RAMIPRIL PILLS 5MG

Tradename:Ramipril

International non-proprietary name: Ramipril

Dosage Form: pills.

Description

pills of white or white with a grayish shade of color, round, flat-cylindrical, with a chamfer.

Pharmacotherapeutic group: Angiotensin-converting enzyme (ACE) inhibitor.

Pharmacological properties.

Pharmacodynamics.
The active metabolite of ramipril, ramiprilat, formed under the influence of “liver” enzymes, is a long-acting ACE inhibitor, which is a peptidyl dipeptidase. ACE in plasma and tissues catalyzes the conversion of angiotensin I to angiotensin II and the breakdown of bradykinin.
Therefore, when ramipril is taken orally, the formation of angiotensin II is reduced and the accumulation of bradykinin occurs, which leads to the expansion of blood vessels and a decrease in the arterial pressure (BP). The increased activity of the kallikrein-kinin system in the blood and tissues causes the cardioprotective and endothelioprotective action of ramipril due to the activation of the prostaglandin system and, accordingly, an increase in the synthesis of prostaglandins,stimulating the formation of nitric oxide (NO) in endotheliocytes.
Angiotensin II stimulates the production of aldosterone, so taking ramipril leads to a decrease in the secretion of aldosterone and an increase in serum concentrations of potassium ion.
By reducing the concentration of angiotensin II in the blood, its inhibitory effect on renin secretion by the type of negative feedback is eliminated, which leads to an increase in plasma renin activity.
It is assumed that the development of some undesirable reactions (in particular, "dry" cough) is also associated with an increase in the concentration of bradykinin.
In patients with arterial hypertension taking ramipril leads to a decrease in blood pressure in the prone position and standing, without a compensatory increase in heart rate (HR). Ramipril significantly reduces total peripheral vascular resistance (OPS), almost without causing changes in the renal blood flow and glomerular filtration rate. The antihypertensive effect begins to appear within 1-2 hours after ingestion of a single dose of the drug, reaching its highest value in 3-9 hours, and persists for 24 hours. In exchange intake, the hypotensive effect may gradually increase, usually stabilizing by 3-4 weeks of regular use of the drug and then persisting for a long time. A sudden stop of taking the drug does not lead to a rapid and significant increase in blood pressure (no withdrawal syndrome).
In patients with arterial hypertension, ramipril slows down the development and progression of myocardial and vascular wall hypertrophy.
In patients with chronic heart failure ramipril reduces round fistula (reduced afterload on the heart), increases the capacity of the venous bed and reduces the filling pressure of the left ventricle, which, respectively, leads to a decrease in preload on the heart. In these patients, when receiving ramipril, there is an increase in cardiac output, ejection fraction, and improvement in exercise tolerance.
With diabetic and non-diabetic nephropathy reception of ramipril slows down the rate of progression of renal failure and the time of onset of end-stage renal failure, and thereby reduces the need for hemodialysis procedures or kidney transplantation. In the initial stages of diabetic or non-diabetic nephropathy, ramipril reduces the severity of albuminuria.
In patients at high risk of developing cardiovascular disease due to the presence of vascular lesions (diagnosed ischemic heart disease, history of peripheral arterial disease, history of stroke) or diabetes mellitus with at least one additional risk factor (microalbuminaria, arterial hypertension, increased concentrations of total cholesterol (OX), reduction of high-density lipoprotein cholesterol (HDL-C) cholesterol,smoking) joining ramipril to standard therapy significantly reduces the incidence of myocardial infarction, stroke and mortality from cardiovascular causes. In addition, ramipril reduces overall mortality, as well as the need for revascularization procedures, and slows the onset or progression of chronic heart failure.
In patients with heart failure that developed in the first days of acute myocardial infarction (2-9 days), when taking ramipril, starting from 3 to 10 days of acute myocardial infarction, the risk of mortality decreases (by 27%), the risk of sudden death (by 30%), the risk of progression of chronic heart failure to severe (III-IV functional class according to NYHA classification ) / resistant to therapy (by 27%), the likelihood of subsequent hospitalization due to the development of heart failure (by 26%).
In the general population of patients, as well as in patients with diabetes mellitus, both with arterial hypertension and with normal blood pressure, ramipril significantly reduces the risk of nephropathy and microalbuminuria.

Pharmacokinetics.

After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract (50-60%). Meal slows down its absorption, but does not affect the completeness of absorption. Ramipril is subjected to intensive presystemic metabolism / activation (mainly in the liver by hydrolysis), which results in the formation of its only active metabolite, ramiprilat, which is approximately 6 times more active than ramipril in inhibiting ACE.In addition, as a result of ramipril metabolism, non-pharmacologically active diketopiperazine is formed, which is then conjugated with glucuronic acid, ramie-prilate is also glucuronated and metabolized to diketopiperazinic acid. The bioavailability of ramipril after oral administration ranges from 15% (for a dose of 2.5 mg) to 28% (for a dose of 5 mg). The bioavailability of the active metabolite - ramiprilat - after oral administration of 2.5 mg and 5 mg of ramipril is approximately 45% (compared with its bioavailability after intravenous administration in the same doses).
After ingestion of ramipril inside, maximum plasma concentrations of ramipril and ramiprilat are reached after 1 and 2 - 4 hours, respectively. The decrease in plasma concentration of ramiprilat occurs in several stages: the distribution phase and excretion with a half-life (T1/2a) ramiprilata of approximately 3 hours, then an intermediate phase with T1/2 ramiprilat, which is approximately 15 hours, and the final phase with a very low concentration of ramiprilat in the blood plasma and T1/2 ramiprilata, constituting approximately 4-5 days. This final phase is due to the slow release of ramiprilat from a strong bond to the ACE receptors. In spite of the prolonged final phase with a single dose of ramipril administered orally within a day at a dose of 2.5 mg or more, the equilibrium plasma concentration of ramie-inlate is reached after approximately 4 days of treatment. In the course of the appointment of the drug "effective" T1/2 depending on the dose is 13-17 hours.
Communication with plasma proteins is approximately 73% for ramipril, and 56% for ramiprilat.
After intravenous administration, the volume of distribution of ramipril and ramiprilat is approximately 90 liters and approximately 500 liters, respectively.
After ingestion of radiolabeled ramipril (10 mg), 39% of the radioactivity is eliminated through the intestines and about 60% by the kidneys. After intravenous ramipril, 50-60% of the dose is found in the urine in the form of ramie-prila and its metabolites. After intravenous ramiprilat, about 70% of the dose is found in the urine as ramiprilat and its metabolites, in other words, with intramuscular administration of ramipril and ramiprilat, a significant portion of the dose is eliminated through the intestine with bile, bypassing the kidneys (50% and 30%, respectively). After ingestion of 5 mg of ramipril in patients with drainage of the bile ducts, almost the same amount of ramipril and its metabolites are excreted by the kidneys and through the intestines during the first 24 hours after ingestion.
Approximately 80-90% of metabolites in urine and bile were identified as ramiprilat and ramiprilat metabolites. Ramipril glucuronide and ramipril diketopiperazin account for approximately 10–20% of the total amount, and unmetabolized ramipril in the urine is approximately 2%.
In animal studies, ramipril has been shown to be secreted into human milk.
With impaired renal function with creatinine clearance (CC) of less than 60 ml / min, the elimination of ramiprilat and its metabolites by the kidneys slows down.This leads to an increase in the plasma concentration of ramiprilat, which decreases more slowly than in patients with normal renal function.
When taking ramipril in high doses (10 mg), impaired liver function leads to a slower presystemic metabolism of ramipril to active ramiprilat and a slower elimination of ramiprilat.
In healthy volunteers and in patients with arterial hypertension after two weeks of ramipril treatment in a daily dose of 5 mg, there is no clinically significant accumulation of ramipril and ramiprilat.
In patients with chronic heart failure, after two weeks of ramipril treatment in a daily dose of 5 mg, there is a 1.5-1.8 fold increase in plasma concentrations of ramiprilat and the area under the concentration-time pharmacokinetic curve (AUC).
In healthy elderly volunteers (65-76 years), the pharmacokinetics of ramipril and ramiprilat are not significantly different from those in young healthy volunteers.

Indications for use

• Essential hypertension.
• Chronic heart failure (as part of combination therapy, in particular, in combination with diuretics).
• Diabetic or non-diabetic nephropathy is a preclinical and clinically significant stage, including with severe proteinuria, especially when combined with arterial hypertension.
• Reducing the risk of myocardial infarction, stroke or cardiovascular mortality in patients with high cardiovascular risk:
  • in patients with confirmed coronary heart disease, myocardial infarction with or without a history, including patients undergoing percutaneous transluminal coronary angioplasty, coronary artery bypass surgery;
  • in patients with a history of stroke;
  • in patients with occlusive lesions of peripheral arteries;
  • in patients with diabetes mellitus with at least one additional risk factor (microalbuminuria, arterial hypertension, increased plasma concentrations of TC, decreased plasma concentrations of HDL-C, smoking).

• Heart failure that developed during the first few days (from the 2nd to the 9th day) after acute myocardial infarction (see the Pharmacodynamics section).

Contraindications

• Hypersensitivity to ramipril, other ACE inhibitors, or to any of the components of the drug (see "Composition" section).
• Angioedema (hereditary or idiopathic, as well as after taking ACE inhibitors) in history - the risk of rapid development of angioedema (see the “Side Effects” section).
• Hemodynamically significant renal artery stenosis (bilateral or unilateral in the case of a single kidney).
• Arterial hypotension (systolic blood pressure less than 90 mmHg) or conditions with unstable hemodynamic parameters.
• Hemodynamically significant aortic or mitral valve stenosis or hypertrophic obstructive cardiomyopathy (GOKMP).
• Primary hyper aldosteronism.
• Severe renal failure (CC less than 20 ml / min with a body surface of 1.73 m2) (experience with clinical use is insufficient). Hemodialysis (experience with clinical use is insufficient).
• Pregnancy.
• Lactation period.
• Nephropathy, which is treated with glucocorticosteroids, nonsteroidal anti-inflammatory drugs, immunomodulators and / or other cytotoxic agents (experience with clinical use is insufficient, see the section "Interaction with other drugs").
• Chronic heart failure in the stage of decompensation (experience of clinical use is insufficient).
• Age up to 18 years (experience of clinical use is insufficient).
• Hemodialysis or hemofiltration using some membranes with a negatively charged surface, such as high-flow polyacrylonitrile membranes (risk of developing hypersensitivity reactions) (see sections “Interactions with other drugs”, “Special instructions”).
• Apheresis of low-density lipoproteins using dextran sulfate (risk of developing hypersensitivity reactions) (see section "Special Instructions").
• Hyposensitization therapy in cases of hypersensitivity to the poisons of insects, such as bees, wasps (see section "Special Instructions").
• Cardiogenic shock.
• Severe hepatic impairment (no clinical experience).
• As in the case of other ACE inhibitors, the combined use of ramipril and aliskiren in patients with diabetes mellitus or renal failure (CC less than 60 ml / min) is contraindicated.

Additional contraindications when using the drug ramipril in the acute stage of myocardial infarction:

• severe heart failure (functional class IV according to the NYHA classification);
• unstable angina;
• life-threatening ventricular arrhythmias;
• "Pulmonary" heart.

Carefully

• Conditions in which an excessive decrease in blood pressure is particularly dangerous (with atherosclerotic lesions of the coronary and cerebral arteries).
• Conditions associated with an increase in the activity of the renin-angiotensin-aldosterone system (RAAS), in which, when ACE is inhibited, there is a risk of a sharp decrease in blood pressure with deterioration of kidney function:
  • severe arterial hypertension, especially malignant arterial hypertension;
  • chronic heart failure, especially severe or due to which other drugs with hypotensive action are taken;
  • hemodynamically significant unilateral renal artery stenosis (in the presence of both kidneys);
  • prior diuretic use;
  • violations of water and electrolyte balance as a result of insufficient consumption of liquid and salt, diarrhea, vomiting, and profuse sweating.

• Liver dysfunction (lack of experience with the use of: possible as reinforcement,and the weakening of the effects of ramipril; in patients with cirrhosis of the liver with ascites and edema, significant activation of the RAAS is possible, see above, “Conditions accompanied by an increase in the activity of the RAAS”).
• Renal dysfunction (CC more than 20 ml / min with a body surface of 1.73 m2) due to the risk of hyperkalemia and leukopenia.
• Condition after kidney transplantation.
• Systemic diseases of the connective tissue, including systemic lupus erythematosus, scleroderma, concomitant therapy with drugs that can cause changes in the pattern of peripheral blood (possibly inhibition of bone marrow hematopoiesis, development of neutropenia or agranulocytosis, see section "Interaction with other drugs").
• Diabetes mellitus (risk of developing hyperkalemia).
• Older age (over 65) (increased risk of concomitant disorders of the liver and / or kidneys and heart failure).
• Hyperkalemia.
• Hypertrophic obstructive cardiomyopathy.
• The simultaneous use of lithium preparations of immunosuppressants and saluretics.

Use during pregnancy and during breastfeeding

Ramipril is contraindicated during pregnancy, as it can have an adverse effect on the fetus: impaired development of the kidneys of the fetus, lowering blood pressure of the fetus and newborns, impaired renal function, hyperkalemia, hypoplasia of the bones of the skull, oligohardramnion, contracture of the extremities, deformation of the bones of the skull, hypoplasia of the lungs.
Therefore, before starting the drug in women of childbearing age, pregnancy should be excluded.
If a woman is planning a pregnancy, the treatment with ACE inhibitors should be stopped.
If pregnancy occurs during ramipril treatment, it should, as soon as possible, stop taking it and transfer the patient to other drugs, the use of which will have the lowest risk for the child.
If ramipril treatment is necessary during breastfeeding, breastfeeding should be discontinued.

Dosage and administration

pills must be swallowed whole (do not chew) and drink plenty of water (1/2 cup) of water, regardless of the meal (that is, pills can be taken both before and during or after meals). The dose is selected depending on the therapeutic effect and tolerability of the drug to patients. To ensure the following dosing regimen (dose 1.25 mg), it is necessary to use the drug Rami-prila in another dosage form: 2.5 mg pills with a risk.
Treatment with the drug ramipril is usually long, and its duration in each case is determined by the doctor.
Unless otherwise prescribed, the following dosing regimens are recommended for normal kidney and liver function.
With hypertension
Usually the initial dose is 2.5 mg 1 time per day in the morning. If, when taking the drug in this dose for 3 weeks or more, it is not possible to normalize blood pressure, then the dose may be increased to 5 mg of ramipril per day.With insufficient effectiveness of the dose of 5 mg in 2-3 weeks, it can be doubled to the maximum recommended daily dose of 10 mg per day (1 pill 5 mg 2 times a day is possible).
As an alternative to increasing the dose to 10 mg per day with insufficient hypotensive efficacy of a daily dose of 5 mg, other antihypertensive agents, in particular diuretics or “slow” Calcium channel blockers, can be added to the treatment.
In chronic heart failure
Recommended initial dose: 1.25 mg 1 time per day. Depending on the response to the patient's therapy, the dose may increase. It is recommended to double the dose at intervals of 1-2 weeks.
The maximum recommended daily dose is 10 mg.
With diabetic or non-diabetic nephropathy
Recommended initial dose: 1.25 mg 1 time per day. The dose may be increased to 5 mg once a day.
To reduce the risk of myocardial infarction, stroke or cardiovascular mortality in patients with high cardiovascular risk
The recommended initial dose: 2.5 mg 1 time per day. Depending on the patient's tolerance of the drug, the dose can be gradually increased. It is recommended to double the dose after 1 week of treatment, and in the next 3 weeks of treatment to increase it to the usual maintenance dose of 10 mg 1 time per day.
The use of the drug in patients with QA less than 0.6 ml / sec has not been studied enough.
In case of heart failure that developed during the first few days (from the 2nd to the 9th day) after acute myocardial infarction
The recommended initial dose is 5 mg per day, divided into two single doses of 2.5 mg, one of which is taken in the morning and the second in the evening. If the patient does not tolerate this initial dose (there is an excessive decrease in blood pressure), then it is recommended that he give 1.25 mg 2 times a day for two days.
Then, depending on the response of the patient, the dose may be increased. It is recommended that the dose with its increase doubled with an interval of 1-3 days. Later, the total daily dose, which was initially divided into two doses, can be given once.
The maximum recommended dose is 10 mg.
Currently, the experience of treating patients with severe heart failure (III-IV functional class according to the NYHA classification), which arose immediately after an acute myocardial infarction, is insufficient. If such patients decide to administer ramipril, it is recommended that treatment should be started with the lowest possible dose - 1.25 mg 1 time per day and special care should be exercised at each dose increase.
The use of the drug ramipril in certain groups of patients
Patients with impaired renal function
When QA is from 50 to 20 ml / min per 1.73 m2 of body surface, the initial daily dose is usually 1.25 mg. The maximum permissible daily dose is 5 mg.
Patients with incompletely corrected fluid and electrolyte loss, patients with severe arterial hypertension, as well as patients for whom excessive blood pressure reduction presents a certain risk (for example, in severe atherosclerotic lesions of the coronary and cerebral arteries)
The initial dose is 1.25 mg per day.
Patients with prior diuretic therapy
It is necessary, if possible, to cancel diuretics in 2-3 days (depending on the duration of the diuretic action) before starting treatment with ramipril, or at least reduce the dose of diuretics taken. Treatment of such patients should begin with the lowest dose of 1.25 mg of ramipril, taken once a day, in the morning. After taking the first dose and each time after increasing the dose of ramipril and (or) "loopback" diuretics, patients should be under medical supervision for at least 8 hours to avoid an uncontrolled hypotensive reaction.
Elderly patients (over 65)
The initial dose is reduced to 1.25 mg per day.
Patients with impaired liver function
The response of blood pressure to taking the drug ramipril can either increase (by slowing the removal of ramiprilat) or decrease (by slowing down the conversion of low-active ramipril to active ramiprilat). Therefore, at the beginning of treatment requires careful medical observation. The maximum permissible daily dose is 2.5 mg.

Overdose

Symptoms: excessive peripheral vasodilation with the development of a pronounced decrease in blood pressure, shock; bradycardia, impaired water-electrolyte balance, shock, acute renal failure, stupor.
Treatment: in mild cases of overdose: gastric lavage, the introduction of adsorbents, sodium sulfate (preferably within the first 30 minutes after ingestion). The function of vital organs should be monitored. In more severe cases, measures aimed at stabilizing blood pressure: intravenous administration of a 0.9% sodium chloride solution, plasma substitutes, installation of a temporary artificial pacemaker for drug-resistant bradycardia, hemodialysis. With a marked decrease in blood pressure, the introduction of alpha-adrenergic agonists (norepinephrine, dopamine) can be added to the therapy to replenish the circulating blood volume and restore the water-electrolyte balance. In the case of bradycardia, atropine is recommended or prescribed