Ramipril - instructions for use, dose, side effects, contraindications

It inhibits the conversion of circulating angiotensin I to angiotensin II and the synthesis of angiotensin II in tissues.Oppresses the tissue renin-angiotensin system, including the vascular wall. It inhibits the release of norepinephrine from the end of neurons and weakens vasoconstrictor reactions due to increased neurohumoral activity. Reduces the secretion of aldosterone and degradation of bradykinin. Expands kidney vessels, induces reversion of left ventricular hypertrophy and pathological remodeling in the cardiovascular system. Cardioprotective effect is a consequence of the effect on prostate biosynthesis and stimulation of the formation of nitric oxide (NO) in the endothelium. Reduces the overall peripheral vascular resistance, especially in renal vessels, to a lesser extent - in internal organs, including the liver, the skin and slightly - in the muscles and brain. Increases the regional blood flow in these organs. Increases the sensitivity of tissues to insulin, the level of fibrinogen, activates the synthesis of tissue activator plasminogen, promoting thrombolysis.

Pharmacokinetics:

When ingested absorption is 50-60%, food does not affect the degree of absorption, but slows absorption. The maximum concentration is achieved in 2-4 hours.In the liver, it is metabolized to form an active metabolite of ramiprilate (6 times more active inhibits ACE than ramipril), inactive diketopiperazine and glucuronize. All metabolites formed, with the exception of ramiprilate, have no pharmacological activity. Binding to plasma proteins for ramipril - 73%, ramiprilata - 56%. Bioavailability after oral administration of 2.5-5 mg of ramipril - 15-28%; for ramiprilate - 45%. After a daily intake of ramipril at a dose of 5 mg / day, the steady concentration of ramiprilate in plasma is reached by day 4.

The half-life for ramipril is 5.1 hours; in the distribution and elimination phase, the drop in the concentration of ramiprilata in the serum occurs with a half-life of 3 hours, followed by a transitional phase with a half-life of 15 hours, and a long final phase with very low plasma ramiprilate concentrations and a half-life of 4-5 days. The elimination half-life increases with chronic renal failure. The volume of distribution of ramipril - 90 liters, ramiprilata - 500 liters. The kidneys excrete 60%, through the intestines - 40% (mainly in the form of metabolites). If the renal function is impaired, excretion of ramipril and itsmetabolites slowed down in proportion to a decrease in creatinine clearance; when the liver function is impaired, the conversion into ramiprilat is slowed down; with heart failure, the concentration of ramiprilate increases 1.5-1.8 times.

Indications:Arterial hypertension; chronic heart failure; heart failure, developed in the first few days after an acute myocardial infarction; diabetic and nondiabetic nephropathy; decreased risk of myocardial infarction, stroke and cardiovascular systemmortality in patients with high cardiovascularincluding patients with confirmed coronary artery disease (with or without a history of heart attack), patients undergoing percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, history of stroke, and patients with occlusive lesions of peripheral arteries.

ICD-10

IX.I10-I15.I10 Essential [primary] hypertension

IX.I10-I15.I15 Secondary Hypertension

IX.I10-I15.I15.0 Renovascular hypertension

IX.I20-I25.I25 Chronic ischemic heart disease

IX.I30-I52.I50.9 Heart failure, unspecified

XIV.N00-N08.N03 Chronic nephritic syndrome

XIV.N00-N08.N08.3 * Glomerular lesions in diabetes mellitus (E10-E14 + with the common fourth sign .2)

Contraindications:Hypersensitivityto ramipril or other ACE inhibitors; angioedemaa history of edema, including those associated with previous therapy with ACE inhibitors; pregnancy, breast-feeding, age under 18 years (safety and efficacy not determined), hemodynamically significant stenosis of the renal arteries (bilateral or unilateral in the case of a single kidney), arterial hypotension (systolic blood pressure less than 90 mmHg) or unstable state hemodynamics, hemodynamically significant stenosis of the aortic or mitral valve, or hypertrophic obstructive cardiomyopathy; primary hyperaldosteronism; marked renal failure (creatinine clearance less than 20 ml / min) or hemodialysis (lack of sufficient clinical experience); hemodialysis; Nephropathy, the treatment of which is carried out glucocorticosteroidoid, non-steroidal anti-inflammatory(NSAIDs), the immunomodulatorand / or other cytotoxic agents; chronic heart failure in the stage of decompensation; extracorporeals treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high flow-through membranes (polyacrylonitrilelovye membranes) and low density lipoprotein apheresis with dextran sulfate (high risk of severe anaphylactoid reactions); hyposensitizerAtherosclerosis with reactions of hypersensitivity to poisons HymenopteraInsects such as bees, wasps; simultaneous use with aliskiren and alikiren containingwith drugs in patients with diabetes mellitus and / or renal dysfunction (glomerular filtration rate less than 60 ml / min); lactase deficiency, galactose intolerance, malabsorption syndrome, or glucose and galactose (because of the content of lactose in the composition of the drug); simultaneous use with angiotensin II receptor antagonists in patients with diabetic nephropathy.

Carefully:

Severe autoimmune diseases (systemic lupus erythematosus, scleroderma, and other systemic collagen), hemodynamically significant bilateral renal artery stenosis or stenosis of the artery to a solitary kidney; condition afterkidney transplantation; malignant hypertension, bone marrow suppression (leukopenia, thrombocytopenia), insufficiency of coronary or cerebral circulation, obliterating atherosclerosis of the lower limbs; aortic, mitral stenosis or other obstructive changes that hinder the flow of blood from the heart; severe liver failure, chronic obstructive pulmonary disease, diabetes mellitus (due to the risk of developing hyperkalemia), severe renal failure (serum creatinine level above 300 μmol / L or 3.5 mg / dL) and hyperkalemia (above 5.5 mmol / l), hyponatremia or sodium restriction in the diet, dialysis procedures, dehydration of the body, primary aldosteronism, simultaneous reception with immunosuppressants and saluretic drugs, elderly age.

With caution apply during work drivers of vehicles and people whose profession is associated with increased concentration of attention.

Pregnancy and lactation:

Contraindicated in pregnancy. Before starting treatment, make sure that there is no pregnancy.If the patient becomes pregnant during the treatment period, it is necessary to replace the drug therapy with ramipril as soon as possible with another therapy. Otherwise, there is a risk of damage to the fetus, especially in the first trimester of pregnancy.

Influence on the fetus: impaired fetal kidney development, decreased blood pressure in the fetus and newborn, impaired renal function, hyperkalemia, skull hypoplasia, oligohydramnia, limb contracture, skull deformity, lung hypoplasia.

Action category for the fetus by FDA - D.

For the duration of treatment, breastfeeding should be discontinued.

Dosing and Administration:Inside, with hypertension - the initial dose - 2.5 mg 1 time per day, with prolonged therapy - 2.5-20 mg / day in 1-2 divided doses. With heart failure in the postinfarction period in the initial dose of 2.5 mg 2 times a day; in case of inefficiency - 5 mg twice a day, with severe hypotension or against a background of diuretics - 1,25 mg 2 times a day. With renal failure (glomerular filtration less than 40 ml / min and creatinine level more than 0.22 mmol / l), the initial dose is 1/4 normal with a gradual increase to 5 mg / day (not more).

Side effects:

From the side cardiovascular system and blood (hematopoiesis, hemostasis): hypotension (10.7%), including postural (2.2%), angina pectoris (2.9%), syncope (2.1%), heart failure (2%), myocardial infarction (1.7% ), vertigo (1.5%), chest pain (1.1%), less than 1% - arrhythmia, palpitation, hemolytic anemia, myelodepression, pancytopenia, thrombocytopenia, eosinophilia, agranulocytosis; vasculitis.

From the side organs of the digestive tract: Nausea (2.2%), vomiting (1.6%), diarrhea (1.1%), less than 1% dry mouth or salivation, anorexia, dyspepsia, dysphagia, constipation, abdominal pain, gastroenteritis, pancreatitis, hepatitis, a violation of liver function (cholestatic jaundice, fulminant liver necrosis with a lethal outcome), a change in the level of transaminases.

From the side nervous system and sense organs: dizziness (4.1%), headache (1.2%), asthenia (0.3%), less than 1% - cerebrovascular disorders, amnesia, drowsiness, convulsions, depression, sleep disorder, neuralgia, neuropathy, paresthesia , tremor, hearing loss, impaired vision.

From the side respiratory system: non-productive cough (7.6%), upper respiratory tract infections, less than 1% - dyspnoea, pharyngitis, sinusitis, rhinitis, tracheobronchitis, laryngitis, bronchospasm.

From the side genitourinary system: renal dysfunction (1.2%), less than 1% - proteinuria, oliguria, edema; impotence.

From the side skin integument: urticaria, prurigo, rash, erythema multiforme, photosensitization.

Other: less than 1% - weight loss, anaphylactoid reactions, increased urea nitrogen and creatinine, angioedema (0.3%), arthralgia / arthritis, myalgia, fever, increased antiserum antibody titre, hyperkalemia, changes in enzyme activity, bilirubin concentrations , uric acid, glucose.

Overdose:

Symptoms: acute arterial hypotension, cerebral circulation disorder, angioedema, myocardial infarction, thromboembolic complications.

Treatment: reduction of dose or complete withdrawal of the drug; gastric lavage, transfer of the patient to a horizontal position, carrying out measures to increase bcc (introduction of isotonic sodium chloride solution, transfusion of other blood-substituting fluids), symptomatic therapy: epinephrine (subcutaneously or intravenously), hydrocortisone (intravenously), antihistamines.

Interaction:

Amlodipine + Telmisartan. If the combination is applied simultaneously amlodipine + telmisartan with ramipril may increase the hypotensive effect.

Acetylsalicylic acid reduces the hyponatremic and hypotensive effects of ramipril.

Bumetanide enhances the hypotensive effect of ramipril.

Verapamil. Ramipril strengthens (mutually) the hypotensive effect.

Hydrochlorothiazide. Strengthens (mutually) antihypertensive effect.

Hydrochlorothiazide + Telmisartan. With the combined use of telmisartan (in combination hydrochlorothiazide + telmisartan) and ramipril (in one study) there was an increase in AUC0-24 and a maximum concentration of ramipril and ramiprilate (an active metabolite of ramipril) 2.5 times. The clinical significance of this interaction is not established.

Diclofenac. Ramipril increases (mutually) the risk of developing kidney failure and hyperkalemia. Against the background of diclofenac, the hypotensive effect of ramipril decreases.

On the background ibuprofen the hypotensive effect of ramipril is weakened.

Indapamide. Strengthens (mutually) the hypotensive effect.

Indomethacin. Strengthens the delay of potassium, increases (mutually) the risk of hyperkalemia.Against the background of indomethacin, the antihypertensive effect is weakened.

Potassium chloride. Increases (mutually) the risk of hyperkalemia.

Ketoprofen. Increases (mutually) the risk of developing kidney failure and hyperkalemia. Against the background of ketoprofen, the hypotensive effect decreases.

Ketorolac. Increases (mutually) the risk of developing kidney failure and hyperkalemia. Against the background of ketorolac, the hypotensive effect decreases.

Meloksikam. Against the background of meloxicam the hypotensive effect decreases, the risk of developing renal failure increases.

Methyldopa. Ramipril enhances (mutually) antihypertensive effect.

Mephenamic acid. Strengthens (mutually) the risk of hyperkalemia and renal insufficiency.

Nabumethon. Strengthens (mutually) the risk of hyperkalemia and renal insufficiency.

Naproxen. Ramipril increases (mutually) the risk of developing kidney failure and hyperkalemia. Against the background of naproxen, the hypotensive effect is reduced.

Nitroglycerine. Strengthens (mutually) the hypotensive effect.

Piroxicam. Increases (mutually) the risk of developing kidney failure and hyperkalemia. Against the background of piroxicam, the hypotensive effect decreases.

Risperidone. Strengthens (mutually) antihypertensive effect.

Rofecoxib. Strengthens (mutually) the risk of hyperkalemia and renal insufficiency.

Spironolactone. It inhibits the release of aldosterone, significantly increases the risk of hyperkalemia. Against the background of spironolactone, the hypotensive effect is enhanced.

Sulindak Strengthens (mutually) the risk of hyperkalemia and renal insufficiency.

Telmisartan. With the simultaneous use of telmisartan and ramipril, an increase in AUC0-24 and a maximum concentration of ramipril and ramiprilate were observed 2.5-fold. The clinical significance of this phenomenon is not established.

Terazosin. Ramipril strengthens (mutually) the hypotensive effect; at the combined appointment, a sharp decrease in blood pressure, which requires dose reduction, is possible.

Triamterene strengthens the hypotensive effect of ramipril, increases (mutually) the risk of hyperkalemia.

Phenylbutazone. Strengthens (mutually) the risk of hyperkalemia and renal insufficiency.

Fenoprofen. Strengthens (mutually) the risk of hyperkalemia and renal insufficiency.

Furosemide enhances the hypotensive effect of ramipril.

Chlorthalidone enhances the hypotensive effect of ramipril.

Celecoxib reduces the hypotensive effect of ramipril, increases (mutually) the risk of hyperkalemia and renal failure.

Etacrynic acid. In the initial period of co-therapy with ramipril, you should stop taking etacrylic acid or lower the dose of ramipril to avoid severe arterial hypotension. Against the background of ramipril, the hypokalemic effect of ethacrynic acid decreases.

This is eelander. Strengthens (mutually) the risk of hyperkalemia and renal insufficiency.

Effects of ramipril increase antihypertensives, including beta-blockers, including with significant systemic absorption from ophthalmic forms, diuretics, opioid analgesics, anesthesia, alcohol, weaken - estrogen, NSAIDs, sympathomimetics.

Potentiates hypoglycemic effect oral antidiabetic drugs, oppressive action alcohol on the central nervous system. Reduces secondary hyperaldosteronism and hypokalemia caused by diuretics.

Increases plasma level digoxin and lithium (increases toxicity).

Cyclosporine, potassium-containing medicines and supplements, salt substitutes, milk with low salt content increase the risk of hyperkalemia.

Means that provide myelodepressive effect, increase the risk of developing neutropenia and / or agranulocytosis with a fatal outcome.

Special instructions:

Treatment is carried out with regular medical supervision.

Prior to the start of treatment (for 1 week), previous antihypertensive therapy, including diuretics should be canceled (if it is impossible to cancel diuretics, you need to reduce doses and adjust the water-electrolyte balance).

In patients with malignant course of hypertension, the doses are increased gradually, every 24 hours under the control of blood pressure until the maximum effect is achieved.

During the therapy, monitoring of blood pressure, constant monitoring of the peripheral blood picture (before the start of treatment, the first 3-6 months of treatment and at periodic intervals for up to 1 year, especially in patients with an increased risk of neutropenia), the level of protein, potassium in plasma, urea nitrogen, creatinine, kidney function, body weight, diet compliance. When the patient develops hyponatremia and dehydration, correction of the dosing regimen (reduction of doses) is necessary.

With the development of cholestatic jaundice and the progression of fulminant liver necrosis, treatment is discontinued.

Hemodialysis should be avoided through high-performance polyacrylonitrile metal allyl sulfate membranes (eg AN69), hemofiltration or LDL-apheresis (anaphylaxis or anaphylactoid reactions are possible).

It should be borne in mind that when using ramipril in patients with autoimmune diseases and syndromes, the risk of developing neutropenia increases. Hyposensitivity therapy can increase the risk of anaphylactic reactions. It is recommended to exclude the use of alcoholic beverages during treatment.

Instructions

Ramipril (Ramiprilum)