Rational combinations of antihypertensive drugs

Pharmacodynamics and pharmacokinetics

Co-Perineva is a combination drug containing perindopril and indapamide .

The drug has an antihypertensive effect, the effectiveness of which does not depend on the patient’s age, body position, and is not accompanied by tachycardia. Does not affect lipid metabolism, including in patients with diabetes . When taking the drug, the risk of hypokalemia .

The antihypertensive effect persists throughout the day.

After just a month of taking the drug, a decrease in blood pressure is achieved. If treatment is stopped, there is no risk of withdrawal syndrome .

Perindopril is extremely effective in the fight against arterial hypertension (all forms of severity). 4-6 hours after taking the medicine, the maximum antihypertensive effect develops, which lasts throughout the day.

Perindopril after administration is quickly absorbed from the gastrointestinal tract. Bioavailability is 65-70%. 3-4 hours after administration, the maximum level of the drug in the blood plasma is reached. It is metabolized in the liver, forming an active (perindoprilat) and five inactive metabolites. A small amount of perindoprilate passes into breast milk and through the placenta. Excreted through the kidneys.

The elimination of perindoprilate is slowed down in patients with heart and renal failure and patients over 65 years of age. In patients suffering from liver cirrhosis, hepatic clearance is reduced by half, however, the level of perindoprilate is not reduced.

Indapamide is almost completely absorbed from the gastrointestinal tract; simultaneous intake of food can slow down this process. After an hour, the maximum level in the blood is reached. Metabolized in the liver. Excreted through the kidneys and intestines.

Pharmacokinetics

The combined use of perindopril and indapamide does not change their pharmacokinetic parameters compared to the separate administration of these drugs.

Perindopril after oral administration is rapidly absorbed from the gastrointestinal tract. Bioavailability is 65–70%. Eating reduces the conversion of perindopril to perindoprilat. T1/2 of perindopril from blood plasma is 1 hour.

Cmax in blood plasma is achieved 3–4 hours after oral administration. Since taking with food reduces the conversion of perindopril to perindoprilat and the bioavailability of the drug, perindopril should be taken once a day in the morning, before breakfast. Taking perindopril once a day, equilibrium concentration is achieved within 4 days.

It is metabolized in the liver to form an active metabolite - perindoprilate. In addition to the active metabolite perindoprilate, perindopril forms 5 more inactive metabolites. The binding of perindoprilate to plasma proteins is dose-dependent and amounts to 20%. Perindoprilat easily passes through histohematic barriers, excluding the blood-brain barrier; a small amount penetrates the placenta and into breast milk. Excreted by the kidneys, T1/2 of perindoprilate is about 17 hours. It does not accumulate.

In elderly patients and in patients with renal and heart failure, the elimination of perindoprilate is slowed down.

In case of renal failure, it is recommended to reduce the dose of perindopril depending on the severity of renal failure (creatinine clearance). The dialysis Cl of perindoprilate is 70 ml/min.

The kinetics of perindopril is altered in patients with liver cirrhosis: hepatic clearance is reduced by half. However, the amount of perindoprilate formed does not decrease, which does not require dose adjustment.

Indapamide. Quickly and almost completely absorbed into the gastrointestinal tract. Eating slightly slows down absorption, but does not significantly affect the amount of indapamide absorbed. Cmax in blood plasma is achieved 1 hour after oral administration of a single dose. Binds to plasma proteins by 79%. T1/2 ranges from 14 to 24 hours (average 18 hours). Does not accumulate.

Metabolized in the liver. It is excreted by the kidneys (70%) mainly in the form of metabolites (the fraction of the unchanged drug is about 5%) and by the intestines with bile in the form of inactive metabolites (22%). In patients with renal failure, the pharmacokinetic parameters of indapamide do not change significantly.

Contraindications

The drug Co-Perineva is contraindicated in the following cases:

• sensitivity to any element of the drug;
• lactose intolerance;
• refractory hyperkalemia;
• angioedema;
• bilateral renal artery stenosis;
• lactase deficiency;
• liver failure;
• glucose-galactose malabsorption;
• renal failure;
• renal artery stenosis;
• pregnancy, lactation, children under 18 years of age.

You should take the drug with caution in the following cases:

• connective tissue diseases ( scleroderma , SLE );
• immunosuppressant therapy;
• inhibition of bone marrow hematopoiesis;
• angina pectoris;
• renovascular hypertension;
• decrease in blood volume;
• hyperuricemia;
• diabetes;
• cerebrovascular diseases.

Side effects

The use of the drug may cause the following side effects:

• thrombocytopenia , agranulocytosis , hemolytic anemia , leukopenia , aplastic anemia ;
• vertigo , paresthesia , dizziness , headache , unstable mood, sleep disturbance, in rare cases - confusion ;
• tinnitus, blurred vision;
• orthostatic hypotension , arrhythmias ( bradycardia , atrial fibrillation , ventricular tachycardia ), myocardial infarction , angina pectoris ;
• dry cough , shortness of breath , bronchospasm , rhinitis , eosinophilic pneumonia ;
• dry mouth, constipation , nausea, abdominal pain, loss of appetite, epigastric pain, vomiting , diarrhea , dyspepsia , pancreatitis , jaundice ;
• angioedema (face, lips, limbs, here, tongue, larynx), rash, urticaria , itching ;
• muscle spasms;
• renal failure;
• impotence;
• asthenia , increased sweating.

Instructions for use (Method and dosage)

The medicine Co-Perineva is taken 1 time per day, orally, in the morning before breakfast, with water.

Doses are listed in the indapamine/perindopril ratio.

To begin with, you should take one tablet (0.625/2 mg) per day. If it is not possible to achieve blood pressure control within a month, the dose is increased to one tablet (1.25/4 mg). To achieve the most pronounced effect, you should increase the daily dose to the limit - one tablet (2.5/8 mg).

For elderly patients, the initial dose is one tablet (0.625/2 mg). Treatment with the drug can be prescribed in case of control of blood pressure and kidney function.

Patients with moderate renal impairment are started on the lowest dose, with the maximum allowed dose being 1.25/4 mg.

PERINEVA (tablets)

she woke up and said: “Your heart works, like an athlete’s, in a gentle mode.
It will last a long time." It's good to be reassured and reassured. But 7-8 years after that conversation, a heart attack still hit me. This happened in 2013. At the regional hospital they performed a stent, and I am back in action. Both in the hospital and after it, I continued to drink Concor. And in the summer of 2016, I suddenly had an angina attack at night, which prompted me to see a cardiologist. The doctor is young, not even 30. Theoretically well-versed, but weak in practice. The clinic is not the level where experience is gained.

After looking at the cardiogram and measuring the pressure and pulse, the doctor advised reducing the dose of Concor by half, supplementing it with Perineva to increase the pulse rate. The scheme is as follows: in the morning, instead of a whole tablet of Concor 5 mg, I take only half (2.5 mg), and in the evening - half a tablet (2 mg) of Perineva. I tried it. The next day the blood pressure was normal. But this was not the merit of the new drug. It’s just that Concor has the excellent ability to accumulate a therapeutic effect, and if you forget to take a pill in the morning, you don’t have to worry, your blood pressure will still be normal.

But the next day my upper blood pressure rose to 155 against the working 130. I didn’t like this, and I drank another half tablet of Perineva at about 11 o’clock, and in the evening I drank not half, but a whole one. The pressure returned to normal, but a day later it was 150 again. I added a whole tablet of Perineva. It turns out that instead of half (2 mg) you need to drink 2.5 tablets of Perineva and half a tablet of Concor per day.

I clearly don't like this arrangement. Moreover, the pulse, which was 49 at the cardiologist’s appointment, became 52-55 beats per minute with Perineva. The difference is small. Of course, I’ll finish these pills, but then I’ll try others (the cardiologist suggested 2 options).

And Perineva costs only 260 rubles. The tablets are packed in a cardboard box with a nice design.

The package contains 30 oblong tablets with a dividing strip. They break easily and come out of the blister without any problems. But the blister itself is soft, breaks and assembles into an accordion.

Visually, I immediately liked them, but, alas, there was almost no effect from them, although my body reacts very sensitively to various medications. Manufacturer of tablets: KRKA-RUS LLC from the city of Istra, Moscow region. Telephone, fax and address are indicated on the package.

Judging by the reviews, Perineva helps many, but I cannot recommend these tablets, because in relation to my pressure they work poorly, reducing only the lower (cardiac) pressure, which, by the way, is much more difficult to reduce than the upper. This is the paradox.

Overdose

Symptoms of overdose: vomiting , nausea , muscle cramps , drowsiness , dizziness , confusion , decreased water and electrolyte balance, oliguria , significant decrease in blood pressure.

If the above symptoms appear, you should rinse your stomach, then take activated charcoal to restore the water and electrolyte balance. If the pressure decreases significantly, the patient should lie on his back and raise his legs, then inject a 0.9% sodium chloride solution.

Rational combinations of antihypertensive drugs

Lecture transcript

XXVI All-Russian Educational Internet Session for doctors
Total duration: 20:10

Oksana Mikhailovna Drapkina, executive director of the Internet Session, secretary of the interdepartmental council on therapy of the Russian Academy of Medical Sciences: - It is with great pleasure that I give the floor to Professor Maria Genrikhovna Glezer. "Rational combinations of antihypertensive drugs"

00:10

Glezer Maria Genrikhovna, Doctor of Medical Sciences:

– Dear colleagues. Arterial hypertension is currently the No. 1 risk factor. In 2010, it was recognized by the World Health Organization as the No. 1 killer. It is high blood pressure that determines more than 50% of all cases of coronary heart disease and strokes.

What are the classes of drugs for long-term treatment of arterial hypertension. 8 classes. But we must first use the first 5 classes:

• diuretics;
• beta blockers;
• ACE inhibitors;
• sartans;
• calcium channel blockers.

Alone or in combination, these drugs are used to reduce the risk of complications.

There is a sufficient evidence base for these first five drugs. These classes of drugs may reduce cardiovascular morbidity and death.

What are the main pathophysiological mechanisms involved in increased blood pressure?

This is the activation of the renin-angiotensin system. Activation of the sympathetic nervous system. Increase in circulating blood volumes (changes in water and electrolyte balance).

Ultimately, these systems will lead to changes in intracellular calcium transport. The drugs that we have affect different stages of pathogenesis.

Beta blockers, sympatholytics, imidazoline receptor agonists - for increased activity of the sympathetic nervous system. Diuretics – for increased circulating blood volume, lipid metabolism disorders. Calcium antagonists – to change intracellular calcium transport. 3 groups of drugs (inhibitors, sartans and direct renin inhibitors) - on the activated rhinin-angiotensin system.

We know well from clinical practice that all patients with arterial hypertension are different. The contribution of each pathogenetic mechanism may vary from person to person. For some, an increase in circulating blood volume prevails. Some people have predominantly increased activity of the renin-angiotensin system. Some people (especially young people) experience an increase in the activity of the sympathetic nervous system.

It is clear that it is most often impossible to solve the problem with one class of drugs.

02:34

Athena Study.

More than 2,000 women in the Russian Federation were analyzed. Where hypertension was controlled, 2-component, 3-component or more drugs were more often used to treat high blood pressure.

Where there was no control (in fact, this was the majority), either these patients were not treated at all, or monotherapy was used. This is further evidence that different classes of drugs need to be combined in order to achieve blood pressure goals.

Categories of patients most likely to require combination therapy:

• persons who have a significant increase in blood pressure (above 160/100 mm Hg);
• patients with diabetes mellitus (DM);
• people who have certain lesions of organ systems. For example, kidney damage;
• left ventricular hypertrophy (LVH);
• people who smoke, are obese, have sleep disordered breathing.

Combination therapy is the key to success in achieving the goal (based on the pathogenetic mechanisms that I have already mentioned and the complications that often occur in patients).

What do we call a goal? The best evidence to date is that the goal is to achieve target blood pressure values.

In September 2010, there were some changes to the target values. Now, regardless of the degree of risk, they try to keep the pressure below 140 and 130. Up to 140 mm Hg. Art. systolic and 90 – 80 mm Hg. Art. by diastolic.

Not a single large study (probably how they were structured) has proven that a decrease of less than 130 and 80 mm Hg. Art. provides an additional reduction in morbidity and mortality. At the same time, a decrease from 130 is a very difficult moment, requiring a lot of effort and financial costs.

In persons over 80 years of age, based on data from the HYVET study, target values ​​for systolic pressure are set at less than 150 mmHg. Art. Low numbers remain with significant proteinuria.

05:04

A meta-analysis of 147 studies in older people aged 60–69 years showed that while one standard-dose drug reduces the risk of coronary heart disease by 25% and stroke by 35%, then a combination of three drugs at half the dosage reduces the risk of developing both coronary heart disease and stroke is almost twice as high.

A very interesting analysis was published in 2009. A 2-drug combination has been shown to be 5 times more effective in lowering systolic blood pressure (SBP) than doubling the dose of either drug class. Be it beta blockers, diuretics, inhibitors, calcium antagonists. This is proof that it is combination therapy that allows you to achieve the desired values.

In addition, combination therapy can undoubtedly lead to a faster, more pronounced reduction in blood pressure.

The VALUE study clearly showed: if during the first month from the start of treatment the pressure decreases by more than 10 mm Hg. Art., then the number of fatal/non-fatal cardiovascular events, strokes and death from all causes becomes significantly less than in those people who did not achieve a reduction during the first month.

06:29

The second point that you should pay attention to: you should still strive to achieve the target numbers within 6 months. This is less than 140 mmHg. Art. Then all outcomes, including fatal events, heart attacks, strokes, deaths from all causes, and hospitalization will be significantly lower.

In my opinion, how should the decision-making process proceed when treating patients with arterial hypertension.

Certainly. We can start with monotherapy. This ensures the safety of treatment for our patients. If you see a person for the first time and you do not know what the reaction will be to antihypertensive therapy, you can start with monotherapy.

But you don’t need to go further in this vicious circle: you reached the maximum increase in dose, you became convinced that it was ineffective, you changed the drug, and so on. Patients stop this treatment, they leave the doctor.

Correct decision-making process: Tried monotherapy. We realized that it was quite effective and safe, and switched to combination therapy. We are moving further along the path of increasing doses of combination drugs. This is the principle I preach.

Plus one: the patient came - the treatment was not effective enough - the next class of drugs was added. If something else doesn’t suit you, the next class is added. Then you will be more likely to succeed.

When it comes to combination therapy, they always say: “This is polypharmacy, it is bad for patients, and so on.” Correct, because combination therapy must undoubtedly be rational.

What is rational therapy? This is when the effectiveness of treatment increases, while the incidence of side effects decreases.

This can lead to an increase in efficiency. We use different classes of drugs, influence different parts of the pathogenesis of the disease and eliminate the activation of counter-regulatory systems. If you use drugs in smaller dosages, then dose-related side effects may, of course, be reduced.

The side effects of one of the components can be eliminated by using another component.

08:51

Recommended combinations of drugs for hypertension.

Diuretics plus inhibitors or sartans. Best time to use: Where there is a high risk of heart failure.

Beta blockers and dihydropyridine calcium antagonists. When is it best to use: for ischemic heart disease.

Metabolically neutral class of drugs, sartan inhibitors, calcium antagonists. In persons at high metabolic risk.

Today, this is probably how one can imagine rational combinations. It's a diuretic plus something. Anything – these are inhibitors or sartans.

Another type of combination. Calcium antagonists plus ACE inhibitor or calcium antagonists plus sartans. Dihydropyridine calcium antagonists are used with beta blockers in patients with coronary artery disease.

Currently, the combination of diuretics plus calcium antagonists is considered irrational because this combination almost doubles the risk of myocardial infarction. Diuretics plus beta blockers had the best effect in this case.

The final picture looks like this: 1) calcium antagonists plus inhibitors or sartans and 2) diuretics, inhibitors and sartans.

The slide shows the recommended combinations of antihypertensive drugs in a trapezoid.

This trapezoid is considered the most rational today.

I took the liberty of slightly modifying the picture shown in the European recommendations. I drew a triangle. At the top I put a group of drugs that inhibit the activity of the renin-angiotensin system (RAS) plus diuretics or plus calcium antagonists. Or the three of us together in the center of the class. There will be effective treatment.

What is the rationale for saying that a combination of diuretics, inhibitors or sartans is an effective and rational combination. It is known that diuretics and inhibitors (sartans) are powerful antihypertensive drugs with pronounced organoprotective properties that can reduce the incidence of morbidity and mortality in arterial hypertension (AH).

The enhancement of the hypotensive effect is due to the fact that conditions are created for the most pronounced action of both components. The activation of counter-regulatory mechanisms is eliminated: diuretics reduce sodium levels, thereby stimulating the production of renin. This leads to a more pronounced antihypertensive effect of drugs that inhibit the activity of the angiotensin system.

At the same time, inhibitors or sartans, by reducing the production of aldosterone, reduce the excretion of potassium from the body, which is always not good when prescribing diuretics. In addition, inhibitors and sartans have a beneficial effect on purine metabolism and reduce the severity of hyperuricemia.

11:50

The combination with diuretics allows you to achieve the same reduction in blood pressure 4 weeks earlier compared to monotherapy with any of the drugs. This leads to the fact that better treatment results can be achieved.

ACE inhibitors (in general, probably the same with sartans) are drugs with pronounced organotensive properties. They influence vascular remodeling, reducing or normalizing the ratio between the lumen of blood vessels and the intima-media complex. This is very important for persistently maintaining blood pressure at normal levels and avoiding crises. The data are given for one of the long-acting ACE inhibitors - the drug Lisinopril. In our country it is often used in the form of the drug “Diroton”. Normalization of the vascular ratio in arterial hypertension.

Indicators related to heart function improve. In particular, improving the diastolic function of the heart. The ratio of peak E to peak A returns to almost normal. The time of isovolumic relaxation improves, the diameter of cardiomyocytes decreases. It is very important that myocardial fibrosis is reduced in patients with arterial hypertension. This is one of the first steps to developing a particular form of heart failure. Heart failure, which is caused by hypertension with preserved ejection fraction.

13:27

ACE inhibitors are known to work very well in obesity because the activity of the renin-angiotensin system is increased in obesity. Each fat cell produces the angiotensin gene in an amount equal to 70 liver cells.

One of the first studies that was conducted demonstrated that lisinopril was effective in approximately 60 patients. Hydrochlorothiazide (HTC) is less effective. The most important thing is that this effect is detected at doses of “Lisinopril” of 10 mg, and “Hydrochlorothiazide” - 50 mg. The side effects of Hydrochlorothiazide may already be quite pronounced.

A very interesting study was conducted in Russia - the Desire study. This study showed that the use of lisinopril can normalize the abnormal daily blood pressure profile. In particular, Lisinopril in women halved the night-picker type when there is a sharp increase in blood pressure at night.

Another achievement that was shown in this study. The use of the drug in the evening allows to normalize blood pressure to a greater extent and reduce the disturbed profile. This is important because night-pickers have a higher incidence of strokes, adverse events, and so on.

Combination with diuretics. Diuretics are one of the most important classes of drugs for the treatment of arterial hypertension. Returning to the Athena study, I would like to say that the difference is in the prescription of drugs where it was ineffective: diuretics were used less often. All other classes were used approximately equally. If diuretics are not prescribed, then it is even difficult to say that something is effective or ineffective.

15:22

Two studies: UKPDS and LIFE. In the UKPDS study, the target blood pressure was 160/90 mmHg. Art. 60% of patients were already on diuretics. In the LIFE study, where the target numbers were 140/90 mmHg. Art. 90% of patients required diuretics.

In our country, the use of diuretics is somewhere around 30%. This is not a sufficient purpose. According to the LIFE study, people who received diuretic drugs had a 30-40% lower risk of various adverse events (cardiovascular death, heart attack, stroke), and a 45% lower overall mortality rate. This is a very important class of drugs that should be used in combination therapy.

I'll say it again. We can say that hypertension is resistant to treatment if a combination of three antihypertensive drugs prescribed in adequate dosages does not reduce blood pressure, but one of these drugs is a diuretic. Thus, this is a very important way to achieve target blood pressure values.

The use of ready-made combination forms is an easier path to success in treating patients with arterial hypertension.

Where hypertension was controlled, a higher percentage of cases used preformed combination dosage forms than in groups where there was no sufficient effect.

I want to show you one more study. Where a combination of Lisinopril and Hydrochlorothiazide was used (in our country, the drug Co-Diroton), patient adherence to treatment was higher than when Lisinopril and Hydrochlorothiazide were used in 2- x different tablets.

The creation of finished dosage forms follows the path of rational combinations, that is, a diuretic plus an ACE inhibitor, or a diuretic plus sartan. Or a combination based on calcium antagonists, to which inhibitors, sartans or beta blockers are added in the treatment of patients with coronary heart disease.

Now a drug has been released that contains a combination of 3 groups. This is Amlodipine plus Valsartan plus Hydrochlorothiazide. This is the right direction: when you have selected certain dosages, then you can already use ready-made combined forms.

In a nutshell about the combination of calcium antagonists with inhibitors or sartans. Calcium antagonists are good at reducing the risk of stroke, inhibitors are good at reducing the risk of myocardial infarction. This provides a reduction in the risk of major cardiovascular events.

18:14

Advantages and disadvantages of mono- and combination therapy for arterial hypertension.

Of course, if you use combination therapy, there is always a higher response rate. This is a very high possibility of dose titration, because you can take a quarter of a tablet from one package, a full tablet from another, and so on. The incidence of side effects is lower if we use rational combinations.

But it becomes difficult to accept. Patients with hypertension will not use anything that is complicated. As soon as the necessary dosages have been selected, you need to switch to fixed combinations, which has an advantage in absolutely all positions.

In conclusion, I want to say what rational combination antihypertensive therapy is. This is an impact on different parts of the pathogenesis of hypertension and elimination of the activation of counter-regulatory mechanisms. Based on this, the effectiveness of treatment increases. When it is effective, people will be more committed (commitment increases).

A good combination is a decrease in the frequency of side effects - which means an increase in adherence. Increasing adherence means increasing the effectiveness of treatment.

Let's look at the second part of this circle. Increasing efficiency, increasing adherence means decreasing cost. Any change in therapy entails, of course, an increase in the cost of treatment. And when it’s not so expensive, people will be more committed. They will better follow the doctor's orders. You should always think about this.

Thank you for your attention.

Oksana Drapkina: Thank you very much, Maria Genrikhovna.

Interaction

You should not combine Co-Perineva with ACE inhibitors and lithium preparations, as the level of lithium in the blood may increase. If co-administration is necessary, lithium levels should be monitored.

Baclofen with extreme caution , as it may increase the hypotensive effect. Blood pressure and kidney function should be monitored and the dose adjusted if necessary.

Neuroleptics and tricyclic antidepressants enhance the effect of hypotension and increase the likelihood of orthostatic hypotension.

Tetracosactide and GCS help reduce the hypotensive effect.

When taken simultaneously with any other antihypertensive drugs, there is a possibility of a stronger manifestation of the hypotensive effect.

Perindopril

At the same time, it is not recommended to use it with potassium-sparing diuretics ( Spironolactone , Amiloride , Eplerenone , Triamterene ) and potassium supplements. When used in parallel, the level of potassium in the blood may increase, which can lead to death. If joint therapy is necessary (for hypokalemia), it is necessary to monitor potassium levels and ECG parameters.

It is recommended to take Co-Perineva together with insulin and hypoglycemic agents with extreme caution. leukopenia increases when used with cytostatic immunosuppressants, Allopurinol , GCS and procainamide . When used with general anesthesia agents, their hypotensive effect may increase. When used in high doses, thiazide and loop diuretics can lead to hypovolemia .

Indapamide

Drugs that cause ari must be taken with caution, since there is a possibility of developing hypokalemia . It is recommended to take Indapamide with caution with medications such as antipsychotics ( cyamemazine , trifluoperazine , chlorpromazine , etc.), antiarrhythmic drugs ( Amiodarone , hydroquinidine , ibutilide , tosylate etc.), benzamides ( sultopride , Tiapride , Sulpiride , Amisulpride ), butyrophenones ( Haloperidol , Droperidol ), other drugs ( Astemizole , mizolastine , sparfloxacin , methadone , bepridil , halofantrine , terfenadine , cisapride ).

Medicines that can cause hypokalemia : tetracosactide , laxatives that stimulate intestinal motility, Amphotericin B , glucocorticoids, mineralocorticoids, cardiac glycosides.

lactic acidosis increases when used with Metformin .

Patients taking high-dose iodine contrast agents are at risk of kidney failure. Hypercalcemia can develop when taking medications containing calcium salts.

Perineva

Use during pregnancy and breastfeeding

During pregnancy, the use of the drug is contraindicated.
If pregnancy is confirmed, Perineva® should be discontinued as soon as possible. Use in the 2nd and 3rd trimesters of pregnancy can cause fetotoxic effects (decreased renal function, oligohydramnios, delayed ossification of fetal skull bones) and neonatal toxic effects (renal failure, arterial hypotension, hyperkalemia). If the drug is used in the second and third trimesters of pregnancy, it is necessary to conduct an ultrasound examination of the fetal kidneys and skull bones. The use of Perineva® during lactation is not recommended due to the lack of data on the possibility of perindopril passing into breast milk. If it is necessary to use the drug during lactation, breastfeeding should be discontinued.

Use for liver dysfunction

Patients with liver disease do not require dose adjustment. In patients with liver cirrhosis, the hepatic clearance of perindopril changes, while the total amount of perindoprilate formed does not change, and no adjustment of the dosage regimen is required.

Use for renal impairment

In patients with kidney disease, the dose of Perineva is determined depending on the degree of renal dysfunction. During treatment, the content of potassium ions and creatinine in the blood serum should be regularly monitored. Recommended doses are presented in the table.

*- Dialysis clearance of perindoprilate is 70 ml/min. Perineva should be taken after a dialysis session.

Use in children

Contraindicated: under 18 years of age (efficacy and safety have not been established).

Use in elderly patients

In elderly patients, the recommended starting dose is 2 mg/day. In the future, the dose can be gradually increased to 4 mg and, if necessary, to a maximum of 8 mg/day, provided that the lower dose is well tolerated.

special instructions

Stable ischemic heart disease

In patients with coronary artery disease who develop an episode of unstable angina (significant or not) during the first month of therapy with Perineva®, it is necessary to assess the benefit/risk ratio of therapy with this drug.

Arterial hypotension

When treating arterial hypertension, ACE inhibitors can cause a sharp decrease in blood pressure. In patients with uncomplicated hypertension, symptomatic hypotension rarely occurs after the first dose. The risk of excessive reduction in blood pressure is increased in patients with reduced blood volume during diuretic therapy, while following a strict salt-free diet, hemodialysis, as well as with diarrhea or vomiting, or in those suffering from severe renin-dependent arterial hypertension. Severe arterial hypotension was observed in patients with severe chronic heart failure, both in the presence of concomitant renal failure and in its absence. The most common arterial hypotension can develop in patients with more severe chronic heart failure, taking high-dose loop diuretics, as well as in the presence of hyponatremia or renal failure. In such patients, careful medical monitoring is recommended during initiation of therapy and during dosage titration. The same applies to patients with coronary artery disease or cerebrovascular diseases, in which an excessive decrease in blood pressure can lead to myocardial infarction or cerebrovascular complications.

If arterial hypotension develops, it is necessary to place the patient in a horizontal position with elevated legs, and, if necessary, administer an intravenous solution of sodium chloride to increase blood volume. Transient arterial hypotension is not a contraindication for further therapy. After restoration of blood volume and blood pressure, treatment can be continued subject to careful selection of the dose of the drug.

In some patients with chronic heart failure and normal or low blood pressure, an additional decrease in blood pressure may occur during therapy with Perineva®. This effect is expected and is usually not a reason to discontinue the drug. If arterial hypotension is accompanied by clinical manifestations, dose reduction or discontinuation of Perineva® may be required.

Aortic or mitral valve stenosis/hypertrophic cardiomyopathy

ACE inhibitors, incl. Perindopril should be prescribed with caution to patients with mitral valve stenosis and left ventricular outflow tract obstruction (aortic valve stenosis and hypertrophic cardiomyopathy).

Renal dysfunction

In patients with renal insufficiency (creatinine clearance less than 60 ml/min), the initial dose of Perineva should be adjusted according to the clinical clearance and then depending on the therapeutic response. For such patients, regular monitoring of the concentration of potassium ions and creatinine in the blood serum is necessary.

In patients with symptomatic heart failure, arterial hypotension that develops during the initial period of therapy with ACE inhibitors can lead to deterioration of renal function. Cases of acute renal failure, usually reversible, have sometimes been reported in such patients.

In some patients with bilateral renal artery stenosis or renal artery stenosis of a solitary kidney (especially in the presence of renal failure), an increase in serum concentrations of urea and creatinine was observed during therapy with ACE inhibitors, which was reversible after discontinuation of therapy. In patients with renovascular hypertension during therapy with ACE inhibitors, there is an increased risk of developing severe arterial hypotension and renal failure. Treatment of such patients should begin under close medical supervision, with small doses of the drug and with further adequate dose selection. During the first weeks of therapy with Perineva®, it is necessary to discontinue diuretics and regularly monitor renal function. In some patients with arterial hypertension in the presence of previously undetected renal failure, especially with concomitant diuretic therapy, there was a slight and temporary increase in serum urea and creatinine concentrations. In this case, it is recommended to reduce the dose of Perineva® and/or discontinue the diuretic.

Hemodialysis patients

Several cases of persistent, life-threatening anaphylactic reactions have been reported in patients undergoing dialysis using high-flux membranes and concomitantly taking ACE inhibitors. If hemodialysis is necessary, a different type of membrane must be used.

Kidney transplantation

There is no experience with the use of perindopril in patients with recent kidney transplantation.

Hypersensitivity/angioedema

Rarely in patients taking ACE inhibitors, incl. perindopril, angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx developed. This condition can develop at any time during treatment. If angioedema develops, treatment should be stopped immediately, and the patient should be under medical supervision until symptoms disappear completely. Angioedema of the lips and face usually does not require treatment; Antihistamines can be used to reduce the severity of symptoms. Angioedema of the tongue, glottis, or larynx can be fatal. If angioedema develops, it is necessary to immediately administer epinephrine (adrenaline) subcutaneously and ensure airway patency.

Patients with a history of angioedema not related to the use of ACE inhibitors have a higher risk of developing angioedema while taking an ACE inhibitor.

Anaphylactoid reactions during LDL apheresis procedure

In patients prescribed ACE inhibitors during the procedure of LDL apheresis using dextran sulfate absorption, in rare cases, an anaphylactic reaction may develop. It is recommended to temporarily discontinue the ACE inhibitor before each apheresis procedure.

Anaphylactic reactions during desensitization

In patients receiving ACE inhibitors during a course of desensitization (for example, hymenoptera venom), in very rare cases, life-threatening anaphylactic reactions may develop. It is recommended to temporarily discontinue the ACE inhibitor before each desensitization procedure.

Liver failure

During therapy with ACE inhibitors, it is sometimes possible to develop a syndrome that begins with cholestatic jaundice and then progresses to fulminant liver necrosis, sometimes with death. The mechanism of development of this syndrome is unclear. If jaundice or elevated liver enzymes occur while taking an ACE inhibitor, the ACE inhibitor should be discontinued immediately and the patient should be closely monitored. It is also necessary to conduct an appropriate examination.

Neutropenia, agranulocytosis, thrombocytopenia, anemia

Cases of neutropenia/agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitor therapy. With normal renal function in the absence of other complications, neutropenia rarely develops. Perineva® should be used with great caution in patients with systemic connective tissue diseases (for example, SLE, scleroderma), simultaneously receiving immunosuppressive therapy, allopurinol or procainamide, as well as when combining all of these factors, especially with existing renal impairment. Such patients may develop severe infections that do not respond to intensive antibiotic therapy. When carrying out therapy with Perineva® in patients with the above factors, it is recommended to periodically monitor the number of leukocytes in the blood and warn the patient about the need to inform the doctor about the appearance of any symptoms of infection.

In patients with congenital deficiency of glucose-6-phosphate dehydrogenase, isolated cases of hemolytic anemia have been reported.

Negroid race

The risk of developing angioedema in black patients is higher. Like other ACE inhibitors, perindopril is less effective in lowering blood pressure in black patients, possibly due to the higher prevalence of low-renin conditions in this population of patients with arterial hypertension.

Cough

During therapy with ACE inhibitors, a persistent, non-productive cough may develop, which stops after discontinuation of the drug. This should be taken into account in the differential diagnosis of cough.

Surgery/general anesthesia

In patients whose condition requires major surgery or anesthesia with drugs that cause hypotension, ACE inhibitors, including perindopril, may block the formation of angiotensin II with compensatory renin release. One day before surgery, therapy with ACE inhibitors must be discontinued. If the ACE inhibitor cannot be canceled, then arterial hypotension developing according to the described mechanism can be corrected by increasing the volume of blood volume.

Hyperkalemia

During therapy with ACE inhibitors, including perindopril, the concentration of potassium ions in the blood may increase in some patients. The risk of hyperkalemia is increased in patients with renal and/or heart failure, decompensated diabetes mellitus, and in patients using potassium-sparing diuretics, potassium supplements, or other drugs that cause hyperkalemia (eg, heparin). If it is necessary to prescribe these drugs simultaneously, it is recommended to regularly monitor the potassium content in the blood serum.

Diabetes

In patients with diabetes mellitus taking oral hypoglycemic agents or insulin, blood glucose concentrations should be carefully monitored during the first few months of ACE inhibitor therapy.

Lithium

Concomitant use of lithium and perindopril is not recommended.

Potassium-sparing diuretics, potassium-containing drugs, potassium-containing foods and nutritional supplements

It is not recommended to use in combination with ACE inhibitors.

Lactose

Perineva® tablets contain lactose. Therefore, patients with hereditary galactose intolerance, lapp lactase deficiency or glucose-galactose malabsorption syndrome should not take this drug.

Impact on the ability to drive vehicles and operate machinery

It is necessary to take into account the possibility of developing arterial hypotension or dizziness, which may affect driving and working with technical equipment.

Analogs

Level 4 ATX code matches:
Akkuzid

Enap-N

Iruzid

Co-Diroton

Enalozide

Enap NL

Enapril-N

Capozide

Tritace Plus

Enzix

Liprazid

Co-Renitec

Hartil N

Hartil D

Noliprel

Kaptopres

special instructions

It is not recommended to take it in parallel with lithium preparations.

Therapy is strictly contraindicated in patients with impaired renal function. Patients suffering from hypertension may experience symptoms of renal failure . In this case, you should stop treatment with Co-Perineva. Later, therapy can be repeated, prescribing minimal doses, or indapamide and perindopril can be used in monotherapy. These patients should have their blood creatinine and potassium levels checked every two weeks.

The combination of indapamide and perindopril cannot prevent the development of hypokalemia , especially in cases where the patient has diabetes mellitus or renal failure. In this case, the level of potassium in the blood must be monitored regularly.

Perineva®

IHD: reducing the risk of cardiovascular complications in patients who have previously had myocardial infarction and/or coronary revascularization

If unstable angina develops during the first month of therapy with Perineva®, the benefits and risks should be assessed to decide whether to continue therapy.

Arterial hypotension

ACE inhibitors can cause a sharp decrease in blood pressure. Symptomatic hypotension rarely develops in patients with uncomplicated arterial hypertension. The risk of a pronounced decrease in blood pressure is increased in patients with reduced blood volume, which can be observed during diuretic therapy, while following a strict salt-free diet, hemodialysis, diarrhea and vomiting, as well as in patients with severe arterial hypertension with high renin activity (see sections “Interaction” with other drugs" and "Side effects"). In patients at increased risk of developing symptomatic hypotension, blood pressure, renal function and serum potassium levels should be carefully monitored during therapy with Perineva®.

A similar approach is used in patients with coronary artery disease and cerebrovascular diseases, in whom severe arterial hypotension can lead to myocardial infarction or cerebrovascular accident.

If arterial hypotension develops, the patient should be transferred to the supine position with legs elevated. If necessary, the blood volume should be replenished by intravenous administration of 0.9% sodium chloride solution. Transient arterial hypotension is not an obstacle to further taking the drug. After restoration of blood volume and blood pressure, treatment can be continued.

In some patients with CHF and normal or reduced blood pressure, Perineva® may cause an additional decrease in blood pressure. This effect is predictable and does not usually require discontinuation of therapy. If symptoms of a pronounced decrease in blood pressure appear, the dose of the drug should be reduced or discontinued.

Mitral stenosis/aortic stenosis/HOCM

Perineva®, like other ACE inhibitors, should be administered with caution to patients with left ventricular outflow tract obstruction (aortic stenosis, HOCM), as well as to patients with mitral stenosis.

Renal dysfunction

For patients with renal failure (creatinine clearance < 60 ml/min), the initial dose of Perineva® is selected depending on the clearance value (see section “Method of administration and dosage”) and then depending on the therapeutic effect. For such patients, regular monitoring of creatinine concentration and potassium content in the blood serum is necessary (see section "Side effects").

Hypotension, which sometimes develops when starting ACE inhibitors in patients with symptomatic CHF, can lead to deterioration of renal function. It is possible to develop acute renal failure, which is usually reversible. In patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney (especially in the presence of renal failure), during therapy with ACE inhibitors, there may be an increase in the concentration of urea and creatinine in the blood serum, which usually resolves when therapy is discontinued. The additional presence of renovascular hypertension causes an increased risk of severe hypotension and renal failure in such patients.

Treatment of such patients begins under close medical supervision using low doses of the drug and further adequate selection of doses. Treatment with diuretics should be temporarily discontinued and serum potassium and creatinine concentrations regularly monitored during the first few weeks of therapy.

In some patients with arterial hypertension without indication of pre-existing renal vascular disease, serum urea and creatinine concentrations may increase, especially with simultaneous use of diuretics. These changes are usually mild and reversible. The likelihood of developing these disorders is higher in patients with a history of renal failure. In such cases, it may be necessary to discontinue or reduce the dose of Perineva® and/or the diuretic.

Hemodialysis

In patients undergoing hemodialysis using high-flux membranes (for example, AN69®), cases of anaphylactic reactions have been reported during therapy with ACE inhibitors. The use of ACE inhibitors should be avoided when using this type of membrane.

Kidney transplant

There are no data on the use of perindopril in patients after kidney transplantation.

Hypersensitivity, angioedema

When using ACE inhibitors, including perindopril, in rare cases and during any period of therapy, the development of angioedema of the face, upper and lower extremities, lips, mucous membranes, tongue, vocal folds and/or larynx may be observed (see section “Adverse reactions”). action"). If symptoms appear, Perineva® should be discontinued immediately and the patient should be observed until signs of edema have completely disappeared. If the swelling affects only the face and lips, it usually resolves on its own, although antihistamines may be used to treat symptoms.

Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction. If these symptoms occur, emergency treatment is required, including subcutaneous injection of epinephrine (adrenaline) and/or airway management. The patient should be under medical supervision until symptoms disappear completely and permanently.

Patients with a history of angioedema not associated with taking ACE inhibitors may have an increased risk of developing it when using drugs of this group (see section "Contraindications").

In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without previous angioedema of the face and with normal C1-esterase activity. Diagnosis was made using abdominal computed tomography, ultrasound, or surgery. Symptoms disappeared after discontinuation of ACE inhibitor therapy. Therefore, in patients with abdominal pain receiving ACE inhibitors, when carrying out differential diagnosis, it is necessary to take into account the possibility of developing angioedema of the intestine (see section “Side effects”).

Neutral endopeptidase inhibitors

When ACE inhibitors are used simultaneously with drugs containing sacubitril (neprilysin inhibitor), the risk of developing angioedema increases, and therefore the simultaneous use of these drugs is contraindicated. ACE inhibitors should be prescribed no earlier than 36 hours after discontinuation of drugs containing sacubitril. Prescription of drugs containing sacubitril is contraindicated in patients receiving ACE inhibitors, as well as within 36 hours after discontinuation of ACE inhibitors.

Tissue tasminogen activators

Observational studies have shown an increased incidence of angioedema in patients taking ACE inhibitors following the use of alteplase for thrombolytic therapy of ischemic stroke.

An increased risk of angioedema was observed in patients concomitantly taking ACE inhibitors and drugs such as mTOR inhibitors (temsirolimus, sirolimus, everolimus), DPP-4 inhibitors (sitagliptin, saxagliptin, vildagliptin, linagliptin), estramustine, neutral endopeptidase inhibitors (racecadotril). , sacubitril) and tissue plasminogen activators.

Anaphylactoid reactions during LDL apheresis

In rare cases, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be temporarily discontinued before each apheresis procedure.

Anaphylactoid reactions during desensitization

There are isolated reports of the development of anaphylactoid reactions in patients receiving therapy with ACE inhibitors during desensitization therapy, for example, hymenoptera venom. ACE inhibitors should be used with caution in patients susceptible to allergic reactions undergoing desensitization procedures. The use of ACE inhibitors should be avoided in patients receiving bee venom immunotherapy. However, this reaction can be avoided by temporarily discontinuing the ACE inhibitor before starting the desensitization procedure.

Liver dysfunction

In rare cases, during the use of ACE inhibitors, a syndrome of development of cholestatic jaundice with transition to fulminant liver necrosis, sometimes with death, was observed. The mechanism of development of this syndrome is unclear. If jaundice or a significant increase in the activity of liver enzymes in the blood plasma occurs during the use of ACE inhibitors, the drug should be stopped (see section “Side Effects”), the patient should be under appropriate medical supervision.

Neutropenia/ agranulocytosis/ thrombocytopenia/ anemia

Neutropenia/agranulocytosis, thrombocytopenia and anemia may occur during the use of ACE inhibitors. In patients with normal renal function and in the absence of other aggravating factors, neutropenia rarely develops. Perineva® should be used with extreme caution in patients with systemic connective tissue diseases, while taking immunosuppressants, allopurinol or procainamide, especially in patients with impaired renal function.

Some patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When using the drug Perineva®, such patients are recommended to periodically monitor the number of leukocytes in the blood. Patients should report any signs of infectious diseases (eg, sore throat, fever) to their doctor.

Ethnic differences

It should be taken into account that patients of the Negroid race have a higher risk of developing angioedema. Like other ACE inhibitors, Perineva® is less effective in lowering blood pressure in black patients.

This effect may be associated with a pronounced predominance of low-renin status in black patients with arterial hypertension.

Cough

During therapy with ACE inhibitors, a persistent dry cough may occur, which stops after discontinuation of the drug. This should be taken into account when carrying out the differential diagnosis of cough.

Surgery, general anesthesia

The use of ACE inhibitors in patients undergoing surgery under general anesthesia can lead to a significant decrease in blood pressure, especially when using drugs for general anesthesia that have an antihypertensive effect. Taking Perineva® should be stopped one day before surgery. If arterial hypotension develops, blood pressure should be maintained by replenishing blood volume. It is necessary to warn the surgeon/anesthesiologist that the patient is taking ACE inhibitors.

Hyperkalemia

Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. Risk factors for the development of hyperkalemia are impaired renal function, age over 70 years, diabetes mellitus, some concomitant conditions (dehydration, acute heart failure, metabolic acidosis), simultaneous use of potassium-sparing diuretics (such as spironolactone and its derivative eplerenone, triamterene, amiloride), food potassium supplements/preparations or potassium-containing table salt substitutes, as well as the use of other drugs that increase serum potassium levels (for example, heparin trimethoprim or co-trimoxazole (trimethoprim + sulfamethoxazole) and especially aldosterone antagonists or angiotensin receptor blockers).

The use of potassium supplements/preparations, potassium-sparing diuretics, and potassium-containing table salt substitutes can lead to a significant increase in serum potassium levels, especially in patients with reduced renal function. Hyperkalemia can cause serious, sometimes fatal, abnormal heart rhythms. If simultaneous use of Perineva® and the above drugs is necessary, treatment should be carried out with caution against the background of regular monitoring of potassium levels in the blood serum (see section “Interaction with other drugs”).

Diabetes

When using perindopril in patients with diabetes mellitus who are receiving oral hypoglycemic agents or insulin, during the first month of therapy it is necessary to regularly monitor the concentration of glucose in the blood (see section “Interaction with other drugs”).

Lithium preparations

The simultaneous use of Perineva® and lithium preparations is not recommended (see section “Interaction with other drugs”).

Potassium-sparing diuretics, potassium supplements, potassium-containing table salt substitutes and food supplements

Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving perindopril. Concomitant use of potassium-sparing diuretics (such as spironolactone, triamterene, amiloride), potassium supplements, or potassium-containing supplements or salt substitutes may lead to hyperkalemia.

Caution should also be exercised when co-prescribing perindopril with other drugs that increase serum potassium, such as heparin, trimethoprim and co-trimoxazole (trimethoprim + sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic (such as amiloride). Therefore, the combination of perindopril with the above drugs is not recommended.

If it is necessary to use perindopril and the drugs listed above simultaneously, caution should be exercised and the potassium level in the blood serum should be regularly monitored.

Double blockade of the RAAS

Cases of hypotension, syncope, stroke, hyperkalemia and renal dysfunction (including acute renal failure) have been reported in susceptible patients, especially when used concomitantly with drugs that affect this system.

Concomitant use of ACE inhibitors with aliskiren and drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients .

Concomitant use of ACE inhibitors with ARB II is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Primary aldosteronism

Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs that act by inhibiting the RAAS. Therefore, the use of Perineva® in this group of patients is not recommended.

Special information on excipients

The drug Perineva® contains lactose, therefore its use is contraindicated in patients with congenital galactose intolerance, lactase deficiency, and glucose-galactose malabsorption syndrome.

Ko-Perineva price, where to buy

The cost of the drug in Russia on average is about 500 rubles per package of 1.25 mg + 4 mg 30 pcs. and 900 rubles for 1.25 mg + 4 mg 90 pcs. packaged.

• Online pharmacies in RussiaRussia

ZdravCity

• KO-Perineva tablets 4mg+1.25mg 30 pcs. Krka-Rus LLC
  484 rub. order
• KO-Perineva tablets 8mg+2.5mg 30 pcs. Krka-Rus LLC

  RUR 513 order

• KO-Perineva tablets 2mg+0.625mg 30 pcs. Krka-Rus LLC

  RUB 291 order

• KO-Perineva tablets 4mg+1.25mg 90 pcs. Krka-Rus LLC

  830 rub. order

• KO-Perineva tablets 8mg+2.5mg 90 pcs. Krka-Rus LLC

  RUB 973 order