Pharmacological properties
Pharmacodynamics. Ramipril is a prodrug, after absorption it is metabolized in the liver to form ramiprilat. Ramiprilat is a potent long-acting ACE inhibitor. ACE catalyzes the conversion of angiotensin I into a vasoconstrictor substance - angiotensin II. ACE is an analogue of kininase - an enzyme that catalyzes the breakdown of bradykinin. Inhibition of ACE activity leads to a decrease in the concentration of angiotensin II in the blood plasma, an increase in the concentration of renin, an increase in the effect of bradykinin and a decrease in the secretion of aldosterone. The latter can lead to an increase in the level of potassium in the blood serum. In patients with AG, the hypotensive effect of ramipril and its effect on hemodynamics are due to the expansion of resistant vessels and a decrease in OPSS, which leads to a gradual decrease in HELL. Heart rate usually does not change. With prolonged treatment, the severity of left ventricular hypertrophy decreases without affecting heart function. The hypotensive effect appears 1-2 hours after taking a single dose, reaches a maximum within 3-6 hours and usually lasts for 24 hours.
Ramipril is also effective in the treatment of chronic heart failure. Its use in patients with clinical signs of chronic heart failure after myocardial infarction reduces the risk of sudden death, progression of heart failure to severe or refractory heart failure, and reduces the frequency of hospitalizations for heart failure.
According to published data, ramipril significantly reduces the incidence of myocardial infarction, stroke, and cardiovascular mortality in patients with an increased risk due to these diseases (e.g. active coronary artery disease, previous stroke, or peripheral vascular disease) or diabetes mellitus, in patients with at least one additional risk factor (microalbuminuria, hypertension, elevated total cholesterol, low HDL, smoking).
The drug also reduces overall mortality and the need for revascularization, and delays the onset and progression of chronic heart failure. Ramipril significantly reduces the likelihood of microalbuminuria and the risk of developing nephropathy in patients with diabetes mellitus, as well as other patients.
Pharmacokinetics. Ramipril is rapidly absorbed from the gastrointestinal tract. Absorption is 50-60% and is independent of food intake. C max in blood plasma is achieved within 1 hour after administration. T ½ of ramipril is 1 hour.
Ramipril is metabolized in the liver. The main metabolite is ramiprilat, which has 6 times greater ACE inhibitory activity than ramipril. In addition to ramiprilat, inactive metabolites (diketopiperazine ester and diketopiperazine acid, as well as compounds) have also been identified.
C max of ramiprilat in blood plasma is reached 2-4 hours after administration, the equilibrium concentration in blood plasma is reached after 4 days.
Approximately 73% of ramipril and 56% of ramiprilat bind to plasma proteins.
Ramipril and ramiprilat are mainly excreted in the urine (approximately 60%), mainly as metabolites, and 2% of the dose is excreted as unchanged ramipril.
Ramiprilat is eliminated in several phases. After taking ramipril in a therapeutic dose, the final T½ is 13-17 hours.
Animal studies have shown that this drug is excreted in breast milk. Studies in healthy volunteers aged 65 to 76 years have shown that the kinetics of ramipril and ramiprilat in this category are the same as in young healthy volunteers.
In patients with renal insufficiency, the elimination of ramipril, ramiprilat and their metabolites is slowed down, therefore the dose should be adjusted depending on renal function (see Method of administration).
In patients with hepatic insufficiency (possibly due to decreased hepatic esterase activity), the metabolic conversion of ramipril to ramiprilat may be slowed down and plasma ramipril concentrations may increase.
Indication
Treatment, including as part of complex therapy:
arterial hypertension;
congestive heart failure;
patients with clinical signs of chronic heart failure in the first few days after acute myocardial infarction;
diabetic or non-diabetic nephropathy.
Reducing the risk of myocardial infarction, stroke and cardiovascular mortality in patients at high risk of cardiovascular disease, including coronary heart disease (regardless of history of myocardial infarction), stroke and peripheral arterial disease.
Application
The dosage and duration of treatment depend on the patient's condition, needs, and possible use of other medications, and are therefore determined individually.
Treatment of hypertension. The recommended initial dose of ramipril for patients not taking diuretics and who do not have heart failure is 2.5 mg once daily. Depending on the appropriate response to treatment, the dose may be increased by 2 times every 2-3 weeks. The usual maintenance dose is 2.5-5 mg/day, and the maximum daily dose is 10 mg.
The initial dose of ramipril for patients with hypertension who were taking a diuretic before starting treatment, as well as for patients with arterial hypertension and heart failure with or without renal impairment, is 1.25 mg once a day. Treatment is started in a hospital under close medical supervision.
Treatment of congestive heart failure. The recommended initial dose of ramipril for stable patients receiving diuretics is 1.25 mg once daily. Depending on the appropriate response to treatment, the dose may be increased by 2 times every 1-2 weeks. If the required dose is 2.5 mg of ramipril and above, it can be taken once or divided into 2 doses. The maximum daily dose is 10 mg.
If the patient is taking a diuretic in high doses, the dose should be reduced before starting treatment with ramipril.
Treatment after myocardial infarction. Ramipril treatment can only be started in a hospital setting between the 3rd and 10th day after the infarction. The recommended initial dose of ramipril is 2.5 mg twice daily (morning and evening); after 2 days the dose is increased to 5 mg twice daily (morning and evening). The usual maintenance dose of ramipril is 2.5-5 mg twice daily.
If the patient does not tolerate this initial dose well (e.g. hypotension occurs), it should be reduced to 1.25 mg twice daily. After 2 days, this dose can be increased again to 2.5 mg twice daily, and every 1-3 days the dose can be increased to 5 mg twice daily. The maximum daily dose is 10 mg.
If the patient does not tolerate an increase in dose to 2.5 mg twice daily, ramipril treatment should be discontinued.
There is limited experience in patients with severe (NYHA class IV) heart failure immediately after myocardial infarction. If, despite this, it is decided to treat such patients with this drug, it is recommended to start therapy with the lowest effective daily dose (1.25 mg ramipril once daily) and any increase should be carried out with extreme caution.
Treatment of diabetic or non-diabetic nephropathy. The recommended initial dose is 1.25 mg once daily. This dose should be increased to 5 mg once daily every 2-3 weeks depending on tolerability. The maximum daily dose is 5 mg once daily.
Reduction of the risk of myocardial infarction, stroke and cardiovascular mortality. The recommended initial dose is 1.25 mg 1 time per day. Depending on the appropriate response to treatment, the dose should be gradually increased. It is recommended to increase the dose by 2 times during the first week of treatment and after another 2-3 weeks to increase it to the usual maintenance dose - 10 mg 1 time per day.
Doses above 20 mg ramipril once daily have not been adequately studied in controlled clinical trials.
Dosage in renal impairment. In patients with creatinine clearance ≥5 ml/s (30 ml/min), no dose adjustment is required. In patients with creatinine clearance ≥5 ml/s (30 ml/min), the initial dose should be 1.25 mg, and the maximum daily dose should be 5 mg.
Dosage in hepatic impairment. The initial dose of ramipril is 1.25 mg once daily, and the maximum daily dose is 2.5 mg.
Particularly careful monitoring is necessary in elderly patients (over 65 years of age), patients taking diuretics, patients with heart failure and impaired renal or hepatic function. The dose of ramipril should be adjusted according to the desired reduction in blood pressure. The recommended initial dose is 1.25 mg of ramipril 1 time per day. The tablet should be swallowed whole with sufficient liquid (approximately 1/2 glass). The tablets should not be chewed or crushed. The tablets can be taken before, during or after meals.
Contraindication
Hypersensitivity to ramipril or any other component of the drug, as well as to other ACE inhibitors, components of the drug, history of angioedema, renal artery stenosis (bilateral or stenosis of the artery to a solitary kidney), arterial hypotension or hemodynamically unstable conditions, primary hyperaldosteronism.
The use of Ampril or other ACE inhibitors in combination with extracorporeal therapy methods that may cause blood to come into contact with negatively charged surfaces should be avoided, as there is a risk of developing a severe anaphylactoid reaction, which can sometimes lead to severe anaphylactic shock.
Thus, when taking Ampril, dialysis or hemofiltration procedures using poly (acrylonitrile, sodium-2-methylsulfonate) membranes with high ultrafiltration activity (for example, AN69) and low-density lipoprotein apheresis procedures using dextrasulfate cannot be performed.
Side effects
Nervous system: headache, balance disorder, weakness, drowsiness, dizziness or slowed reaction, fatigue, irritability, depression, depressed mood, tremor, restlessness, sleep disturbances, confusion, feeling of anxiety, fainting, paresthesia.
On the part of the organ of vision: visual impairment.
On the part of the organ of hearing: tinnitus, hearing impairment.
On the part of the urinary system: increased levels of urea and creatinine in the blood serum (the likelihood increases with the additional use of diuretics), deterioration of renal function, increased serum potassium concentration, decreased sodium level, as well as increased pre-existing proteinuria (despite the fact that ACE inhibitors usually reduce proteinuria) or increased urine output (due to improved cardiac function). In isolated cases, renal dysfunction may progress.
Respiratory: dry (non-productive) tickling cough (cough often worsens at night and during rest (e.g. lying down) and occurs more often in women and non-smokers), nasal congestion, sinusitis, bronchitis, bronchospasm and dyspnea.
On the part of the immune system, skin and subcutaneous tissue: angioedema (angioedema caused by ACE inhibitors occurs more often in patients of the Negroid race than in patients of other races), severe anaphylactic or anaphylactoid reactions, rash, itching, urticaria, maculopapular rashes, pemphigoid, exacerbation of psoriasis, psoriasiform, pemphigoid or lichenoid rash and enanthema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, alopecia, onycholysis or photosensitivity.
The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom are increased by ACE inhibition. It is believed that this effect may also be observed with respect to other allergens.
On the part of the digestive tract and liver: nausea, increased serum levels of liver enzymes and / or bilirubin, cholestatic jaundice, dry mouth, glossitis, inflammatory reactions in the oral cavity and digestive tract, feeling of discomfort in the abdominal cavity, stomach pain (including pain similar to that of gastritis), indigestion, dyspepsia, constipation, diarrhea, vomiting and increased pancreatic enzymes, pancreatitis, liver damage (including acute liver failure), hepatitis, intestinal obstruction.
Blood and lymphatic system disorders: Decreased red blood cell and haemoglobin count, leukocyte and platelet counts, agranulocytosis, pancytopenia and bone marrow depression. Possible signs of agranulocytosis include fever, lymph node enlargement and sore throat. Signs of bleeding tendency due to thrombocytopenia may include petechiae, purpura or difficult-to-control bleeding from the gums.
Hematological reactions to ACE inhibitors are more likely to occur in patients with impaired renal function and in patients with concomitant collagen disease (e.g. systemic lupus erythematosus or scleroderma), or in those taking other drugs that can cause changes in the blood composition. In isolated cases, hemolytic anemia may develop.
Other effects: conjunctivitis, muscle spasms, decreased libido, loss of appetite, impaired sense of smell and taste (e.g. metallic taste in the mouth) or partial, sometimes complete loss of taste, increased fatigue, temporary erectile dysfunction, increased sweating. In isolated cases, vasculitis, myalgia, arthralgia, fever, fever and eosinophilia, as well as increased titers of antinuclear antibodies are observed.
Special instructions
Angioedema. Angioedema of the face, extremities, lips, tongue, glottis or pharynx has been reported in patients treated with ACE inhibitors. If angioedema occurs, ramipril treatment should be discontinued immediately. Emergency treatment of life-threatening angioedema involves immediate administration of adrenaline (s.c. or slow i.v.), simultaneously with ECG and PHE monitoring. Hospitalization is recommended, the patient should be observed for at least 12-24 hours, and discharge should be considered only after the symptoms have completely resolved. Angioedema of the intestine has been reported in patients treated with ACE inhibitors. These patients complained of abdominal pain (with or without nausea or vomiting).
Caution: Renal function should be monitored at the beginning of treatment. Renal function should be monitored during treatment, especially in patients with impaired renal function, heart failure, bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, and in patients who have undergone kidney transplantation.
Similar reactions have been observed during treatment with low-density lipoprotein apheresis with dextran sulfate, therefore this method of treatment is not recommended for patients taking ACE inhibitors. During treatment with ramipril, an increase in the concentration of urea and creatinine in the blood serum may also occur in patients with normal renal function, especially if they are taking diuretics at the same time. In such cases, treatment can be continued with a lower dose of ramipril or the drug can be discontinued. In patients with impaired renal function, the risk of developing hyperkalemia is increased. In patients with impaired hepatic function, the metabolism of ramipril and the formation of the active metabolite may be slowed down due to a decrease in the activity of hepatic esterases. Therefore, treatment of such patients should be started only under close medical supervision. After the start of ramipril in patients with uncomplicated hypertension, symptomatic hypotension may sometimes develop.
Patients with an activated renin-angiotensin system. Particular caution should be exercised when treating patients with an activated renin-angiotensin system. Such patients are at risk of an unexpected and pronounced decrease in blood pressure and deterioration of renal function as a result of ACE inhibition, especially when an ACE inhibitor or concomitant diuretic is administered for the first time or at a higher dose. Blood pressure should be monitored closely at the start of treatment or when the dose is increased, as long as there is a risk of a sharp decrease. Increased renin-angiotensin system activity can be expected, in particular:
in patients with severe, and especially malignant hypertension. Special medical supervision is required in the initial phase of treatment; in patients with heart failure, especially severe or treated with other drugs that lower blood pressure. In the case of severe heart failure, special medical supervision is required in the initial phase of treatment; in patients with hemodynamically significant disorders of the inflow or outflow of blood from the left ventricle (for example, due to aortic stenosis or mitral valve stenosis or hypertrophic cardiomyopathy). Special medical supervision is required in the initial phase of treatment; in patients with hemodynamically significant renal artery stenosis. Special medical supervision is required in the initial phase of treatment. It may be necessary to stop the initiated diuretic treatment; in patients who have previously taken diuretics. If discontinuation or reduction of the diuretic dose is not possible, special medical supervision is required in the initial phase of treatment; in patients who are or may become fluid or salt depleted as a result of inadequate fluid or salt intake or, for example, due to diarrhoea, vomiting or excessive sweating, in cases where compensation for fluid and salt depletion is inadequate. Correction of dehydration, hypovolaemia or salt depletion is generally recommended before treatment is initiated (however, in patients with heart failure, such corrective measures should be carefully assessed in terms of the possible risk of volume overload). In clinically significant conditions, treatment with Ampril should only be initiated or continued if appropriate measures are taken to prevent excessive reduction in blood pressure and deterioration of renal function.
Patients with liver disease. In patients with impaired liver function, the severity of the response to treatment with Ampril may be either increased or decreased. In addition, in patients with severe cirrhosis of the liver with edema and / or ascites, the activity of the renin-angiotensin system may be significantly increased; therefore, special caution should be observed when treating these patients.
Patients with a significant decrease in blood pressure are at particular risk. Patients for whom a significant decrease in blood pressure poses a particular risk (e.g. patients with hemodynamically significant stenosis of the coronary arteries or vessels supplying the brain) require special medical supervision during the initial phase of treatment.
Elderly: Elderly patients may respond more to ACE inhibitors. Assessment of renal function is recommended at the start of treatment.
Monitoring of renal function: It is recommended to monitor renal function, especially during the first weeks of treatment with an ACE inhibitor. Particularly careful monitoring is necessary in patients with:
heart failure; vasorenal disease, including patients with hemodynamically significant unilateral renal artery stenosis. In the latter group of patients, even a slight increase in serum creatinine may indicate unilateral deterioration of renal function; deterioration of renal function; transplanted kidney.
Hematological monitoring. It is recommended to monitor the white blood cell count for the early detection of possible leukopenia. More frequent monitoring is recommended in the initial phase of treatment in patients with impaired renal function, with concomitant collagen disease (e.g. systemic lupus erythematosus or scleroderma) or those treated with other drugs that may cause changes in the blood picture.
Use during pregnancy and breastfeeding. The use of ACE inhibitors is contraindicated during pregnancy. If pregnancy is confirmed, treatment with Ampril should be stopped immediately and an alternative therapeutic agent should be used as soon as possible.
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy is inconclusive; however, a small increased risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, ACE inhibitor treatment should be stopped immediately, and, if possible, alternative therapy should be started. The use of ACE inhibitors during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).
If the use of ACE inhibitors is necessary in the second trimester of pregnancy, it is recommended to perform an ultrasound scan of the fetal kidney function and the fetal skull. Infants whose mothers took ACE inhibitors should be carefully examined for arterial hypotension.
Animal studies have shown that ramipril passes into breast milk. Since it is not known whether ramipril passes into human breast milk, the use of the drug is contraindicated during breastfeeding.
Children. The use of ramipril in children has not been studied, therefore the drug is not recommended for use in the treatment of children.
Ability to influence the speed of reactions when driving or operating other mechanisms. Some side effects (certain symptoms of low blood pressure, such as dizziness or vertigo) may affect the ability to drive or operate other mechanisms. Patients are advised to avoid such activities until their individual response to treatment with the drug is determined.
Interactions
The concomitant use of ramipril and other antihypertensive agents (e.g. diuretics) or other drugs that lower blood pressure (e.g. nitrates, tricyclic antidepressants, anesthetics) may increase the hypotensive effect of ramipril. Serum sodium levels should be monitored in patients taking diuretics.
Concomitant use of ramipril and potassium supplements or potassium-sparing diuretics may lead to hyperkalemia. Therefore, when using these drugs simultaneously, it is necessary to regularly monitor the level of potassium in the blood serum.
Vasopressor sympathomimetics (e.g. adrenaline, noradrenaline) may reduce the hypotensive effect of ramipril, therefore, when these drugs are used simultaneously, it is necessary to monitor blood pressure more frequently.
The simultaneous administration of ramipril and allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics or other drugs capable of changing blood parameters increases the likelihood of changes in these parameters.
Other ACE inhibitors may reduce the excretion of lithium and thereby lead to an increase in its plasma level with the risk of toxic effects. Therefore, when lithium preparations and ramipril are used simultaneously, it is necessary to monitor the level of lithium in the blood plasma.
ACE inhibitors may enhance the effect of antidiabetic agents (e.g. insulin or sulfonylureas), which may in some cases lead to the development of hypoglycemia. Therefore, at the beginning of such combination therapy, it is necessary to monitor blood glucose levels especially closely.
The simultaneous use of ramipril and some non-steroidal anti-inflammatory drugs (e.g. acetylsalicylic acid or indomethacin) may reduce the hypotensive effect of ramipril. In addition, the simultaneous use of these drugs may cause the development of hyperkalemia and increase the risk of renal dysfunction.
Concomitant administration of ramipril and heparin may cause hyperkalemia.
Overdose
If hypotension occurs, the patient should be placed in a horizontal position with the lower extremities slightly elevated. If necessary, it is recommended to increase the blood plasma volume by infusion of 0.9% sodium chloride solution. In case of significant overdose, gastric lavage is recommended, adsorbents and sodium sulfate are administered (in the first 30 minutes, when possible). It is necessary to carefully monitor blood pressure, renal function and the level of potassium in the blood plasma. In case of hypotension, in addition to volume and electrolyte compensation, an α 1 -adrenergic receptor agonist (for example, noradrenaline, dopamine) and angiotensin II (angiotensinamide) can be administered. The effectiveness of dialysis in the treatment of intoxication has not been proven.
Storage conditions
In the original packaging to protect from moisture, at a temperature not exceeding 25 °C.
