardium. Expands the arteries to a greater extent than the veins, while the reflex increase in heart rate is not observed. The hypotensive effect is more pronounced with a high concentration of renin in the blood plasma than with normal or reduced. Reducing blood pressure in therapeutic limits does not affect cerebral circulation. Improves blood supply to ischemic myocardium. Enhances renal blood flow, while the glomerular filtration rate does not change. In patients with initially reduced glomerular filtration, its rate usually increases. The maximum effect of enalapril develops in 6–8 hours and lasts up to 24 hours. Hydrochlorothiazide is a moderately strong thiazide diuretic. Reduces the reabsorption of sodium ions at the level of the cortical segment of the loop of Henle, without affecting its part, which passes in the medulla of the kidney. Blocks carbonic anhydrase in the proximal convoluted tubule, enhances kidney excretion of potassium ions, bicarbonates and phosphates. Practically does not affect the acid-base state. Increases the excretion of magnesium ions. Detains in the body calcium ions. The diuretic effect develops after 1-2 hours, reaches a maximum after 4 hours, lasts 10-12 hours. The effect decreases with a decrease in the glomerular filtration rate and stops when its value is less than 30 ml / min.Reduces blood pressure by reducing bcc, changes in the reactivity of the vascular wall. Using the combination of enalapril and hydrochlorothiazide leads to a more pronounced decrease in blood pressure in comparison with monotherapy for each of the drugs separately and allows you to maintain the hypotensive effect of Enap-NL 20 for at least 24 h
Pharmacokinetics
Enalapril Absorption and MetabolismAfter oral administration, absorption is 60%. Food intake does not affect absorption. C max enalapril is achieved after 1 h. In the liver it is metabolized to form the active metabolite enalaprilat, which is a more effective ACE inhibitor than enalapril. Cmax enalaprilat in the serum is achieved after 3-4 hours. DistributionThe binding of plasma proteins to enalaprilat is 50-60%. Enalaprilat easily passes through histohematogenous barriers, excluding the BBB, a small amount penetrates the placenta and into breast milk. ExcretionThe renal clearance of enalapril and enalaprilat is 0.005 ml / s (18 l / h) and 0.00225-0.00264 ml / s (8.1-9.5 l / h ), respectively. T1 / 2 enalaprilat - 11 h. Excreted mainly by the kidneys - 60% (20% - in the form of enalapril and 40% - in the form of enalaprilat), through the intestine - 33% (6% - in the form of enalapril and 27% - in the form of enalaprilat) Pharmacokinetics in special clinical situationsEnalaprilat is removed during hemodialysis (38-62 ml / min) or peritoneal dialysis, the serum concentration of enalaprilat after 4-hour hemodialysis is reduced by 45-57%. In patients with reduced kidney function, the deceleration slows down, which requires a change in dosage in accordance with the function of the kidneys, especially in patients ntov with severe renal insufficiency. In patients with hepatic insufficiency, enalapril metabolism can be slowed down without changing its pharmacodynamic effect. In patients with chronic heart failure, absorption and enalaprilat metabolism are slowed down, Vd also decreases. guts. Absorption is 70% and increases by 10% when taken with food. Cmax is reached in 1.5-5 hours. Bioavailability is 70%. The distribution of Vd is about 3 l / kg. Binding to plasma proteins - 40%. In the therapeutic range of doses, the average AUC increases in direct proportion to the increase in dose, with the appointment of 1 time / day cumulation is negligible. It penetrates the placental barrier and into breast milk. It accumulates in the amniotic fluid.Serum concentration of hydrochlorothiazide in the blood of the umbilical vein is almost the same as in maternal blood. The concentration in the amniotic fluid is greater than that in the serum from the umbilical vein (19 times). Output is not metabolized in the liver, is excreted mainly by the kidneys: 95% in unchanged form and about 4% in the form of hydrolyzate 2 m-benzedisulfonamida by glomerular filtration and active tubular secretion in the proximal nephron. The renal clearance of hydrochlorothiazide in healthy volunteers and patients with arterial hypertension is approximately 5.58 ml / s (335 ml / min). Hydrochlorothiazide has a biphasic elimination profile. T1 / 2 in the initial phase is 2 hours, in the final phase (10-12 hours after ingestion) - about 10 hours. Pharmacokinetics in special clinical situations When administering hydrochlorothiazide to patients with chronic heart failure, it has been established that its absorption decreases in proportion to the degree of the disease - by 20–70%. T1 / 2 hydrochlorothiazide increases to 28.9 h; renal clearance is 0.17-3.12 ml / s (10-187 ml / min), average values of 1.28 ml / s (77 ml / min). In patients undergoing intestinal bypass surgery for obesity, the absorption of hydrochlorothiazide can be reduced by 30% , and serum concentration - by 50% compared with healthy volunteers. Simultaneous administration of enalapril and hydrochlorothiazide does not affect the pharmacokinetics of each of them.
Indications
- arterial hypertension (in patients for whom combination therapy is indicated).
Contraindications
- anuria; - pronounced renal dysfunction (CC <30 ml / min); - angioedema edema in history associated with the use of previously ACE inhibitors; - hereditary or idiopathic angioedema; lactose, lactase deficiency or glucose-galactose malabsorption syndrome; - pregnancy; - lactation period; - children and adolescents under 18 years of age (efficacy and safety have not been established); - hypersensitivity to the components of the drug or roizvodnym sulfonamida.S Precautions should be prescribed in patients with severe aortic stenosis or hypertrophic subaortic stenosis, idiopathic, ischemic heart disease,cerebrovascular diseases (including cerebrovascular insufficiency), chronic heart failure, marked atherosclerosis, severe autoimmune systemic diseases of connective tissue (including SLE, scleroderma), bone marrow suppression, diabetes mellitus, hyperkalemia, condition after transplantation , impaired liver function, impaired renal function (CC 30-75 ml / min), conditions accompanied by a decrease in BCC (as a result of diuretic therapy, while limiting the consumption of Oli, diarrhea and vomiting), elderly patients.
Precautionary measures
During treatment, psoriasis may worsen. During pheochromocytoma, propranolol can only be used after taking an alpha blocker. After a long course of treatment, propranolol should be discontinued gradually, under the supervision of a physician. during anesthesia, you must stop taking propranolol or find a remedy for anesthesia with minimal negative inotropic effects. The impact on the ability to drive vehicles and control mechanisms of patients whose activities require increased attention, the question of the use of propranolol on an outpatient basis should be addressed only after evaluating the individual response of the patient.
Use during pregnancy and lactation
The drug Enap-NL 20 is contraindicated in pregnancy. The effect of ACE inhibitors on the fetus in the first trimester of pregnancy is not installed. The use of ACE inhibitors in the II and III trimesters of pregnancy was accompanied by a negative effect on the fetus and newborn. Newborns developed arterial hypotension, renal failure, hyperkalemia and / or hypoplasia of the skull bones. Perhaps the development of oligohydramnios, apparently due to impaired renal function of the fetus. This can lead to contracture of the extremities, deformation of the bones of the skull, including its facial part, and lung hypoplasia. The use of diuretics during pregnancy is not recommended, as it can cause fetal and newborn jaundice, thrombocytopenia, and possibly other adverse reactions observed in adults. Enalapril hydrochlorothiazide penetrate into breast milk.Therefore, when prescribing the drug Enap-NL 20 during lactation, it is necessary to refuse breastfeeding.
Dosage and administration
The drug Enap-NL 20 should be taken regularly at the same time, preferably in the morning, during or after a meal, without chewing, with a small amount of liquid. The recommended dose is 1 tab. / Day. If necessary, the dose can be increased to 2 tab., Taken 1 time / day, which is the maximum daily dose. In patients on diuretic therapy, it is recommended to cancel treatment or reduce the dose of diuretics at least 3 days before the start of treatment with Enap-NL 20 to prevent the development of symptomatic arterial hypotension. The duration of treatment is determined by the doctor individually. In patients with renal insufficiency (CK 30-75 ml / min), treatment with Enap-NL 20 should begin with appropriate doses of each For the active substance separately, according to the doses in the combined preparation Enap-NL 20.
Side effects
Classification of the incidence of side effects WHO: 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, including individual messages). From the hematopoietic system: rarely - neutropenia, decreased hemoglobin and hematocrit, thrombocytopenia, leukopenia, bone marrow function suppression. From the metabolic side: infrequently - gout. From the side of the CNS: very often - dizziness, weakness; often - headache, asthenia; infrequently - insomnia, drowsiness, paresthesia, hyperexcitability. From the sensory organs: infrequently - tinnitus. From the cardiovascular system: often - orthostatic hypotension; infrequently - fainting, marked decrease in blood pressure, feeling of heartbeat, tachycardia, chest pain. On the part of the respiratory system: often - cough; infrequently - shortness of breath. From the digestive system: often - nausea; infrequently - diarrhea, vomiting, dyspepsia, abdominal pain, flatulence, constipation, dryness of the oral mucosa; rarely - cholestatic jaundice, fulminant necrosis of the liver, increased activity of hepatic transaminases and bilirubin; very rarely - intestinal angioedema. Allergic reactions: infrequently - Stevens-Johnson syndrome; rarely - angioedema. From the skin: infrequently - skin rash, itching, sweating, skin necrosis, alopecia. From the urinary system: infrequent - renal dysfunction,acute renal failure; rarely - an increase in the concentration of urea and creatinine in the serum. From the reproductive system: infrequently - impotence, decreased libido. From the musculoskeletal system: often - muscle spasms; infrequently - arthralgia. From laboratory parameters: rarely - hyperglycemia, hyperuricemia, hypokalemia, hyperkalemia, hyponatremia. Others: the symptom complex is described, which may include fever, myalgia and arthralgia, serositis, vasculitis, elevation of ESR, leukocytosis, eco-desectancy, eco-dema- antinuclear antibody test.
Overdose
Symptoms: increased diuresis, marked reduction in blood pressure with bradycardia or other heart rhythm disorders, convulsions, impairment of consciousness (including coma), acute renal failure, impaired acid-base and water-electrolyte balance in the blood. Treatment: gastric lavage and ingestion of activated carbon; in more serious cases, transfer the patient to a horizontal position with raised legs, then carry out measures aimed at stabilizing blood pressure - in / in the introduction of plasma substitutes, infusion of a 0.9% sodium chloride solution. The patient should monitor blood pressure, heart rate, respiratory rate, serum concentration of urea, creatinine, electrolytes and diuresis, if necessary, in / in the introduction of angiotensin II, hemodialysis (enalaprilat excretion rate - 62 ml / min).
Interaction with other drugs
The use of potassium supplements, potassium-sparing agents or potassium-containing salt substitutes, especially in patients with renal insufficiency, can lead to a significant increase in serum potassium. The loss of potassium during the administration of thiazide diuretics, as a rule, is reduced by the action of enalapril. The content of potassium in the blood serum usually remains within the normal range. With simultaneous use with lithium preparations, lithium is slowed down (increased cardiotoxic and neurotoxic effects of lithium). Thiazide diuretics can enhance the effect of tubocurarine chloride. Simultaneous use of thiazide diuretics, opioid analgesics or derived phenomas to orthostatic hypotension. Consistent with the use of enalapril beta-blockers,alpha blockers, ganglion blocking agents, methyldopa, or slow calcium channel blockers may further reduce blood pressure. Simultaneous use of ACL inhibitors allopurinol, cytostatics, and immunosuppressants may increase the risk of developing leukopenia. with cyclosporine ACE inhibitors may increase the risk of hyperkalemia. Simultaneous use of NSAIDs (including selective COX-inhibitors 2) can weaken the antihypertensive effect of ACE inhibitors. NVP and ACE inhibitors have an additive effect on the increase in serum potassium, which can lead to a deterioration in renal function, especially in patients with impaired renal function. This effect is reversible. PNPs can reduce the diuretic and antihypertensive effects of diuretics. Antacids can decrease the bioavailability of ACE inhibitors. Sympathomimetics can reduce the antihypertensive effect of ACE inhibitors. Thiazide diuretics can reduce the effect of adrenergic mimics (epinephrine). cause orthostatic hypotension. Epidemiological studies suggest that the simultaneous use of ACE inhibitors and gi The use of glycemic agents can lead to hypoglycemia. More often, hypoglycemia develops in the first weeks of therapy in patients with impaired renal function. Long-term and controlled clinical studies of enalapril do not confirm these data and do not limit the use of enalapril in patients with diabetes mellitus. However, such patients should be under regular medical supervision. The use of hypoglycemic agents for oral administration and insulin with thiazide diuretics may require correction of their doses. Taking Kolestiramine or Colestipol once is reduced intake of hydrochlorothiazide in the gastrointestinal tract by 85% and 43%, respectively. the use of ACE inhibitors and gold preparations (sodium aurothiomalate) IV, a symptom complex is described, including facial flushing, nausea, vomiting and arterial hypotension.
special instructions
Hypotension with all clinical consequences can be observed after the first dose of Enap-NL 20 pills in patients with severe heart failure and hyponatremia, severe renal insufficiency or left ventricular dysfunction, and especially in patients with reduced BCC, as a result of diuretic therapy, salt-free diet, diarrhea, vomiting, or hemodialysis. Arterial hypotension that occurs after taking the first dose is not a contraindication for further treatment. in patients with coronary artery disease, severe cerebrovascular disease, aortic stenosis or idiopathic hypertrophic subaortic stenosis, which prevents the outflow of blood from the left ventricle, severe atherosclerosis, in elderly patients as a result of the risk of arterial hypotension and deterioration of the blood supply to the heart, brain and kidneys. electrolyte balance. Regular monitoring of the serum electrolyte concentration during the treatment period is necessary to identify possible imbalances and timely taking the necessary measures. Determining the serum electrolyte concentration is mandatory for patients with prolonged diarrhea, vomiting. In patients taking the drug Enap-NL 20, it is necessary to identify signs of impaired water and electrolyte balance, such as dry mouth, thirst, weakness, drowsiness, anxiety, myalgia and convulsions (mainly calf muscles), lowering blood pressure, tachycardia, oliguria, and gastrointestinal disturbances (nausea, vomiting). Renal dysfunction Preparation Enap-NL 20 in patients with renal insufficiency (CC 30-75 ml / min) should to be named only after preliminary titration of doses of enalapril and hydrochlorothiazide separately, respectively, the doses in the combination preparation Enap-NL 20. Liver dysfunction The preparation Enap-NL 20 should be used with caution in patients with hepatic insufficiency or progressive liver disease, because hydrochlorothiazide can cause hepatic coma even with minimal disruption of water and electrolyte balance. It was reported on several cases of acute liver failure with cholestatic jaundice, fulminant necrosis of the liver and fatal outcome (rarely) during treatment with ACE inhibitors.If jaundice occurs and liver transaminases increase, Enap-NL 20 treatment should be stopped immediately, patients should be monitored. Metabolic and endocrine effects Caution is necessary in all patients receiving treatment with hypoglycemic oral or insulin, because hydrochlorothiazide can weaken, and enalapril strengthens their action. Thiazide diuretics can reduce calcium excretion by the kidneys and cause a slight and transient increase in serum calcium. Severe hypercalcemia may be a sign of latent hyperparathyroidism. Thiazide diuretics need to be canceled before conducting a study of the function of the parathyroid glands. Against the background of treatment with thiazide diuretics, serum cholesterol and triglyceride concentrations may increase. Some patients may increase their hyperuricemia and / or aggravate the course of gout with thiazide diuretics. However, enalapril increases the excretion of uric acid by the kidneys, thereby counteracting the hyperuricemic effect of hydrochlorothiazide. Allergic reactions / Angioneurotic edema In the event of an angioedema of the face, it is usually enough to discontinue therapy and prescribe antihistamines to the patient. In case of angioedema of the tongue, pharynx or larynx, which can lead to obstruction of the respiratory tract, it is necessary to immediately administer epinephrine (0.3-0.5 ml of epinephrine (adrenaline) solution in the ratio 1: 1000) and maintain the airway patency (intubation or tracheostomy) . Among the patients of the Negroid race, receiving therapy with an ACE inhibitor, the incidence of angioedema is higher than among patients of a different race. Patients with a history of angioedema, not associated with inhibitors ACE, have an increased risk of developing angioedema when taking any ACE inhibitor. In patients taking thiazide diuretics, hypersensitivity reactions can develop with or without allergic reactions.A worsening course of systemic lupus erythematosus has been reported. Due to the increased risk of anaphylactic reactions, Enap-NL should not be prescribed to 20 patients on hemodialysis using high-current polyacrylonitrile membranes (AN 69) undergoing low-density lipoprotein apnea with dextran sulfate and prior to the desensitization procedure, before the desensitization procedure, it was necessary or bee venom. Surgical interventions / general anesthesia Before surgery (including dentistry) must be warned for an anesthesiologist about the use of ACE inhibitors. During surgical interventions or general anesthesia using agents that cause arterial hypotension, ACE inhibitors can block the formation of angiotensin II in response to compensatory release of renin. If this develops a pronounced decrease in blood pressure, explained by a similar mechanism, it can be adjusted by increasing the BCC. Cough A cough was noted when using ACE inhibitors. The cough is dry, long-lasting, which disappears after stopping the use of ACE inhibitors. In differential diagnosis of cough, it is necessary to take into account cough caused by the use of ACE inhibitors. The effect on the ability to drive vehicles and control mechanisms At the beginning of treatment with Enap-NL 20, a pronounced decrease in blood pressure, dizziness and drowsiness can occur, which can reduce the ability to drive vehicles, therefore At the beginning of treatment, it is not recommended to drive vehicles or engage in other potentially hazardous activities that require increased concentration in Iman and psychomotor speed reactions.