2010/06/07

TRITACE

Pharmacological action

Antihypertensive drugs, ACE inhibitor. Ramiprilat, the active metabolite of ramipril, an ACE inhibitor long-acting. In the blood plasma and tissues, this enzyme catalyzes the transfer of angiotensin I to angiotensin II (vasoconstrictor active substance) and the splitting of the active vasodilator bradykinin. Reduced formation of angiotensin II and increasing bradykinin activity leads to expansion of blood vessels and contributes to the cardioprotective effect of ramipril and endotelioprotektivnoe.

Angiotensin II stimulates the release of aldosterone, in connection with the ramipril causes decreased secretion of aldosterone.

Receiving ramipril leads to a significant reduction TPVR generally not causing changes in renal blood flow and glomerular filtration rate. Acceptance of ramipril causes a decrease in blood pressure in the supine position and standing, without compensatory increases in heart rate. The hypotensive effect starts within 1-2 h after single oral dose and persists for 24 h. The maximal antihypertensive effect Tritatse usually develops in 3-4 weeks of continued administration of the drug and maintained for a long time. The sudden cessation of drug administration does not lead to a rapid and significant increase in blood pressure.

Use of the drug reduces mortality (including sudden death), the risk of development of cardiac failure, reduces the number of hospitalizations of patients with clinical signs of chronic heart failure after acute myocardial infarction.

In patients with diabetic and nondiabetic nephropathy, clinically manifested drug reduces the rate of progression of renal failure, and at the preclinical stage of diabetic and nondiabetic nephropathy, ramipril reduces albuminuria.

The preparation is a favorable effect on carbohydrate metabolism and lipid profile, causes a significant reduction in myocardial hypertrophy and vascular wall.


Pharmacokinetics

Absorption

After ingestion is rapidly absorbed from the gastrointestinal tract (50-60%). Food does not affect the completeness of absorption, but slows down absorption.

C max and ramipril ramiprilata achieved in plasma after 1 and 3 h respectively.

Distribution and metabolism

As a prodrug, ramipril is under intense presistemnomu metabolism (mainly in the liver by hydrolysis), resulting in the formation of its only active metabolite - ramiprilat. In addition to the formation of this active metabolite, at glyukuronirovanii ramipril and ramiprilata form inactive metabolites - Ramipril and ramiprilat diketopiperazin diketopiperazin. Ramiprilat about 6 times more actively inhibits ACE than ramipril.

Linking ramipril with blood plasma proteins is 73%, ramiprilata - 56%.

V d ramipril and ramiprilata is approximately 90 liters and 500 liters.

After daily, once a day administration of the drug at a dose of 5 mg C ss in plasma is achieved by 4 day. Reduced plasma concentration ramiprilata occurs in several stages: the initial phase of distribution and excretion of T 1 / 2 ramiprilata approximately 3 h, then the intermediate phase with a period T 1 / 2 ramiprilata approximately 15 h and the final phase with very low concentrations ramiprilata in plasma and T 1 / 2 ramiprilata approximately 4-5 days. This final phase is associated with a slow dissociation of ramiprilata connection with receptors ACE. Despite the long final phase for a single during the day you receive ramipril in a dose of 2.5 mg or more C ss ramiprilata concentration in plasma is reached after approximately 4 days treatment.

Withdrawal

In exchange the prescription of a T 1 / 2 of 13-17 h.

If ingestion is about 60% of the active substance is excreted in the urine and about 40% of the bile, with less than 2% is excreted unchanged in.

Pharmacokinetics in special clinical situations

When violations of renal excretion of ramipril and its metabolites is slowed down proportionally reduce spacecraft. This leads to increased plasma concentrations ramiprilata and their slower decline compared with patients with normal renal function.

Patients suffering from liver diseases, slows the conversion of ramipril to ramiprilat, ramipril concentration in blood plasma can be increased 3-fold, while C max in plasma ramiprilata not changed.

With heart failure there is an increase in the concentration ramiprilata 1.5-1.8 times. However, when you receive ramipril 5 mg 1 time / day for patients with heart failure after 2 weeks of treatment were observed clinically significant accumulation of ramipril and ramiprilata.

In elderly patients the pharmacokinetics of the drug did not significantly change.

In experimental studies on animals have shown that ramipril is excreted in breast milk.


Statement

- Arterial hypertension;

- Chronic heart failure (as part of combination therapy), including develop during the first few days after acute myocardial infarction;

- Diabetic nephropathy and nephropathy in the background of diffuse chronic kidney disease (chronic glomerulonephritis with severe proteinuria) - preclinical and symptomatic stage;

- Preventing the development of myocardial infarction, stroke or coronary death in patients with CHD, with an increased risk of cardiovascular disease, including patients with myocardial infarction, percutaneous transluminal coronary angioplasty, aorto-coronary bypass surgery.


Dosage regimen

Drugs are taken by mouth. Tablets should be swallowed whole (not liquid) before, during or after a meal and drink plenty of (1 / 2 cups) of water. The dose is calculated based on the expected therapeutic effect and tolerability of the drug to patients in each case.

If the patient receives diuretics, they need to lift them for 2-3 days (depending on the duration of action of diuretics) before treatment Tritatse or at least reduce the dose of diuretics.

When renal dysfunction (CC 50-20 ml / min per 1.73 m 2 body surface), the initial dose - 1.25 mg. The maximum daily dose - 5 mg.

If abnormal liver function maximum daily dose - 2.5 mg.

Patients previously taking diuretics, the initial dose - 1.25 mg.

If you can not completely eliminate the violation of water and electrolyte balance in cases of severe hypertension, as well as in patients for whom antihypertensive response is a certain risk (for example, with a decrease in blood flow due to narrowing of the coronary arteries of the heart or brain vessels), the initial dose of -1.25 mg.

Spacecraft can be calculated using figures in serum creatinine by the following formula (Cockcroft equation):

For men:

Body weight (kg) x (140 - age)

CC (ml / min) = ------------------------

72 x serum creatinine (mg / dl)

For women: Multiply the result obtained in the above equation, at 0.85.

Treatment Tritatse usually is long and its duration in each case is determined by your doctor.

In hypertensive medication prescribed 1 time / day, initial dose - 2.5 mg, if necessary, double the dose after 2-3 weeks, depending on the patient's response to the ongoing therapy, supporting daily dose - 2.5-5 mg maximum daily dose - 10 mg.

In the treatment of chronic heart failure, the initial daily dose of -1.25 mg 1 time / day. Depending on the reaction of the patient's dose can be increased. Recommended doubling the dose at intervals of 1-2 weeks. Doses of 2.5 mg or more receive a single dose or divided into 2 admission. The maximum daily dose - 10 mg.

In the treatment of chronic heart failure after myocardial infarction, the initial dose is 5 mg in 2 divided doses - at 2.5 mg in the morning and evening. At this dose of intolerance, it should be lowered to 1.25 mg 2 times / day for 2 days. If the dose is increased, it is recommended to divide into 2 receptions in the first 3 days. Subsequently, the total daily dose, initially divided into 2 divided doses, can be taken once-daily dose. The maximum daily dose - 10 mg.

Patients with severe chronic heart failure (IV degree classification NYHA) after myocardial infarction drug administered in a dose of 1.25 mg 1 time / day. In these patients increase the dose should be with extreme caution.

In the treatment of diabetic and nondiabetic nephropathy, the initial dose - 1.25 mg 1 time / day. Maintenance dose - 2.5 mg. With increasing dose, it should double every 2-3 weeks. The maximum daily dose - 5 mg.

With a view to prevention of myocardial infarction, stroke or coronary death "initial dose - 2.5 mg 1 time / day. Increasing the dose by doubling it after 1 week of treatment. After 3 weeks, the dose may be increased in 2 times the maximum dose - 10 mg.


Side effect

From the urinary system: a higher level of urea in the blood serum, hypercreatininemia (especially while use of diuretics), renal failure, kidney failure, rarely - hyperkalemia, proteinuria, hyponatremia, strengthening existing proteinuria or increase in the number of urine.

Since the cardiovascular system: rare - marked reduction of blood pressure, postural hypotension, myocardial ischemia, or brain, myocardial infarction, arrhythmia, syncope, ischemic stroke, transient cerebrovascular ischemia, tachycardia, peripheral edema (in the ankle joints).

Allergic reaction: angioedema face, lips, eyelids, tongue, glottis and / or throat, redness of skin, sensation of heat, conjunctivitis, pruritus, urticaria, other rashes on the skin or mucous membrane (Makulo-papular rash and enanthema, exudative erythema multiforme (including Stevens-Johnson syndrome), pemphigus (pemphigus), serositis, exacerbation of psoriasis, toxic epidermal necrolysis (Lyell's syndrome), oniholiz, photosensitivity, sometimes - alopecia, Raynaud's syndrome development, increasing titer of antinuclear antibodies, eosinophilia, vasculitis , myalgia, arthralgia, arthritis.

On the part of the respiratory system: often - dry cough reflex, worse at night when the patient is in a horizontal position, most often it occurs in women and non-smokers (in some cases, the effective replacement of ACE inhibitor). In the case of a continuing cough may require removal of the drug. Maybe - catarrhal rhinitis, sinusitis, bronchitis, bronchospasm, dyspnea.

On the part of the digestive system: nausea, pain in the epigastric region, increased activity of enzymes of liver and pancreas, bilirubin, and very rarely - cholestatic jaundice, indigestion, vomiting, diarrhea, constipation and loss of appetite, change in taste (a "metallic" taste), reducing taste, and sometimes even loss of taste, dry mouth, stomatitis, glossitis, pancreatitis, rarely - inflammation of the mucous membrane of the digestive tract, intestinal obstruction, abnormal liver function, with the possible development of acute liver failure.

On the part of the hemopoietic system: rarely - reducing the number of red blood cells and decrease in hemoglobin level from mild to significant, thrombocytopenia and leukopenia, and sometimes - neutropenia, agranulocytosis, pancytopenia, hemolytic anemia.

From the central nervous system and peripheral nervous system: an imbalance, headache, nervousness, tremors, sleep disturbance, fatigue, confusion, depression, feeling of anxiety, paresthesias, muscle cramps.

From the senses: vestibular disorders, breach of taste, smell, hearing and vision, tinnitus.

Other: reduction of erection and sexual desire, fever.


Contraindications

- Patients with a history of instructions for angioedema (risk of rapid development of angioedema, including in the intake of ACE inhibitors);

- Renal failure, severe (CC less than 20 ml / min);

- Hemodialysis;

- Pregnancy

- Lactation;

- Age 18 years (effectiveness and safety have not been established);

- Hypersensitivity to ramipril and the other components of the drug.

Precautions to apply for violations expressed liver function and / or kidneys, with connective tissue disease (including systemic lupus erythematosus, scleroderma - increased risk of developing neutropenia or agranulocytosis), with primary hyperaldosteronism, malignant hypertension, mitral or aortic stenosis , with inhibition of bone marrow hematopoiesis, hyperkalemia, hyponatremia (risk of dehydration, hypotension, renal failure), bilateral renal artery stenosis or stenosis of the artery the only kidney condition after kidney transplantation, the state, accompanied by a decrease in the bcc (including diarrhea, vomiting ), as well as patients, a diet with restriction of sodium in elderly patients, diabetes mellitus (due to the risk of hyperkalemia), severe coronary and cerebral arteries, while the reception with immunosuppressants and saluretikami.


Application of pregnancy and breastfeeding

Tritatse drug is contraindicated in pregnancy. Therefore, before starting treatment should verify the absence of pregnancy.

If a patient becomes pregnant during treatment should be as early as possible to replace Tritatse to another drug. Otherwise, there is a risk of damage to the fetus, especially in the I trimester of pregnancy. Found that the drug causes a disturbance of fetal kidney, blood pressure reduction of fetal and neonatal renal failure, hyperkalaemia, skull hypoplasia, oligogidramnion, contractures of limbs, the deformation of the skull, hypoplasia of the lungs.

For infants who were in utero effects of ACE inhibitors, should be closely monitored to detect arterial hypotension, oliguria and hyperkalemia. If oliguria need to maintain blood pressure and renal perfusion through the introduction of appropriate fluids and vasoconstrictor agent. In newborns and infants are at risk of oliguria and neurologic disorders, possibly due to the reduction of renal and cerebral blood flow due to the reduction of blood pressure, called ACE inhibitors (produced and after pregnancy).

If necessary, the appointment Tritatse lactating breast-feeding should be discontinued.


Application for violations of liver function

Precautions to apply for violations expressed liver function and / or kidneys


Application for violations of renal function

Precautions to apply for violations expressed renal function.

The drug is contraindicated in renal failure, severe (CC less than 20 ml / min at a body surface 1.73 m 2), with hemodialysis.


Cautions

Tritatse Treatment is usually lengthy, its duration in each case is determined by your doctor. It also requires regular medical monitoring, in particular, in patients with impaired liver function and kidney. It is generally recommended before treatment to correct dehydration, hypovolaemia or salt deficiency.

In case of emergency drug treatment can begin or continue only if the time taken appropriate precautions to prevent excessive loss of blood pressure and renal dysfunction.

Need to monitor kidney function, especially during the first weeks of treatment. In patients with vascular diseases of the kidneys (eg, renal artery stenosis is not clinically significant, either unilateral hemodynamically significant renal artery stenosis) in the case of the previous renal dysfunction, as well as patients who underwent a kidney transplant, should be particularly closely monitored.

It should regularly monitor the concentration of potassium and sodium in blood serum. Patients with impaired renal function requires more frequent monitoring of these indicators.

Need to control the number of leukocytes (leukopenia diagnosis). Especially regular monitoring is recommended at the beginning of treatment, as well as in patients at risk - up to 1 times a month in the first 3-6 months of treatment in patients with increased risk of neutropenia - with renal failure, systemic connective tissue disease or receiving high-dose diuretics, as well as at the first sign of infection.

Upon confirmation of neutropenia (neutrophil count less than 2000/mkl) therapy with ACE inhibitors should be discontinued.

If you suspect a violation of immunity due to leukopenia (eg, fever, enlarged lymph nodes, tonsillitis), requires urgent control patterns of peripheral blood. If signs of bleeding (the smallest of petechiae, red-brown rash on the skin and mucous membranes) should also monitor the number of platelets in peripheral blood.

Before and during treatment requires monitoring of blood pressure, kidney function, hemoglobin levels in peripheral blood, creatinine, urea, electrolyte concentration and activity of liver enzymes in the blood.

Be careful when appointing the drug to patients who are at malosolevoy or salt-free diet (increased risk of arterial hypotension). In patients with reduced BCC (as a result of therapy with diuretics), while limiting sodium intake, diarrhea and vomiting can develop symptomatic arterial hypotension.

Transitory hypotension is not a contraindication for further treatment after stabilization of blood pressure. In the case of recurrence of severe arterial hypotension should reduce the dose or repeal the drug.

If a history of guidance on the development of angioedema not associated with intake of ACE inhibitors, then such patients nevertheless there is an increased risk of developing cancer while taking Tritatse.

Caution must be exercised in the performance of physical exercise and / or hot weather because of the risk of dehydration and hypotension, due to reduced volume of liquid.

Avoid drinking alcohol.

Before surgical intervention (including dentistry) must notify the surgeon / anesthetist on the use of ACE inhibitors.

If you experience swelling, for example in the face (lips, eyelids), or language, or violation of swallowing or breathing patient should immediately stop taking the drug. Angioedema of tongue, pharynx, or larynx (possible symptoms - a violation of swallowing or breathing) can be life-threatening and lead to the need for emergency care.

Experience with Tritatse children, patients with severe impaired renal function (CC below 20 ml / min), as well as in patients receiving hemodialysis treatment is insufficient.

After the first dose, as well as an increase in dosage of the diuretic and / or ramipril, patients should be in for 8 hours under medical supervision to avoid the uncontrolled development of hypotensive reactions. In patients with chronic heart failure receiving the drug can lead to the development of severe arterial hypotension, which in some cases accompanied by oliguria and azotemia, and rarely - the development of acute renal failure.

Patients with malignant hypertension, or concomitant severe heart failure should start treatment in hospital.

Patients receiving ACE, described life-threatening, rapidly developing anaphylactoid reactions, sometimes up to the development of shock, during hemodialysis using certain vysokoprotochnyh membranes (eg polyacrylonitrile). Against the background of treatment with Tritatse should avoid using such membranes, such as for urgent hemodialysis or hemofiltration. In the case of the need for these procedures, preferably using other membranes or cancellation of the drug. Similar reactions were observed during LDL apheresis using dextran sulfate. Therefore, this method should not be used in patients who receive ACE inhibitors.

Use in Pediatrics

Safety and efficacy in children and adolescents under the age of 18 are not installed, so the appointment is contraindicated.

Effects on ability to drive vehicles and management mechanisms

During treatment the patient should abstain from classes of potentially hazardous activities that require high concentration and speed of psychomotor reactions, because dizziness, especially after the initial dose Tritatse in the case of receiving diuretic drugs.


Overdose

Symptoms: marked reduction of blood pressure, shock, marked bradycardia, disorders of water and electrolyte balance, acute renal failure, stupor.

Treatment: gastric lavage, reception adsorbents, sodium sulphate (if possible during the first 30 minutes). In the case of arterial hypotension to therapy to fill the bcc and restore the salt balance can be added to the introduction of alpha 1-adrenostimulyatorov (norepinephrine, dopamine) and angiotensin II (angiotenzinamid).


Drug Interactions

At simultaneous application with Tritatse potassium salts, potassium-sparing diuretics (eg, amiloride, triamterene, spironolactone) is observed hyperkalemia (requires control of the content of potassium in blood serum).

With simultaneous application Tritatse with antihypertensive drugs (in particular, with diuretics) and other drugs to lower blood pressure leads to a tightening of ramipril.

With the simultaneous use with drugs, and opioid analgesic may be a sharp decline in AD.

Sympathomimetic vasopressor drugs (epinephrine) and estrogens may lead to the weakening of ramipril.

With simultaneous application of Tritatse with allopurinol, procainamide, cytostatics means, immunosuppressants, systemic GCS and other drugs that can change the pattern of blood may reduce the number of leukocytes in the blood.

When applied simultaneously with the preparations of lithium may increase the concentration of lithium in plasma, which leads to increased cardio-and neurotic actions of lithium.

When applied simultaneously with oral hypoglycemic Tritatse drugs (derivatives of sulfonylurea, biguanide), insulin is increased hypoglycemia.

NSAIDs (indomethacin, acetylsalicylic acid) may decrease the effectiveness of ramipril.

When applied simultaneously with heparin may increase the concentration of potassium in the blood serum.

Table salt reduces the effectiveness of ramipril.

Ethanol enhances the hypotensive effect of ramipril.


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Drug prescription.


Terms and Conditions of storage

List B. The drug should be stored away from children at or above 25 ° C. Shelf life - 5 years.