Ramipril

General characteristics. Structure:

Active ingredient: 1,25 mg 2,5 mg, 5 mg or 10 mg of a ramipril in 1 tablet.

The drug rendering a hypotensive, vazodilatiruyushchy, cardioprotective and natriuretic effect.

Pharmacological properties:

Pharmacodynamics. Slows down transformation of the circulating angiotensin I into angiotensin II and synthesis of angiotensin II in fabrics. Oppresses fabric a renin-angiotenzinovuyu system, including and a vascular wall. Slows down release of noradrenaline from the terminations of neurons and weakens the vasopressor reactions caused by increase in neurohumoral activity. Lowers secretion of Aldosteronum and degradation of bradikinin. Expands renal vessels, induces reversion of a hypertrophy of a left ventricle and pathological remodeling in cardiovascular system. The cardioprotective effect is a consequence of influence on biosynthesis of PG and stimulation of formation of nitrogen oxide (NO) in an endothelium. Reduces OPSS, especially in renal vessels, to a lesser extent — in internals, including a liver, skin and it is insignificant — in muscles and a brain. Increases a regional blood stream in these bodies. Increases sensitivity of fabrics to insulin, fibrinogen level, activates synthesis of a fabric plasminogen activator, promoting a thrombolysis.

After intake anti-hypertensive action begins in 1–2 h, reaches a maximum later 4,5–6,5 h and continues 24 h and more. At daily use hypotensive activity gradually increases during 3–4 weeks and remains at prolonged treatment (within 1–2 years). Efficiency does not depend on a sex, age and the body weight of the patient.

The single dose in a dose of 2,5-20 mg for 60–80% reduces activity of APF during 4 h and by 40–60% in the following of 24 h. Multiple dose in a dose of 2 mg and more blocks APF for 90% during 4 h and for 80% in the following of 24 h. Reduces a lethality during the early and remote periods of a myocardial infarction, frequency of developing of repeated heart attacks, hospitalization, progressing of heart failure (reduces expressiveness of its manifestations), improves quality of life of patients and increases survival. At patients with an acute myocardial infarction limits a zone of distribution of a necrosis, improves the forecast for life. At 6-month reception reduces degree of pulmonary hypertensia at patients with the inborn and acquired heart diseases.

Lowers pressure in a portal vein at portal hypertensia, brakes a microalbuminuria (in initial stages) and deterioration in renal function at patients with the expressed diabetic nephropathy. At not diabetic nephropathy which is followed by a proteinuria (3 g/days and more) and a renal failure, further deterioration in function of kidneys slows down, reduces a proteinuria, risk of increase in level of creatinine or development of a terminal renal failure. At repeated use in a dose of 10 mg ramiprit and its metabolites create low concentration in breast milk.

When using at mice and rats of doses to 500 mg/kg/days within 24 months and to 1000 mg/kg/days within 18 months of cancerogenic properties and influence on fertility of rats (at doses to 500 mg/kg/days) it is not revealed. In doses, to 2500 times (a rat and a mouse), more чемв 12 times (monkey) and more чемв 2 times (rabbits) of the exceeding MRDCh, per body weight, increased the frequency of expansion of a renal pelvis at fruits of rats and a delay of a gain of body weight of newborn mice (without signs of teratogenic action, changes of fertility, reproductive ability or the course of pregnancy). Introduction to mice, rats, dogs and monkeys of the doses considerably exceeding recommended for the person was followed by development of a hypertrophy of a renal periarterial pad. In the researches including the bacterial test of Ames, micronuclear test on mice, the analysis of not reparative synthesis of DNA in culture of cells of the person and direct genovariations (in ovarian cells of the Chinese hamsters) signs of a mutagenicity are not revealed. At rats and mice (10–11 g/kg) increased mortality, caused a gastrointestinal distress syndrome in dogs (more than 1 g/kg).

Pharmacokinetics. At intake absorption makes about 50-60% (meal does not influence extent of absorption, but reduces its speed). Concentration and AUC disproportionately increase at increase in a dose. In a liver, as a result of destruction of radio communication, releases рамиприлат which activity by 6 times exceeds that ramiprit, and forms inactive metabolites (at an abnormal liver function metabolism is slowed down). Cmax of a ramipril is reached during 1–2 h, a ramiprilat — in 2–4 h, linkng with proteins of plasma makes 73% and 56%, T1/2 — 5,1 h and 13–17 h respectively. It is brought with urine (60%, out of them 2% — in not changed look) and with excrements (40%), including in the form of metabolites. At a renal failure T1/2 increases (can exceed 50 h) and AUC (by 3–4 times), excretion goes down. At people of advanced age change is noted With
max and AUC without the expressed clinical value.

Indications to use:

Arterial hypertension; chronic heart failure, including after an acute myocardial infarction at patients with a stable hemodynamics; diabetic nephropathy and chronic diffusion diseases of kidneys (not diabetic nephropathy); decrease in risk of development of a myocardial infarction, stroke or coronary death at patients with an ischemic heart disease, with the increased risk of cardiovascular diseases, including the patients who had a myocardial infarction, chrezkozhny transluminal coronary angioplasty, aortocoronary shunting (at clinically stable state).

Route of administration and doses:

Inside, at hypertensia — an initial dose — 2,5 mg of 1 times a day, at long therapy — 2,5–20 mg/days in 1–2 receptions. At heart failure in the postinfarction period in an initial dose on 2,5 mg 2 times a day; in case of inefficiency — on 5 mg 2 times a day, at the expressed hypotension or against the background of diuretics — on 1,25 mg 2 times a day. At a renal failure (glomerular filtering less than 40 ml/min. and level of creatinine more than 0,22 mmol/l) the initial dose makes 1/4 usual with gradual increase up to 5 mg/days (no more).

Features of use:

Use at pregnancy and feeding by a breast. Contraindicated at pregnancy. Before an initiation of treatment it is necessary to be convinced of lack of pregnancy. If the patient became pregnant during treatment, it is necessary to replace medicinal therapy ramiprily with other therapy as soon as possible. Otherwise there is a risk of damage of a fruit, especially in the I trimester of pregnancy.

Influence on a fruit: disturbance of development of kidneys of a fruit, decrease in the ABP at a fruit and the newborn, a renal failure, a hyperpotassemia, a skull hypoplasia, олигогидрамнион, a contracture of extremities, deformation of a skull, a hypoplasia of lungs.

Category of action on a fruit on FDA — C (the I trimester). Category of action on a fruit on FDA — D (II and III trimesters). For the period of treatment it is necessary to stop breastfeeding.

Treatment is carried out at regular medical control. Prior to treatment (for 1 week) the previous anti-hypertensive therapy, including diuretics it is necessary to cancel (at impossibility of cancellation of diuretics it is necessary to reduce doses and to correct water and electrolytic balance).

At patients with the malignant course of hypertensia of a dose increase gradually, each 24 h, under control of the ABP before achievement of the maximum effect. During therapy monitoring of the ABP, constant control of a picture of peripheral blood (before an initiation of treatment, the first 3–6 months of treatment and with periodic intervals further till 1 year, especially at patients with the increased risk are neutropenias), the level of protein, potassium in plasma, an urea nitrogen, creatinine, function of kidneys, body weight, observance of a diet is necessary. At development in the patient of a hyponatremia and dehydration correction of the mode of dosing (reduction of doses) is necessary.

At development of cholestatic jaundice and progressing of a fulminantny necrosis of a liver treatment is stopped. It is necessary to avoid carrying out a hemodialysis through high-performance membranes from a poliakrilonitrilmetaallilsulfat (for example AN69), haemo filterings or LNP-afereza (development of an anaphylaxis or anaphylactoid reactions is possible).

It must be kept in mind that when using a ramipril at patients with autoimmune diseases and syndromes, the risk of development of a neutropenia increases. Giposensibilizatsionny therapy can increase risk of development of anaphylactic reactions.

It is recommended to exclude the use of alcoholic beverages during treatment. With care to apply in operating time to drivers of vehicles and people whose profession is connected with the increased concentration of attention.

Side effects:

From cardiovascular system and blood (a hemopoiesis, a hemostasis): hypotension (10,7%), including postural (2,2%), stenocardia (2,9%), a syncope (2,1%), heart failure (2%), a myocardial infarction (1,7%), вертиго (1,5%), thorax pain (1,1%), less than in 1% — arrhythmia, heartbeat, hemolitic anemia, a miyelodepressiya, a pancytopenia, thrombocytopenia, an eosinophilia, an agranulocytosis; vasculitis.

From bodies of a GIT: nausea (2,2%), vomiting (1,6%), diarrhea (1,1%), less than in 1% — dryness in oral cavities or increase in salivation, anorexia, dyspepsia, a dysphagy, a lock, an abdominal pain, a gastroenteritis, pancreatitis, hepatitis, an abnormal liver function (cholestatic jaundice, a fulminantny necrosis of a liver with a lethal outcome), change of level of transaminases.

From a nervous system and sense bodys: dizziness (4,1%), a headache (1,2%), an adynamy (0,3%), less than in 1% — cerebrovascular disturbances, amnesia, drowsiness, spasms, a depression, frustration of a dream, neuralgia, neuropathy, paresthesia, a tremor, a hearing impairment, a vision disorder.

From respiratory system: unproductive cough (7,6%), upper respiratory tract infections, less than in 1% — диспноэ, pharyngitis, sinusitis, rhinitis, a tracheobronchitis, laryngitis, a bronchospasm.

From urinogenital system: a renal failure (1,2%), less than in 1% — a proteinuria, an oliguria, hypostases; impotence.

From integuments: small tortoiseshell, пруриго, rash, mnogoformny erythema, photosensitization.

Others: less than in 1% — a body degrowth, anaphylactoid reactions, increase in level of an urea nitrogen and creatinine, a Quincke's disease (0,3%), arthralgia/arthritis, a mialgiya, fever, increase in a caption of antinuclear antibodies, a hyperpotassemia, change of activity of enzymes, concentration of bilirubin, uric acid, glucose.

Interaction with other medicines:

Effects strengthen antihypertensives, including beta adrenoblockers, including at considerable system absorption from ophthalmologic forms, diuretic means, opioid analgetics, anesthetics, alcohol, weaken — estrogen, NPVS, sympathomimetics.

Exponentiates hypoglycemic effect of peroral antidiabetic drugs, the oppressing effect of alcohol on TsNS.

Reduces a secondary hyper aldosteronism and the hypopotassemia caused by diuretics.

Increases the plasma level of digoxin and lithium (increases toxicity). Kaliysberegayushchy diuretics, cyclosporine, kaliysoderzhashchy medicines and additives, salt substitutes, milk with the low content of salts increase risk of development of a hyperpotassemia.

The means having miyelodepressivny effect increase risk of development of a neutropenia and/or agranulocytosis from the death.

Contraindications:

Hypersensitivity to a ramipril or other APF inhibitors; the Quincke's disease in the anamnesis including and connected with the previous therapy by APF inhibitors; pregnancy, feeding by a breast, age after 18 years (safety and efficiency are not defined).

Restrictions to use. Serious autoimmune illness (system lupus erythematosus, scleroderma and other system collagenoses), hemodynamically significant bilateral stenosis of renal arteries or stenosis of an artery of the only kidney; a state after transplantation of a kidney; malignant arterial hypertension, marrow suppression (leukopenia, thrombocytopenia), insufficiency of coronary or cerebral circulation, obliterating atherosclerosis of the lower extremities; the aortal, mitral stenosis or other obstructive changes complicating outflow of blood from heart; the expressed abnormal liver functions, chronic obstructive diseases of lungs, diabetes mellitus (because of risk of development of a hyperpotassemia), a heavy renal failure (level of serumal creatinine is higher than 300 µmol/l or 3,5 mg/dl) and a hyperpotassemia (higher than 5,5 mmol/l), a hyponatremia or restriction of sodium in a diet, holding dialysis procedures, organism dehydration, primary aldosteronism, a concomitant use with immunodepressants and saluretics, advanced age.

Overdose:

Symptoms: acute arterial hypotension, disturbance of cerebral circulation, Quincke's disease, myocardial infarction, tromboembolic episodes.

Treatment: reduction of a dose or full drug withdrawal; a gastric lavage, transfer of the patient in horizontal position, holding actions for increase in OTsK (administration of isotonic solution of sodium of chloride, transfusion of other blood-substituting liquids), symptomatic therapy: Epinephrinum (п / to or in/in), a hydrocortisone (in/in), antihistamines.

Storage conditions:

To store at a temperature of 15-25 °C, in dry, protected from light and the place, unavailable to children. Period of validity 3 years. Not to use after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets of 1,25 mg, 2,5 mg, 5 mg and 10 mg. On 20 tablets in each blister, on one, two or three blisters in cardboard packaging.