Ramipril

Pharmacological properties

ramipril refers to prodrugs, after absorption it is metabolized in the liver with the formation of ramiprilat. ramiprilat is a potent inhibitor of APF with a long-lasting effect. APF catalyzes the conversion of angiotensin i to a vasoconstrictor, angiotensin ii. APF is an analogue of kininase, an enzyme that catalyzes the breakdown of bradykinin. inhibition of apf 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 cause an increase in serum potassium levels. 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, leading to a gradual decrease in hell. heart rate usually does not change. with prolonged treatment, there is a decrease in the severity of left ventricular hypertrophy without affecting heart function. the hypotensive effect is manifested 1–2 hours after 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, the progression of heart failure to severe or resistant to therapy, and reduces the frequency of hospitalizations for heart failure.

According to published data, ramipril significantly reduces the incidence of myocardial infarction, stroke, and mortality from cardiovascular diseases in patients at increased risk for these diseases (for example, active stage of coronary heart disease, stroke, or peripheral vascular disease) or diabetes mellitus, in patients with at least with one additional risk factor (microalbuminuria, hypertension, increased overall cholesterol, low HDL, smoking).

The drug also reduces overall mortality and the need for revascularization, and also delays the onset and progression of chronic heart failure. Ramipril significantly reduces the likelihood of microalbuminuria and the risk of nephropathy in patients with diabetes mellitus, as well as other patients.

Pharmacokinetics Ramipril is rapidly absorbed in the digestive tract. Absorption is 50-60% and does not depend on food intake. C_max in blood plasma is achieved within 1 h after administration. T_½ ramipril is 1 hour.

Ramipril is metabolized in the liver. The main metabolite is ramiprilat, whose activity as an ACE inhibitor is 6 times higher compared to ramipril. In addition to ramiprilat, inactive metabolites (diketopiperazine ether and diketopiperazinic acid, as well as compounds) were also detected.

C_max ramiprilat in blood plasma is reached after 2–4 hours after administration, the equilibrium concentration in 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 in the form of metabolites, and 2% of the dose taken is excreted as unchanged ramipril.

Excretion of ramiprilat has several phases. After taking ramipril in a therapeutic dose, the final T_½ is 13-17 hours

Animal studies have shown that this drug passes into breast milk. Studies involving healthy volunteers aged 65 to 76 years have shown that the kinetics of ramipril and ramiprilat in this category are the same as among young healthy volunteers.

In patients with renal insufficiency, the elimination of ramipril, ramiprilat, and their metabolites is slowed down, so the dose must be corrected depending on the function of the kidneys (see APPLICATION).

In patients with hepatic insufficiency (possibly due to a decrease in the activity of hepatic esterases), the metabolic conversion of ramipril to ramiprilat may slow down, and the concentration of ramipril in the blood plasma may increase.

Indications

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 nondiabetic nephropathy.

Reducing the risk of myocardial infarction, stroke and cardiovascular mortality in patients with a high risk of cardiovascular disease, including coronary heart disease (regardless of a history of myocardial infarction), stroke and peripheral artery disease.

Application

Dosage and duration of treatment depend on the condition of the patient, the needs and possible use of other drugs, therefore, determined individually.

Hypertension treatment. The recommended starting dose of ramipril for patients who do not take diuretics and who do not have heart failure is 2.5 mg once a day. Depending on the corresponding response to treatment, the dose can 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.

If the patient takes a diuretic, it is necessary, if possible, to cancel or at least reduce the dose at least 2-3 days before treatment with ramipril.

The initial dose of ramipril for patients with hypertension who took a diuretic before treatment, as well as for patients with hypertension and heart failure with impaired renal function, is 1.25 mg once a day. Treatment begins in a hospital under close medical supervision.

Treatment of congestive heart failure. The recommended starting dose of ramipril for patients with stable condition taking diuretics is 1.25 mg once daily. Depending on the corresponding response to treatment, the dose can be increased by 2 times every 1-2 weeks. If the required dose is 2.5 mg of ramipril and higher, it can be taken once or divided into 2 doses. The maximum daily dose is 10 mg.

If the patient takes a diuretic in a high dose, it is necessary to reduce the dose before treatment with ramipril.

Treatment after myocardial infarction. Ramipril treatment can only be started in a hospital between the 3rd and 10th day after a heart attack. The recommended initial dose of ramipril is 2.5 mg 2 times a day (morning and evening); after 2 days, the dose is increased to 5 mg 2 times a day (morning and evening). The usual maintenance dose of ramipril is 2.5–5 mg 2 times a day.

If the patient does not tolerate this initial dose (for example, arterial hypotension occurs), it must be reduced to 1.25 mg 2 times a day. After 2 days, this dose can again be increased to 2.5 mg 2 times a day, and every 1-3 days you can increase the dose to 5 mg 2 times a day. The maximum daily dose is 10 mg.

If the patient does not tolerate increasing the dose to 2.5 mg 2 times a day, treatment with ramipril must be discontinued.

Experience in treating patients with severe (grade IV NYHA classification) heart failure immediately after myocardial infarction is not enough. If, despite this, it is decided to treat such patients with this medicine, it is recommended to start therapy with the lowest effective daily dose (1.25 mg of ramipril once a day) and any increase should be carried out with extreme caution.

Treatment of diabetic or non-diabetic nephropathy. The recommended starting dose is 1.25 mg once daily. This dose must be increased to 5 mg once a day every 2-3 weeks, depending on the tolerance of the drug.The maximum daily dose is 5 mg 1 time per day.

Reduce the risk of myocardial infarction, stroke, and cardiovascular mortality. The recommended starting dose is 1.25 mg once daily. 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 once a day.

In controlled clinical trials, the use of a dose of more than 20 mg of ramipril once a day has not been studied enough.

Dosage for impaired renal function. In patients with creatinine clearance of 0.5 ml / s (30 ml / min) dose adjustment is not required. In patients with creatinine clearance of 0.5 ml / s (30 ml / min), the initial dose should be 1.25 mg, and the maximum daily dose should be 5 mg.

Dosage for impaired liver function. The initial dose of ramipril is 1.25 mg once a day, and the maximum daily dose is 2.5 mg.

Particularly careful monitoring is necessary in elderly patients (over 65 years old), patients who take 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 once a day. The tablet must be swallowed whole with a sufficient amount of liquid (approximately ¹/₂ cups). Tablets should not be chewed or crushed. Tablets can be taken before, during or after a meal.

Contraindications

Hypersensitivity to ramipril or any other component of the drug, as well as to other APF inhibitors, drug components, history of angioedema, renal artery stenosis (bilateral or artery stenosis of a single kidney), hypotension or hemodynamically unstable conditions, primary hyperaldosteronism.

Avoid the use of Ampril or other ACE inhibitors in combination with extracorporeal therapy methods, which can cause blood contact with negatively charged surfaces, since there is a risk of developing a severe anaphylactoid reaction, which can sometimes lead to severe anaphylactic shock.

Thus, when taking Ampril, it is impossible to carry out the dialysis or hemofiltration procedure using poly (acrylonitrile, sodium-2-methylsulfonate) membranes with high ultrafiltration activity (for example AN69) and the LDL apheresis procedure using dextran sulfate.

Side effects

From the side of the cardiovascular system: tachycardia, peripheral edema, flushing of the face, palpitations, orthostatic regulation, angina pectoris, cardiac arrhythmias, severe hypotension, myocardial or cerebral ischemia, myocardial infarction, short-term ischemic attack, ischemic stroke, obesity circulatory disorders caused by vascular stenosis, acceleration or intensification of manifestations of the Raynaud phenomenon.

From the side of the nervous system: headache, imbalance, weakness, drowsiness, dizziness or slowing down of the reaction, fatigue, irritability, depression, depressed mood, tremor, anxiety, sleep disturbances, confusion, anxiety, fainting, paresthesia.

From the side of the organ of vision: visual impairment.

On the part of the hearing organ: ringing in the ears, hearing impairment.

From the urinary system: increased serum urea and creatinine (the probability increases with the additional use of diuretics), impaired renal function, increased serum potassium, decreased sodium levels, as well as increased existing proteinuria (despite the fact that ACE inhibitors usually proteinuria is reduced) or an increase in the amount of urine (due to improved cardiac activity). In isolated cases, impaired renal function can progress.

From the respiratory system: dry (unproductive) tickling cough (cough often worsens at night and during rest (for example, when lying down) and more often occurs in women and people who do not smoke), nasal congestion, sinusitis, bronchitis, bronchospasm and dyspnea .

On the part of the immune system, skin and subcutaneous tissue: angioedema (angioedema caused by ACE inhibitors, more often occurs in patients of the Negroid race compared with patients of other races), severe anaphylactic or anaphylactoid reactions, rash, itching, urticaria, maculopapular rash , exacerbation of psoriasis, psoriasiform, pemphigoid or lichenoid exanthema and enanthem, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, alopecia, onycholysis or photosensitivity.

The likelihood of occurrence and severity of anaphylactic and anphylactoid reactions to insect venom during inhibition of ACE increases. It is believed that such an effect can be observed with respect to other allergens.

From the digestive tract and hepatobiliary system: nausea, increased serum levels of liver and / or bilirubin enzymes, cholestatic jaundice, dry mouth, glossitis, inflammatory reactions in the oral cavity and digestive tract, discomfort in the abdominal cavity, pain in the stomach (including pain similar to gastritis), digestive disorders, dyspepsia, constipation, diarrhea, vomiting and increased pancreatic enzymes, pancreatitis, liver damage (including acute liver failure), hepatitis, ki echnaya obstruction.

On the part of the blood and lymphatic system: a decrease in the number of red blood cells and hemoglobin, the number of leukocytes and platelets, agranulocytosis, pancytopenia and inhibition of bone marrow function. Possible signs of agranulocytosis are fever, swollen lymph nodes, and inflammation of the pharynx. Signs of a tendency to bleeding due to thrombocytopenia can be petechiae, as well as purpura or bleeding from the gums, which is difficult to stop.

Hematologic reactions to ACE inhibitors are more likely to occur in patients with impaired renal function and in patients with concomitant collagenosis (for example, systemic lupus erythematosus or scleroderma), or those who use other drugs that can cause changes in the composition of the blood. In isolated cases, hemolytic anemia may develop.

Other effects: conjunctivitis, muscle cramps, decreased libido, loss of appetite, impaired smell and taste (for example, a metallic aftertaste 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

Angioneurotic edema. In patients treated with APF inhibitors, cases of angioedema of the face, limbs, lips, tongue, glottis or pharynx were observed. in case of angioedema, treatment with ramipril should be stopped immediately. emergency treatment of life-threatening angioneurotic edema involves the immediate administration of epinephrine (sc or slowly in / in), simultaneously with the control of ecg and hell. hospitalization, observation of the patient for at least 12-24 hours is recommended, and it can only be prescribed after the symptoms have completely disappeared. In patients treated with APF inhibitors, cases of angioedema of the intestine were observed. these patients complained of abdominal pain (with or without nausea or vomiting).

Warning. At the beginning of treatment, it is necessary to monitor renal function.Monitoring of renal function is necessary during treatment, especially in patients with impaired renal functional activity, heart failure, bilateral renal artery stenosis or stenosis of a single kidney artery, as well as in patients who underwent kidney transplantation.

The risk of hypersensitivity reactions, allergic (anaphylactic) reactions increases in patients who undergo hemodialysis with polyacrylonitrile membranes along with treatment with ACE inhibitors. If hemodialysis is necessary, the patient should first be transferred to a drug from another group, which is indicated for this nosology, or it is necessary to use a different type of membrane in the dialyzer.

Similar reactions were observed during treatment with apheresis of LDL with dextran sulfate, therefore this treatment method is not recommended for patients who take ACE inhibitors. During treatment with ramipril, an increase in the concentration of urea and creatinine in the blood serum can also occur in patients with normal renal function, especially if they simultaneously take diuretics. In this case, treatment can be continued with the introduction of a lower dose of ramipril or stop using this drug. In patients with impaired renal function, the risk of developing hyperkalemia is increased. In patients with impaired liver function, ramipril metabolism and the formation of an active metabolite may slow down due to a decrease in the activity of hepatic esterases. Therefore, treatment of such patients can only begin under close medical supervision. After starting ramipril, patients with uncomplicated hypertension can sometimes develop symptomatic hypotension.

Patients with increased activity of the renin-angiotensin system. In the treatment of patients in whom the activity of the renin-angiotensin system is increased, special care should be taken. Such patients have a risk of unexpected and marked decrease in blood pressure and impaired renal function as a result of ACE inhibition, especially when an ACE inhibitor or concomitant diuretic is prescribed for the first or first time in a higher dose. At the beginning of the use of the drug or with an increase in the dose, careful monitoring of blood pressure should be carried out until there is a risk of a sharp decrease in it. The increased activity of the renin-angiotensin system can be expected, in particular:

• in patients with severe, and especially malignant hypertension. In the initial phase of treatment, special medical monitoring is needed;
• in patients with heart failure, especially severe or one that has been treated with other drugs that can lower blood pressure. In case of severe heart failure in the initial phase of treatment, special medical supervision is necessary;
• in patients with hemodynamically significant impairment of blood flow or outflow from the left ventricle (for example, due to aortic stenosis or mitral valve stenosis or hypertrophic cardiomyopathy). In the initial phase of treatment, special medical supervision is necessary;
• in patients with hemodynamically significant renal artery stenosis. In the initial phase of treatment, special medical supervision is necessary. It may be necessary to stop the started treatment with diuretics;
• in patients who previously took diuretics. If discontinuation or dose reduction of the diuretic is not possible, special medical supervision is necessary at the initial phase of treatment;
• in patients who have or may develop a lack of fluid or salt as a result of unsatisfactory intake of fluid or salt, or, for example, due to diarrhea, vomiting or excessive sweating, in cases where compensation for a lack of fluid and salt is insufficient.In general, correction of dehydration, hypovolemia, or salt deficiency conditions before treatment is recommended (however, for patients with heart failure, such corrective measures should be carefully evaluated in terms of the possible risk of volume overload). In clinically significant conditions, Ampril treatment can be started or continued only when appropriate measures are taken to prevent an excessive decrease in blood pressure and impaired renal function.

Patients with liver disease. In patients with impaired liver function, the severity of the response to Ampril treatment can either be 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 can be significantly increased; therefore, special care must be taken during the treatment of these patients.

Patients with a significant decrease in blood pressure are at particular risk. Patients for whom a significant decrease in blood pressure presents a particular risk (for example, patients with hemodynamically significant stenosis of the coronary arteries or vessels supplying the brain with blood), special medical control is necessary at the initial phase of treatment.

The elderly. In the elderly, the reaction to ACE inhibitors may be more pronounced. At the beginning of their treatment, an assessment of renal function is recommended.

Monitoring kidney function. It is recommended to monitor renal function, especially in the first weeks of treatment with an ACE inhibitor. Particularly careful monitoring is necessary for 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 levels may indicate a unilateral deterioration in renal function;
• impaired renal function;
• transplanted kidney.

Monitoring electrolyte balance. It is recommended that regular monitoring of the concentration of potassium in the blood serum be carried out. More frequent monitoring of serum potassium levels is necessary in patients with impaired renal function.

Hematologic monitoring. It is recommended to monitor the number of white blood cells in order to timely detect possible leukopenia. More frequent monitoring is recommended at the initial phase of treatment in patients with impaired renal function, with concomitant collagen disease (for example, systemic lupus erythematosus or scleroderma) or those treated with other drugs that may cause changes in the blood picture.

Use during pregnancy and lactation. The use of ACE inhibitors is contraindicated during pregnancy. In the event that pregnancy is confirmed, Ampril treatment should be stopped immediately and switch to an alternative therapeutic agent as soon as possible.

The epidemiological findings regarding the risk of teratogenicity after the influence of ACE inhibitors during the first trimester of pregnancy are mixed; however, a slight increase in risk cannot be ruled out. If continued therapy with ACE inhibitors is not considered important, patients planning a pregnancy should be switched to alternative antihypertensive treatment, which has an approved safety profile for use during pregnancy. If pregnancy is established, treatment with ACE inhibitors should be stopped immediately and, if possible, alternative therapy should be started. It is known that the use of ACE inhibitors during the second and third trimester of pregnancy can lead to the development of fetotoxicity (decreased renal function, oligohydramnios, slowed ossification of the skull) and neonatal toxicity (renal failure, hypotension, hyperkalemia).

If it is necessary to use ACE inhibitors in the second trimester of pregnancy, it is recommended to perform an ultrasound of the kidney function of the embryo and the skull of the embryo. Infants whose mothers have taken 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 lactation.

Children. The use of ramipril in children has not been studied, therefore, the drug is not recommended for use in the treatment of children.

The ability to influence the reaction rate when driving vehicles and working with other mechanisms. Some side effects (certain symptoms of a decrease in blood pressure, such as dizziness or vertigo) may affect the ability to drive vehicles or work with other mechanisms. Patients are advised to avoid such activities until an individual response to treatment with the drug is clarified.

Interactions

With the simultaneous use of ramipril and other antihypertensive agents (e.g. diuretics) or other drugs that reduce hell (e.g. nitrates, tricyclic antidepressants, anesthetics), the antihypertensive effect of ramipril may be enhanced. in patients taking diuretics, it is necessary to control the level of sodium in the blood serum.

The simultaneous use of ramipril and potassium preparations or potassium-sparing diuretics can cause hyperkalemia. Therefore, with the simultaneous use of these drugs, it is necessary to regularly monitor the level of potassium in the blood serum.

Vasopressor sympathomimetics (e.g. epinephrine, norepinephrine) can reduce the antihypertensive effect of ramipril, therefore, with the simultaneous use of these drugs, it is necessary to control the level of blood pressure more often.

The simultaneous administration of ramipril and allopurinol, immunosuppressants, GCS, procainamide, cytostatics or other drugs that can change blood counts increases the likelihood of changes in these parameters.

Other ACE inhibitors can reduce the release of lithium and thereby cause an increase in its level in blood plasma with a risk of toxic effects. Therefore, with the simultaneous use of lithium and ramipril preparations, it is required to control the level of lithium in the blood plasma.

ACE inhibitors can enhance the effect of antidiabetic drugs (for example, insulin or sulfonylurea derivatives), which in some cases can lead to the development of hypoglycemia. Therefore, at the beginning of such combination therapy, it is necessary to strictly control the level of glucose in the blood.

The simultaneous use of ramipril and some NSAIDs (for example, acetylsalicylic acid or indomethacin) can reduce the hypotensive effect of ramipril. In addition, the simultaneous use of these drugs can cause the development of hyperkalemia and increase the risk of impaired renal function.

The combined introduction of ramipril and heparin can cause hyperkalemia.

Overdose

An overdose can cause excessive peripheral vasodilation (which is accompanied by severe arterial hypotension, shock), bradycardia, electrolyte imbalance and renal failure.

When hypotension occurs, the patient must be moved to a horizontal position with slightly raised lower limbs. If necessary, it is recommended to increase the volume of blood plasma by infusion of 0.9% sodium chloride solution. In case of a significant overdose, it is recommended to wash the stomach, inject adsorbents and sodium sulfate (in the first 30 minutes, if possible). It is necessary to carefully monitor blood pressure, kidney function and potassium levels in blood plasma. In case of hypotension, in addition to volume compensation and electrolytes, an α agonist can be introduced₁-adrenergic receptors (e.g. norepinephrine, dopamine) and angiotensin II (angiotensinamide). The effectiveness of dialysis in the treatment of intoxication has not been proven.

Storage conditions

In the original packaging to protect against moisture, at a temperature not exceeding 25 ° C.