Description
Pharmacological action
Pharmaceutical group: Antihypertensive drug.
Pharmaceutical action:
Combined preparation containing perindopril (an ACE inhibitor) and indapamide (a diuretic from the sulfonamide group). The pharmacological effect of the drug is due to a combination of the individual properties of each of the components, the combination of which enhances the effect of each other. The drug has antihypertensive, diuretic, vasodilating, cardioprotective effects.
Perindopril PLUS Indapamide has a pronounced dose-dependent hypotensive effect on systolic and diastolic blood pressure in the supine and standing position, regardless of the age and body position of the patient. The effect of the drug lasts 24 hours. A persistent clinical effect occurs less than 1 month after the start of therapy and is not accompanied by tachycardia. Discontinuation of treatment is not accompanied by the development of withdrawal syndrome.
Perindopril PLUS Indapamide reduces the degree of left ventricular hypertrophy, improves arterial elasticity, reduces OPSS, does not affect lipid metabolism (total cholesterol, HDL, LDL, triglycerides) and does not affect carbohydrate metabolism (including in patients with diabetes mellitus).
Perindopril belongs to the group of ACE inhibitors, It has a hypotensive, vasodilating, cardioprotective, natriuretic effect. Inactivates ACE in plasma, endothelium of the vascular wall, possibly in the cells of the renal glomeruli and tubules, lung tissue, heart, adrenal gland and brain. It reduces the level of angiotensin II in the blood and tissues, reduces the production and release of aldosterone from the adrenal glands, inhibits the release of norepinephrine from the ends of the sympathetic nerve fibers and the formation of endothelin in the vessel wall, increases the concentration of bradykinin, vasodilator prostaglandins. Increases the activity of the kallikrein-kinin system, stabilizes the level of atrial natriuretic peptide.
A decrease in the formation of angiotensin II is accompanied by an increase in plasma renin activity.
Reduces OPSS, blood pressure (without the development of tachycardia), filling pressure of the left ventricle. Arterial and venous vasodilation is accompanied by a weakening of post- and preload on the myocardium, a decrease in the final diastolic pressure in the ventricles of the heart, a moderate decrease in heart rate, and an increase in cardiac output. It improves regional (coronary, cerebral, renal, muscle) blood circulation, reduces the need for oxygen in the myocardium during coronary heart disease. By inhibiting tissue renin-angiotensin systems, it has a cardioprotective effect (reduces left ventricular hypertrophy) and an angioprotective effect (prevents hyperplasia and proliferation of vascular smooth muscle cells, induces the reverse development of vascular wall hypertrophy, restores the elasticity of large vessels and the endothelial function, including the ability to release nitric oxide, endothelial relaxing factor).
Inhibits the development of tolerance to nitrates and enhances their vasodilating effect.
In patients with chronic heart failure, statistically significantly reduces the severity of clinical symptoms and increases exercise tolerance. It does not cause fluctuations in blood pressure after the first dose and during prolonged therapy.
Indapamide is close in pharmacological properties to thiazide diuretics (disrupts the reabsorption of sodium ions in the cortical segment of the Henle loop) has a hypotensive, diuretic, vasodilating effect. Increases urinary excretion of sodium, chlorine and, to a lesser extent, potassium and magnesium ions. With the ability to selectively block slow calcium channels, it increases the elasticity of artery walls and reduces OPSS. Helps reduce left ventricular hypertrophy. Reduces the sensitivity of the vascular wall to norepinephrine and angiotensin II, stimulates the synthesis of prostaglandin PgE2 and prostacyclin PgI2, reduces the production of free and stable oxygen radicals.
The hypotensive effect of indapamide is manifested in doses that practically do not cause a diuretic effect.
Pharmacokinetics:
The pharmacokinetic parameters of perindopril and indapamide do not change when combined in comparison with their separate use.
1. Perindopril
When taken orally, perindopril is rapidly absorbed from the gastrointestinal tract. Bioavailability is 65-95%, reduced by 35% while eating. Cmax is reached after 1 h and decreases by the end of the day to 33-44%.
During the metabolism, perindopril is biotransformed with the formation of the active metabolite of perindoprilat (about 20%) and 5 inactive compounds. Cmax of perindoprilat is achieved after 3-4 hours.
Plasma protein binding is negligible, less than 30% and depends on the concentration of the drug. Vd of free perindoprilat is 0.2 l / kg.
Repeated administration of perindopril does not lead to its cumulation and T1 / 2 of perindoprilat with repeated administration corresponds to the period of its activity. Css with repeated use is achieved after 4 days.
Perindoprilat is excreted by the kidneys. T1 / 2 of the free fraction of the metabolite is 3-5 hours. It slowly dissociates due to ACE as a result, T1 / 2, corresponding to the activity of the drug, is 25-30 hours.
Pharmacokinetics in special clinical cases:
In elderly patients, as well as in patients with renal and heart failure, perindopril excretion slows down (correction of the dosage regimen is necessary). The dialysis clearance of perindopril is 70 ml / min.
In patients with cirrhosis, the hepatic clearance of perindopril is reduced by 2 times, while the total amount of perindoprilat formed does not change and correction of the dosage regimen is not required.
2. Indapamide
After oral administration, indapamide is rapidly and completely absorbed from the digestive tract and bioavailability is high. Eating slightly slows down the rate of absorption, but does not affect the total amount of absorbed drug. TCmax in blood plasma – 1-2 hours after ingestion. With repeated doses, fluctuations in the concentration of the drug in plasma in the interval between doses of 2 doses are reduced. Css is established after 7 days of regular intake.
Plasma Protein Binding – 71-79%. Indapamide also binds to elastin of the smooth muscles of the vascular wall. Has a high Vd. Penetrates through histohematological barriers (including placental). Does not cumulate.
Metabolized in the liver. T1 / 2 – 14-24 hours (average 19 hours). 60-70% is excreted by the kidneys in the form of metabolites (about 5-7% is excreted unchanged), through the intestines – 20-23%.
Pharmacokinetics in special clinical cases: In patients with renal failure, the pharmacokinetics of indapamide does not change.
Indications
– arterial hypertension.
Contraindications
– history of angioedema edema
– hypokalemia
– severe renal failure (CC <30 ml / min) – severe hepatic impairment (including with encephalopathy) – II and III trimesters of pregnancy – breastfeeding – children and adolescents under 18 – increased sensitivity to the components of the drug Perindopril PLUS Indapamide – increased sensitivity to other ACE inhibitors srdl kp – hypersensitivity to sulfonamides. Use during pregnancy and lactation The use of perindopril is not recommended in the first trimester of pregnancy. The use of perindopril is contraindicated in the II and III trimesters of pregnancy. Do not start ACE inhibitor therapy during pregnancy. Epidemiological data on the risk of teratogenicity when taking ACE inhibitors in the first trimester of pregnancy do not allow a final conclusion, but there is a possibility of some increase in risk. Except in cases where it is not possible to replace the ACE inhibitor with alternative therapy, patients planning pregnancy should be switched to antihypertensive drug therapy, the safety profile of which for pregnant women is well understood. When pregnancy occurs, ACE inhibitors should be discontinued immediately and, if necessary, other antihypertensive therapy should be prescribed. With the use of ACE inhibitors in the II and III trimesters of pregnancy, a manifestation of fetotoxic action was established (impaired renal function, oligohydramnios, delayed ossification of the bones of the skull) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia). In the case of taking an ACE inhibitor from the second trimester of pregnancy, ultrasound of the kidney and skull bones is recommended. In newborns whose mothers took ACE inhibitors, it is necessary to carefully control blood pressure to prevent the possible development of arterial hypotension. Since there is no information on the use of Perindopril PLUS Indapamide during breastfeeding, it is not recommended to prescribe the drug to lactating women. Consideration should be given to prescribing antihypertensive therapy with drugs, the safety profile of which for nursing women has been well studied. Special instructions Perindopril PLUS Indapamide: Treatment is under the supervision of a physician. Use of the drug Perindopril PLUS Indapamide can cause a sharp decrease in blood pressure, especially with the first dose and during the first 2 weeks of therapy. The risk of developing an excessive decrease in blood pressure is increased in patients with reduced BCC (as a result of following a strict salt-free diet, hemodialysis, vomiting and diarrhea), with severe heart failure (both in the presence of concomitant renal failure and in its absence), with initially low blood pressure, with bilateral renal artery stenosis or stenosis of a single kidney artery, cirrhosis of the liver, accompanied by edema and ascites. A marked decrease in blood pressure at the first dose of the drug is not an obstacle to its further appointment. After the restoration of BCC and blood pressure, treatment can be continued. with the use of a smaller dose of the drug or monotherapy with one of its components. During the treatment period, it is necessary to systematically monitor the concentration of electrolytes (potassium, sodium, magnesium), glucose, uric acid, plasma creatinine and pH. In elderly patients, debilitated patients taking several different drugs, patients with liver cirrhosis, in the presence of edema or ascites, patients with coronary artery disease or heart failure, it is necessary to take into account the risk of a decrease in potassium concentration below the permissible level (less than 3.4 mmol / l). A decrease in potassium levels increases the toxicity of cardiac glycosides and increases the risk of arrhythmias. It should be borne in mind that lactose is included in the excipients of Perindopril PLUS Indapamide. As a result, this drug is not recommended for persons with lactase deficiency, galactosemia or glucose-galactose malabsorption syndrome. You should stop taking the drug before the upcoming surgical treatment (for 12 hours). It is recommended that you avoid alcohol during treatment. 1. Perindopril: Before starting and during therapy, it is recommended to determine the concentration of creatinine, electrolytes and urea (within 1 month). In patients receiving diuretics, they should be canceled 3 days before the start of treatment with perindopril, and against the background of chronic heart failure, reduce the dose (to reduce the risk of developing orthostatic hypotension). During therapy, it is necessary to monitor blood pressure, constant monitoring of the picture of peripheral blood (before treatment, in the first 3-6 months of treatment and subsequently at periodic intervals for 1 year, especially in patients with an increased risk of neutropenia), plasma levels, plasma potassium, urea nitrogen, creatinine, kidney function, body weight, and diet. In patients at risk, especially decompensated chronic heart failure, elderly patients, as well as patients with initially low blood pressure, impaired renal function or receiving high doses of diuretics, the drug should be started under medical supervision. It should be borne in mind that in patients with renal artery stenosis, as well as with hyponatremia, the first dose may be accompanied by severe arterial hypotension and the development of acute renal failure. During treatment with perindopril, especially in the presence of renal and / or heart failure, hyperkalemia may develop. In patients undergoing hemodialysis, the use of polyacrylonitrile membranes should be avoided (anaphylactoid reactions may develop). Caution should be used in cases of renovascular hypertension, severe autoimmune diseases, aortic or mitral stenosis, constrictive pericarditis, hypertrophic cardiomyopathy with hemodynamic impairment, obstructive changes that impede blood flow from the heart, bilateral renal artery stenosis, or bilateral renal artery stenosis or kidney, arteriosclerosis obliterans of the lower limb arteries, common atherosclerosis with coronary and carotid lesions x arteries, with moderate renal failure, hyperkalemia (from 5 to 5.5 mmol / l), hyponatremia, or sodium restriction in diet, dehydration, leukopenia, thrombocytopenia. Care must be taken during any surgical interventions (including dental) during the treatment period. 2. Indapamide: In patients taking cardiac glycosides, laxatives, against the background of hyperaldosteronism, as well as in the elderly, careful monitoring of potassium and creatinine levels is indicated. The most careful control is shown in patients with cirrhosis (especially with edema or ascites – the risk of developing metabolic alkalosis, which increases the manifestations of hepatic encephalopathy), coronary heart disease, and chronic heart failure. Patients with an increased QT interval on the ECG also belong to the high-risk group. The first determination of the concentration of potassium in the blood should be carried out within 1 week. treatment. Hypercalcemia with indapamide may be due to previously undiagnosed hyperparathyroidism. In patients with diabetes, it is extremely important to control blood glucose, especially in the presence of hypokalemia. Significant dehydration can lead to the development of acute renal failure (decreased glomerular filtration). Patients need to compensate for water loss and carefully at the beginning of treatment Significant dehydration can lead to the development of acute renal failure (decreased glomerular filtration). Patients need to compensate for water loss and carefully at the beginning of treatment Significant dehydration can lead to the development of acute renal failure (decreased glomerular filtration). Patients need to compensate for water loss and carefully at the beginning of treatmento monitor kidney function. Indapamide can give a positive result when conducting a doping control. Influence on the ability to drive vehicles and control mechanisms: Due to the risk of developing hypotension and dizziness when taking the drug (especially at the beginning of the course of therapy), patients should be careful when driving vehicles and performing work that requires an increased concentration of attention and speed of psychomotor reactions. Dosage and administration of Perindopril PLUS Indapamide is taken orally 1 time / day. at the same time (preferably in the morning), before eating. Adults, including elderly patients, the drug is prescribed 1 tab. 1 time / day The maintenance dose is selected individually, depending on the tolerance of the drug, therapeutic effect and the patient’s condition. Tablets are taken whole without chewing. Side effects of At recommended doses, the drug is usually well tolerated. Determination of the frequency of side effects: often (1-10%), rarely (0.1-1%), very rarely (less than 0.1%). Effects due to the action of Perindopril Plus From the side of the water-electrolyte balance: hypokalemia is possible. Perindopril, which is part of the drug, has the ability to increase potassium concentration due to inhibition of RAAS, leads to a decrease in potassium loss caused by indapamide. 1. Effects due to the action of perindopril: On the part of the cardiovascular system: often – an excessive decrease in blood pressure and the associated symptoms are very rare – arrhythmia, angina pectoris, myocardial infarction, stroke. From the urinary system: rarely – decreased renal function is very rare – acute renal failure. A slight increase in urine and serum creatinine (reversible after drug withdrawal) is possible – most likely with renal artery stenosis, treatment of hypertension with diuretics, renal failure, temporary hyperkalemia, proteinuria (in patients with glomerular nephropathy). From the respiratory system: often – dry cough, difficulty breathing rarely – bronchospasm very rarely – rhinorrhea. From the digestive system: often – nausea, vomiting, abdominal pain, diarrhea, constipation, taste disturbance rarely – dry mouth is very rare – cholestatic jaundice, pancreatitis. From the side of the central nervous system and peripheral nervous system: often – headache, asthenia, dizziness, ringing in the ears, impaired vision, muscle cramps, paresthesia, taste disturbance rarely – decreased mood, sleep disturbance very rarely – confusion. From the hemopoietic system: rarely – thrombocytopenia, decreased hemoglobin, hematocrit very rarely – agranulocytosis, pancytopenia against the background of deficiency of glucose-6-phosphate dehydrogenase may develop hemolytic anemia. While taking ACE inhibitors in patients after kidney transplantation, hemodialysis, anemia may develop. Allergic reactions: often – skin rash, itching rarely – urticaria, angioedema very rarely – erythema multiforme. Other: rarely – increased sweating, impaired sexual function. 2. Effects due to the action of indapamide: From the side of the central nervous system and peripheral nervous system: rarely – dizziness, headache, asthenia, paresthesia (usually disappear with a decrease in the dose of the drug). From the digestive system: rarely – nausea, constipation, dry mouth, in some cases – pancreatitis with liver failure, the development of hepatic encephalopathy is possible. On the part of the water-electrolyte balance: hypokalemia is possible (especially in patients at risk), a decrease in sodium levels, accompanied by dehydration and orthostatic hypotension. The simultaneous loss of chlorine ions can lead to compensatory metabolic alkalosis (its frequency and severity are small). In some cases, an increase in calcium levels. On the part of the metabolism: an increase in the content of urea and glucose in the blood plasma is possible. From the hemopoietic system: in some cases – thrombocytopenia, leukopenia, agranulocytosis, aplastic anemia, hemolytic anemia. Dermatological reactions: skin rashes, hemorrhagic vasculitis, exacerbation of SLE are possible. Allergic reactions: in predisposed patients, skin manifestations. Overdose Symptoms: marked decrease in blood pressure, nausea, vomiting, convulsions, dizziness, insomnia, decreased mood, polyuria or oliguria, which can go into anuria (as a result of hypovolemia), impaired water-electrolyte balance, bradycardia. Treatment: reducing the dose or completely discontinuing the gastric lavage, taking measures aimed at increasing the BCC (administration of saline and other blood-replacing fluids). With the development of severe arterial hypotension, the patient should be given a horizontal position, lifting his legs up. Symptomatic therapy – epinephrine (s / c or iv), antihistamines, hydrocortisone (iv), dialysis procedures (do not use highly permeable polyacrylonitrile membranes). With the development of bradycardia, atropine is used, the installation of an artificial pacemaker may be required. Active ingredient Indapamide, Perindopril pharmacy terms for lekarstvennaja form tablets Izvarino Pharma, Russia
