Trimetazidine (Preductal MB) is a myocardial cytoprotector that optimizes the energy metabolism of cardiomyocytes under conditions of myocardial ischemia by inhibiting beta-oxidation of fatty acids. Provides antianginal and anti-ischemic effects. Can be used as an additional agent and in combination with other antianginal drugs.

Ivabradine (Coraxan) is a selective and specific inhibitor of If channels of the sinoatrial junction, which has an anti-ischemic and antianginal effect due to a decrease in heart rate. Used to monitor heart rate in patients with sinus rhythm when beta blockers and other antianginal drugs are impossible or ineffective.

Keywords: trimetazidine, modified release (MR), antianginal, anti-ischemic effects, If channels, coraxan.

ANTIANGINAL DRUGS WITH METABOLIC ACTION (TRIMETAZIDINE)

In recent years, there has been noticeable interest in the metabolic direction of treatment stable angina. The use of antianginal and anti-ischemic drugs with metabolic action allows one to avoid adverse consequences when prescribing or increasing doses of antianginal drugs with hemodynamic action (nitrovasodilators, beta-adrenergic receptor blockers, slow calcium channel blockers).

Mechanism of action of trimetazidine

The antianginal, anti-ischemic, and toprotective effect of trimetazidine is determined (mediated) by the optimization of the energy metabolism of cardiomyocytes under conditions of myocardial ischemia.

The myocardium receives energy in the form of adenosine triphosphate (ATP) molecules, which are synthesized directly in cardiomyocytes through the oxidation of energy substrates in mitochondria. ATP consumption in cardiomyocytes is dynamically balanced by its synthesis; Without reproduction of ATP reserves in the cardiomyocyte, there is only enough for a few heartbeats. The main energy substrates for cardiomyocytes are long-chain fatty acids (FA), glucose and lactate (2/3 of ATP are synthesized from FA, 1/3 from glucose and lactate). In cardiomyocytes, glucose undergoes enzymatic glycolytic reactions with the formation ATP molecules, maintaining the gradient of ions (ionic stability) and the integrity of the cell membrane during ischemia, or, with the formation of pyruvate, which requires less oxygen consumption for metabolism than FA.

Increased oxidation of fatty acids, inhibiting the oxidation of pyruvate in the mitochondria of cardiomyocytes, underlies the decrease in the ability

thy myocardium to resist ischemic cell damage. The accumulation of FAs and their metabolites in cardiomyocytes during hypoxia has cytotoxic effects on cell membranes. Excessive amounts of FA uncouple oxidative phosphorylation in mitochondria, further reducing ATP synthesis, disrupting cell contractility and causing irreversible structural changes.

Partial switching of metabolism from the use of the myocardium as an energy substrate of fatty acids to glucose protects cardiomyocytes from ischemic damage and improves the efficiency of the heart. Medicines that can limit the use of fatty acids in favor of glucose oxidation are called cytoprotective anti-ischemic antianginal drugs with a metabolic mechanism of action.

Trimetazidine is a partial inhibitor of beta-oxidation of fatty acids, selectively reducing the activity of DC 3-ketoacyl CoA thiolase, the enzyme beta-oxidation of fatty acids.

Effects of trimetazidine

The use of trimetazidine significantly reduces the frequency of angina attacks, increases the time of exercise, and the time of exercise before the onset of segment depression ST, duration of peak load both in monotherapy and in combination with other antianginal drugs.

An increase in the coronary reserve of patients with coronary artery disease is observed after the 15th day of regular use of the drug.

The combined use of propranolol, as a hemodynamic antianginal drug, with trimetazidine was more effective than the use of propranolol with isosorbide dinitrate - two hemodynamic antianginal drugs per number anginal attacks and stress test tolerance.

The additional antianginal effect of trimetazidine persists with long-term regular use, providing good tolerability and improved quality of life.

Data are reported on the restoration of the function of hibernating myocardium, which can be used for patients who are not subject to angioplasty, or the absence of surgical treatment for ischemic heart disease.

In patients with CHF, the use of trimetazidine led to an improvement in local myocardial contractility, an increase in the left ventricular ejection fraction both at rest and at the peak of pharmacological load, a decrease in the functional class of angina pectoris and CHF, and an increase in the 6-minute walking distance.

Trimetazidine has 2 dosage forms: a regular release form and a modified (slow) release form (preductal MB). Preductal MB has pharmacokinetic and clinical advantages over the conventional dosage form of trimetazidine, providing additional antianginal and anti-ischemic effects throughout the day with control of ischemia in the early morning hours.

Pharmacokinetic parameters of the modified release form of trimetazidine - preductal MB

Modified release form of trimetazidine dosage form preductal MV allows you to maintain therapeutic concentration active substance for 11 hours at a level of 75% of the maximum, which allows the drug to be used 2 times a day to maintain a more stable concentration of trimetazidine throughout the day compared to the usual release form of the active substance. The hydrophilic matrix of the dosage form of Preductal MB, upon contact with the liquid of the gastrointestinal tract after swelling, turns into a gel, forming a kind of barrier that controls the release of trimetazidine and ensures the uniformity and duration of action of the drug. The bioavailability of the drug does not depend on food intake. A stable concentration of the active substance is achieved 2-3 days after the start of regular use of the drug.

The volume of distribution of the drug is 4.8 l/kg, which suggests good diffusion of trimetazidine into tissue. Binding to serum proteins is low, which ensures the safety of combination therapy with other classes of pharmacological agents. Drug interactions trimetazidine has not been described.

Trimetazidine is excreted mainly by the kidneys unchanged. The half-life is 7 hours, increasing to 12 hours in patients over 65 years of age. The renal clearance of trimetazidine directly correlates with creatinine clearance.

Hepatic clearance decreases with age. The drug is not recommended for patients with renal failure with creatinine clearance less than 15 ml/min, as well as for patients with severe liver dysfunction.

Currently, no cases of drug overdose have been reported.

Teratogenic effects have not been established in experimental studies.

Trimetazidine does not affect the ability to drive a car or perform work that requires a high speed of psychomotor reactions.

Indications for use of trimetazidine

Preductal MB is the most studied drug with proven antianginal and anti-ischemic effects.

Currently, this is the only myocardial cytoprotector recommended by experts from cardiological societies in Russia, Europe, and America for the treatment of angina pectoris. According to Russian recommendations, the drug can be prescribed at any stage of the treatment of stable angina to enhance the antianginal effectiveness of beta blockers, calcium antagonists and nitrates to all patients with stable angina pectoris.

If it is impossible to prescribe antianginal classes of drugs with hemodynamic action (beta-blockers, calcium antagonists and nitrates), trimetazidine can take place in the treatment of angina in combination with ivabradine, and in cases where it is impossible to prescribe antianginal drugs of other classes - as a monotherapy drug.

The most justified situations for the use of CF preductal in the treatment of patients with stable angina:

Insufficient effectiveness of traditional antianginal drugs;

Poor tolerability of traditional antianginal drugs or the presence of contraindications to their use;

Diabetes;

Chronic heart failure.

Diabetes mellitus is an important risk factor for myocardial infarction and sudden death in patients with and without ischemic heart disease. In diabetes mellitus, metabolism in the muscles and heart shifts towards the utilization of fatty acids, the utilization of glucose is limited, which leads to a decrease in the efficiency of muscle tissue contraction and resistance to ischemia. Limiting the oxidation of fatty acids and stimulating the utilization of glucose when using trimetazidine restores the balance between glycolysis and glucose oxidation, increases the formation of ATP under conditions of limited oxygen consumption in patients with diabetes.

Side effects of timetazidine and contraindications

Rarely - nausea, vomiting, allergic reactions are possible.

The drug is contraindicated during pregnancy due to the lack of clinical data on the safety of its use.

It is unknown whether trimetazidine is secreted from breast milk, therefore the drug is not recommended during lactation.

SPECIFIC IF CHANNEL INHIBITOR OF SINO-TRIAL COMPOUND (IVABRADINE)

Ivabradine (Coraxan) is a selective and specific inhibitor of If channels of the sinoatrial junction with an anti-ischemic and antianginal effect due to a decrease in heart rate.

An increase in heart rate significantly increases myocardial oxygen demand and increases myocardial blood flow in patients with coronary artery disease. Large epidemiological studies confirm the role of high resting heart rate as a strong predictor of overall and cardiovascular mortality in groups of healthy people, in patients with arterial hypertension, patients with metabolic syndrome, the elderly and patients with coronary heart disease. The use of beta-blockers in patients who have suffered a myocardial infarction has revealed the undeniable benefit of lowering heart rate in reducing mortality in this group.

Electrophysiological properties of cardiomyocytes

Heart rate determines:

Myocardial oxygen consumption and myocardial ischemic threshold;

Diastolic filling time of the coronary arteries and coronary blood flow time;

Increased sympathetic influence of catecholamines, increasing the threshold for ventricular fibrillation, which may lead to increased cardiovascular morbidity and mortality;

Proatherogenic effect.

High heart rate, as a factor of poor physical fitness or poor general health, is associated with higher rates of coronary and cardiovascular mortality and sudden death is associated with increased mortality in patients with coronary artery disease, confirmed myocardial infarction, in elderly patients.

In the mechanism of contraction of cardiomyocytes or the generation of impulses by specialized pacemaker cells of the sinus node, the determining factor is the change in potential between the inner and outer surfaces of the cell membrane - transient depolarization of the cell membranes of the action potential.

Under resting conditions, cardiomyocytes are in a state of polarization, having a constant difference in electrical potential between the inner and outer surfaces of the cell membrane - the resting transmembrane potential. The resting transmembrane potential, approximately -90 mV, is maintained, like the action potential, by ionic cytoplasmic currents of the Na-K ion pump through cell membranes and intercellular junctions.

Cell depolarization occurs when positively charged ions enter the cell, continues until the electrochemical gradient is balanced and determines the action potential that moves along the conduction pathways and, at the level of myocardial cells, stimulates muscle contraction.

In the electrophysiological state of cardiomyocytes, phases of fast depolarization, fast repolarization, plateau, slow repolarization related to the action potential, and the resting potential phase are distinguished (Fig. 17.1). In specialized heart cells with pacemaker properties, the slow phase

repolarization enters the phase of spontaneous diastolic (pacemaker) depolarization, which brings the membrane potential to the threshold voltage, resulting in the initiation of an action potential (Fig. 17.2). Spontaneous diastolic depolarization occurs due to the action of the Na-K ion pump, where the flow of positively charged ions into the cell determines the diastolic change in depolarization.

Mechanism of action of Coraxan

Ivabaradine (coraxan)- a representative of a new class of drugs that selectively and specifically inhibits If channels of the sinoatrial junction, the anti-ischemic and antianginal result of which is due to the effect of reducing heart rate.

When the membrane potential is maintained at a level of -35 mV, i.e., with closed If channels, Coraxan does not bind to the cells of the sinus node. The ability to inhibit f channels occurs at a more negative transmembrane potential when the channel is in the open state. In this case, Coraxan is able to reach the binding site located inside the f-channel pore, suppress the If-current and provide an effective reduction in heart rate.

Rice. 17.1. Electrophysiology of cardiomyocytes. 0 - fast depolarization phase, 1 - fast repolarization phase, 2 - plateau phase, 3 - slow repolarization phase, 4 - resting potential phase

Rice. 17.2. Action potential of sinus node cells

The specific binding property of Coraxan with open f-channels defined the concept of “dependent therapeutic utility”:

The level of coraxan binding depends on the level of f-channel opening and heart rate;

The effectiveness of Coraxan increases with a higher heart rate.

Coraxan reduces the amplitude of If currents depending on the concentration.

Acting at the level of the sinus node, selectively suppressing ionic If currents of open If channels, Coraxan reduces the rate of spontaneous diastolic depolarization without changing the maximum diastolic potential, increasing the time interval between action potentials and reducing the heart rate depending on the degree of its severity and in proportion to the concentration of the active substances.

At a concentration of Coraxan 100 times higher than the therapeutic one (10 μ/mol), there was a slight decrease in the activity of L-type calcium channels, which did not lead to a significant suppression of the current of calcium ions. These data suggest the absence of a negative inotropic effect of Coraxan on contractions.

tive myocardial function, however, the use of Coraxan in patients with systolic myocardial dysfunction requires additional clinical confirmation.

The effect of Coraxan on T-type calcium channels in the formation of the action potential of the sinus node was not detected.

The effect of Coraxan on the I-potassium current of the repolarization phase of the action potential was noted only when the therapeutic concentration was exceeded by more than 30 times.

Anti-ischemic and hemodynamic effects of Coraxan

The anti-ischemic and anti-anginal effects of Coraxan (5 mg, 7.5 mg or 10 mg 2 times a day) in controlling angina attacks and reducing myocardial ischemia in patients with stable angina are comparable to the anti-anginal and anti-ischemic effects of atenolol and amlodipine (100 mg and 10 mg per day, respectively). Heart rate and double product (HR x BP) at rest and at maximum physical activity as an indicator of myocardial oxygen consumption were significantly lower in the group of patients receiving Coraxan compared to the group receiving amlodipine.

The incidence of adverse side effects was comparable, and Coraxan showed high tolerability.

The antianginal effect of Coraxan is maintained with long-term regular use without the development of pharmacological tolerance. There was no development of withdrawal syndrome after stopping the drug.

The benefits of the drug are especially evident when it is necessary to control the heart rate of patients who have contraindications to the use of beta-adrenergic blockers.

The hemodynamic effect of Coraxan is determined by an increase in the time interval between two action potentials of the sinus node, providing a decrease in heart rate without systemic hemodynamic effects, dose-dependently reducing oxygen consumption by the myocardium, providing improvement in regional myocardial contractility in the area of ​​​​reduced coronary blood flow. During therapy with Coraxan, there is no change in the average blood pressure, decreased contractility

ability of the myocardium, the isochoric type of relaxation rate of the left ventricular myocardium is maintained (which is important for maintaining the volume of the left ventricle in heart failure). In the case of left ventricular dysfunction with inadequate tissue perfusion and the need for the use of positive inotropic drugs, these drugs can increase the severity of tachycardia and hypotension (dobutamine) or, by stimulating beta-1 adrenergic receptors, increase the release of norepinephrine (dopamine), which will cause increased myocardial ischemia. In such a situation, the use of ivabradine will help important role in limiting heart rate without reducing the positive inotropic effect, providing improvement in myocardial blood flow while stabilizing the hemodynamics of patients with heart failure or in conditions of cardiogenic shock. The benefits of ivabradine are also revealed in the treatment of patients with postural orthostatic syndrome, sinus node re-entry tachycardia, excessive sinus tachycardia, when it is not possible to prescribe beta-adrenergic receptor blockers or slow calcium channel blockers - drugs with a negative inotropic and/or hypotensive effect that can enhance symptoms of the disease.

Effect of Coraxan on the QT interval. Prolongation of the QT interval for drugs with negative chronotropic effects is associated with a higher risk of mortality in both patients with heart disease and the general population. Prolongation of the QT interval is a predisposing factor for the occurrence of potentially fatal ventricular tachycardia (torsade de pointes) due to changes in the process of ventricular repolarization. Data from a study of the effect of ivabradine on the corrected (heart rate-related) QT interval (QTc) confirmed the absence of changes in the QTc interval during therapy with ivabradine.

In patients with stable angina and normal electrophysiological parameters, the use of ivabradine did not reveal a significant slowdown in the conduction of impulses through the atria or ventricles of the heart. These results demonstrate the ability of ivabradine to preserve the atrial refractory period, atrioventricular conduction time, and the duration of the repolarization period.

The combined use of Coraxan with drugs that prolong the QT interval: quinidine, disopyramide, bepredil, sotalol, ibutilide, amiodarone, pimazide, zipraside, sertindole, mefloquine, halofantrine, pentamidine, cisapride, erythromycin.

Concomitant use with drugs that prolong the QT interval may increase the decrease in heart rate, which requires increased cardiac control.

Pharmacokinetic properties of Coraxan

The drug is rapidly absorbed after oral administration. Peak plasma concentrations are reached after 1-1.5 hours, regardless of the dose of the drug. Changes in drug kinetics after meals are not clinically significant. The bioavailability of the drug after oral administration approaches 40%, regardless of the dose of the drug.

The average volume of distribution of the drug in patients is 1.4 l/kg. Plasma protein binding is about 70%.

The average plasma concentration upon reaching steady state is 10 mg/ml. The equilibrium concentration of the drug is achieved within 24 hours.

The drug undergoes active metabolism, 22 metabolites have been identified.

The main metabolism occurs in the liver with the participation of cytochrome CYP3A4; the combined administration of potent CYP3A4 inhibitors leads to an increase in the maximum concentration and half-life of the drug, with an increase in the severity of the decrease in heart rate. The use of hepatic metabolism inducers can reduce the area under the pharmacokinetic curve of the drug without affecting electrocardiographic parameters.

The half-life of Coraxan under regular use is about 2 hours. It is excreted in the form of metabolites equally by the liver and kidneys. Less than 10% of an orally administered dose is found unchanged in urine.

Side effects

Visual impairment

The most common side effects when using Coraxan are visual changes in perception (photopsia), moderately pronounced, spontaneously disappearing during therapy.

Photopsia as passing changes in brightness in a limited area of ​​the visual field; they were initiated by a sharp change in illumination intensity, when viewing shiny objects in bright light, and occurred in 14.5% of patients. In only 1% of patients, the appearance of photopsia was the reason for refusing treatment or changing the usual daily routine.

The mechanism of photopsia is inhibition of f-channels in retinal cells.

A common side effect is blurred vision. Side effects from vision may limit the use of the drug in patients managing various types vehicles or working on production lines.

From the cardiovascular system: frequent - bradycardia, AV block of the first degree, ventricular extrasystole; rare - palpitations, supraventricular extrasystole.

From the gastrointestinal tract: rare - nausea, constipation, diarrhea.

General disorders: frequent - headache, dizziness, rare - shortness of breath, muscle cramps.

Laboratory changes: rare - hyperuricemia, eosinophilia, increased plasma creatinine levels.

Indications and contraindications

Benefits of Coraxan for concomitant conditions

Stable angina + asthma/COPD

Stable angina + sexual dysfunction

Stable angina + peripheral atherosclerosis

Stable angina + symptoms of weakness

Stable angina + depression

Stable angina + sleep disturbances

Stable angina + no effect of beta blocker

Stable angina + moderate A-V disorders carrying out

Stable angina + diabetes with significant fluctuations in glycemia

Stable angina + normal blood pressure Warnings for prescribing Coraxan

Sinus arrhythmia A-V block II degree

Combination with other drugs that reduce heart rate

Arterial hypotension

Acute period of stroke CHF stage II according to NYHA

Moderate liver failure

Severe renal failure

Retinal pigmentary degeneration

Contraindications

Increased sensitivity to ivabradine or any of the excipients of the drug

Resting heart rate less than 60 beats per minute (before treatment)

S-A blockade

A-V blockade III degree

Presence of an artificial pacemaker

Acute myocardial infarction

Cardiogenic shock

Unstable angina

Expressed arterial hypotension(BP below 90/50 mmHg)

CHF stage III-IV according to NYHA

Severe liver failure (more than 9 points according to the Child-Pug classification)

Concomitant use with strong inhibitors of cytochrome P 4503A4 (antifungals of the azole group - ketaconazole, intraconazole; macrolides - clarithromycin, erythromycin for oral administration, josamycin, telithromycin; HIV protease inhibitors - nelfinavir, ritonavir; nefozadone)

Pregnancy, breastfeeding.

Coraxan was registered by the European Medicines Registration Agency in July 2005 and by the Russian Pharmacological Committee in November 2005 as symptomatic treatment stable angina in patients with sinus rhythm who have a contraindication or intolerance to beta-blockers.

Ivabradin(Koraksan).

In recent years, selective I f -inhibitors (specific blockers of the incoming ion current through mixed Na + /K + channels activated at the moment of hyperpolarization) have been intensively studied. Ion current I f plays an important role in pacemaker activity, since it is responsible for the occurrence of the phase of spontaneous slow diastolic depolarization in the cells of the sinus node, and therefore determines the heart rate. As a result of blockade of I f channels in the sinoatrial node, due to a decrease in heart rate, the myocardial oxygen demand decreases without a concomitant decrease in the force of heart contractions (dose-dependent effect).

One of the drugs - I f -channel blockers - is Ivabradin(Coraxan), prescribed 5-10 mg 2 times a day. When using the usual recommended dose (7.5 mg 2 times a day), there is a decrease in heart rate by approximately 10 beats/min at rest and during exercise. This reduces the work of the heart and reduces oxygen consumption by the myocardium.

The drug is comparable in antianginal activity to atenolol, but unlike β-blockers, it does not cause bronchospasm, AV blockade and erectile dysfunction. Ivabradine is contraindicated in case of bradycardia (heart rate less than 50 beats/min), grade II-III AV block, sick sinus syndrome.

Side effects are mainly due to the effect of the drug on the f-channel related h-channels of the retina, which is the cause visual symptoms varying degrees severity in 10-15% of patients (photopsia, increased brightness in the visual field, blurred vision). These symptoms, as a rule, occur in the first 2 months of therapy, are moderate, reversible and do not require special treatment.

Indications for use

Treatment of stable angina in patients with normal sinus rhythm:

If you are intolerant or have contraindications to the use of beta-blockers.
In combination with beta-blockers in case of inadequate control of stable angina on the background of the optimal dose of beta-blocker.

Chronic heart failure:

To reduce the incidence of cardiovascular complications in patients with chronic heart failure, with sinus rhythm and heart rate of at least 70 beats/min.

Description of the effect on the body

Ivabradine is a drug that slows the heart rate, the mechanism of action of which is to selectively and specifically inhibit the If channels of the sinus node, which control spontaneous diastolic depolarization in the sinus node and regulate heart rate. Ivabradine has a selective effect on the sinus node, without affecting the timing of impulses along the intraatrial, atrioventricular and intraventricular pathways, as well as myocardial contractility and ventricular repolarization. Ivabradine may also interact with Ih channels of the retina, similar to the If channels of the heart, involved in the occurrence of temporary changes in the visual perception system due to changes in the retinal reaction to bright light stimuli. Under provoking circumstances, partial inhibition of Ih channels by ivabradine causes the phenomenon of changes in light perception .
Photopsia is characterized by a transient change in brightness in a limited area of ​​the visual field. The main pharmacological feature of ivabradine is its ability to dose-dependently reduce heart rate.
An analysis of the dependence of the magnitude of the decrease in heart rate on the dose of the drug was carried out with a gradual increase in the dose of ivabradine to 20 mg 2 times a day and revealed a tendency to achieve a plateau effect, which reduces the risk of developing severe bradycardia. When the drug is prescribed in recommended doses, the degree of decrease in heart rate depends on its initial value and is approximately 10-15 beats/min at rest and during physical activity.
As a result, the work of the heart decreases and the myocardium’s need for oxygen decreases.
Ivabradine does not affect intracardiac conduction, myocardial contractility, or the process of repolarization of the ventricles of the heart.
In clinical electrophysiological studies, ivabradine had no effect on the timing of impulses along the atrioventricular or intraventricular pathways, as well as on corrected QT intervals.
In studies involving patients with left ventricular dysfunction of 30-45%), it was shown that ivabradine does not affect myocardial contractility. It was found that ivabradine at a dose of 5 mg 2 times a day improved the performance of stress tests after 3-4 weeks of therapy.
Efficacy was also confirmed for a dose of 7.5 mg 2 times a day.
In particular, an additional effect when increasing the dose from 5 mg to 7.5 mg 2 times / day was established in a comparative study with atenolol.
The time for performing physical activity increased by approximately 1 min after just 1 month of using ivabradine at a dose of 5 mg 2 times a day, while after an additional 3-month course of taking ivabradine at a dose of 7.5 mg 2 times a day orally, a further increase in this indicator by 25 was noted sec.
The antianginal and anti-ischemic efficacy of ivabradine was also confirmed in patients aged 65 years and older.
The effectiveness of ivabradine when used in doses of 5 mg and 7.5 mg 2 times a day was noted in these studies in relation to all indicators of stress tests, and was also accompanied by a decrease in the incidence of angina attacks by approximately 70%.
The use of ivabradine 2 times a day provided constant therapeutic efficacy for 24 hours. In patients taking ivabradine, additional effectiveness of ivabradine was shown in relation to all indicators of stress tests when added to maximum dose atenolol at a decline in therapeutic activity. There is no improvement in the effectiveness of ivabradine when added to the maximum dose of amlodipine at the decline in therapeutic activity, while at the maximum of activity the additional effectiveness of ivabradine has been proven. In clinical efficacy studies of the drug, the effects of ivabradine were fully maintained over the 3- and 4-month treatment periods.
During treatment, there were no signs of the development of tolerance, and after cessation of treatment, no withdrawal syndrome was observed.
The antianginal and anti-ischemic effects of ivabradine were associated with a dose-dependent decrease in heart rate, as well as a significant decrease in work product, both at rest and during physical activity.
The effect on blood pressure and peripheral vascular resistance was minor and clinically insignificant.
A sustained reduction in heart rate has been demonstrated in patients taking ivabradine for at least 1 year.
No effect on carbohydrate metabolism and lipid profile was observed. In patients with diabetes mellitus, the efficacy and safety of ivabradine were similar to those in the general patient population.
There were no differences between the groups of patients taking ivabradine against the background of standard therapy, and in patients with stable angina and left ventricular dysfunction, 86.9% of whom received beta-blockers, and placebo, in the total incidence of deaths from cardiovascular diseases, hospitalization for acute myocardial infarction, hospitalization for new cases of heart failure or worsening symptoms of chronic heart failure and in the subgroup of patients with a heart rate of at least 70 beats/min. The use of ivabradine in patients with a heart rate of at least 70 beats/min showed a reduction in the frequency of hospitalizations for fatal and non-fatal myocardial infarction by 36% and in the frequency of revascularization by 30%. In patients with exertional angina, a decrease was noted while taking ivabradine. relative risk the occurrence of complications by 24%.
The noted therapeutic benefit is achieved primarily by reducing the frequency of hospitalization for acute myocardial infarction by 42%. Reducing the frequency of hospitalization for fatal and non-fatal myocardial infarction in patients with heart rate more than 70 beats/min.
even more significant and reaches 73%.
In general, the drug was well tolerated and safe. When using ivabradine in patients with CHF II-IV functional class according to the NYHA classification with LVEF less than 35%, a clinically and statistically significant reduction in the relative risk of complications by 18% was shown.
The absolute risk reduction was 4.2%.
A pronounced therapeutic effect was observed 3 months from the start of therapy. A decrease in mortality from cardiovascular diseases and a decrease in the frequency of hospitalizations due to increased symptoms of CHF was observed regardless of age, gender, functional class of CHF, the use of beta-blockers, ischemic or non-ischemic etiology of CHF, the presence diabetes mellitus or arterial hypertension in the anamnesis. Patients with symptoms of CHF in sinus rhythm and with a heart rate of at least 70 beats/min received standard therapy, including the use of beta-blockers, ACE inhibitors and/or angiotensin II receptor antagonists, diuretics and aldosterone antagonists. It has been shown that the use of ivabradine for 1 year can prevent one death or one hospitalization due to cardiovascular disease for every 26 patients taking the drug. The use of ivabradine has shown an improvement in the functional class of CHF according to the NYHA classification. In patients with a heart rate of 80 beats/min, a decrease in heart rate by an average of 15 beats/min was noted.

Contraindications to the drug

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Concomitant use with strong inhibitors of the cytochrome P450 3A4 isoenzyme system, such as azole antifungals, macrolide antibiotics, HIV protease inhibitors and nefazodone.
Lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.
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Hypersensitivity to ivabradine or any component of the drug.

WITH caution the drug should be prescribed for moderate liver failure, severe renal failure, congenital elongation QT interval, concomitant use of drugs that prolong the QT interval, concomitant use of moderate inhibitors of the CYP 3A4 isoenzyme and grapefruit juice, asymptomatic left ventricular dysfunction, second degree AV block, recent stroke, retinal pigmentary degeneration, arterial hypotension, simultaneous use with slow calcium channel blockers that reduce heart rate, such as verapamil or diltiazem.

Side effects on the body

The drug was studied in studies involving almost 14,000 patients. The most common side effects of ivabradine were dose-dependent and related to the mechanism of action of the drug.

The frequency of adverse reactions that were noted in clinical studies is given in the following gradation: very often; often; infrequently; rarely; very rarely; unspecified frequency.

From the side of the organ of vision:
Very often - changes in light perception.

The following adverse events identified in clinical studies occurred with equal frequency in both the group of patients receiving ivabradine and in the comparison group, which suggests their connection with the disease itself and not with taking ivabradine: sinus arrhythmia, angina pectoris, incl. h. unstable, atrial fibrillation, myocardial ischemia, myocardial infarction and ventricular tachycardia.

Cautions for use

During pregnancy:

Coraxan ® is contraindicated for use during pregnancy. IN currently There is insufficient data on the use of the drug during pregnancy.

Preclinical studies of ivabradine revealed embryotoxic and teratogenic effects.

The use of Coraxan ® during breastfeeding is contraindicated. There is no information on the penetration of ivabradine into breast milk.

Heart rhythm disturbances:

Coraxan ® is not effective for the treatment or prevention of arrhythmias. Its effectiveness decreases against the background of the development of tachyarrhythmia. The drug is not recommended for patients with atrial fibrillation or other types of arrhythmias associated with sinus node function.

During therapy, patients should be clinically monitored for atrial fibrillation. When clinically indicated, routine monitoring should include an ECG.

Use in patients with bradycardia:

Coraxan ® is contraindicated if, before starting therapy, the resting heart rate is less than 60 beats/min. If, during therapy, heart rate at rest decreases to values ​​less than 50 beats/min, or the patient experiences symptoms associated with bradycardia, it is necessary to reduce the dose of the drug. If, when the dose of the drug is reduced, the heart rate remains less than 50 beats/min, or symptoms associated with bradycardia persist, then taking Coraxan ® should be discontinued.

Combined use as part of antianginal therapy:

The use of Coraxan ® in combination with blockers of “slow” calcium channels that reduce heart rate, such as verapamil or diltiazem, is not recommended.

With the combined use of ivabradine with nitrates and blockers of “slow” calcium channels - dihydropyridine derivatives, such as amlodipine, no changes in the safety profile of the therapy were noted. It has not been established that combined use with blockers of “slow” calcium channels increases the effectiveness of ivabradine.

Functions of visual perception:

Coraxan ® affects the function of the retina. Currently, no toxic effects of ivabradine on the retina have been identified, but the effect of the drug on the retina with long-term use is currently unknown. If visual impairments that are not described in these instructions occur, you should consider stopping taking the drug Coraxan ® . Patients with retinal pigmentary degeneration should take Coraxan ® with caution.

Excipients:

The drug contains lactose, therefore Coraxan ® is not recommended for patients with lactase deficiency, lactose intolerance, or glucose-galactose malabsorption syndrome.

Arterial hypotension:

Due to insufficient clinical data, the drug should be prescribed with caution to patients with arterial hypotension.

Coraxan ® is contraindicated in cases of severe arterial hypotension.

Atrial fibrillation - cardiac arrhythmias:

There is no proven increase in the risk of developing severe bradycardia while taking the drug Coraxan ® during recovery sinus rhythm during pharmacological cardioversion. However, due to the lack of sufficient data, if it is possible to delay electrical cardioversion, Coraxan ® should be discontinued 24 hours before it is performed.

Use in patients with congenital long QT syndrome or patients taking drugs that prolong the QT interval:

Coraxan ® should not be prescribed for congenital syndrome prolonged QT interval, as well as in combination with drugs that prolong the QT interval. If such therapy is necessary, strict ECG monitoring is necessary.

Moderate liver failure:

In case of moderately severe liver failure, therapy with Coraxan ® should be carried out with caution.

Severe renal failure:

In case of severe renal failure, therapy with Coraxan ® should be carried out with caution.

Impact on the ability to drive vehicles and operate machinery:

The use of the drug Coraxan ® does not impair the quality of driving. Coraxan ® does not affect the ability to drive vehicles or perform work that requires a high speed of psychomotor reactions. However, one should remember the possibility of photopsia with a sharp change in lighting intensity, especially when controlling vehicles at night time.

How to use

Coraxan ® should be taken orally 2 times a day, morning and evening with meals.

For stable angina pectoris, the recommended initial dose of the drug is 10 mg/day. Depending on the therapeutic effect, after 3-4 weeks of use, the dose of the drug can be increased to 15 mg. If during therapy with Coraxan ® the resting heart rate decreases to values ​​less than 50 beats/min, or the patient experiences symptoms associated with bradycardia, it is necessary to reduce the dose of Coraxan ® 2 times a day). If, when the dose of the drug Coraxan ® is reduced, the heart rate remains less than 50 beats/min or symptoms of severe bradycardia persist, the drug should be discontinued:

If the heart rate is stable at no more than 50 beats/min or if symptoms of bradycardia appear, such as dizziness, fatigue or arterial hypotension the dose can be reduced to 2.5 mg 2 times / day.

If the heart rate is in the range from 50 to 60 beats/min, it is recommended to use the drug Coraxan ® at a dose of 5 mg 2 times a day.

If, during the use of the drug, the heart rate at rest is consistently less than 50 beats/min or if the patient has symptoms of bradycardia, for patients receiving the drug Coraxan ® at a dose of 5 mg 2 times / day or 7.5 mg 2 times / day, the dose of the drug should be reduced.

If in patients receiving Coraxan ® at a dose of 2.5 mg 2 times / day or 5 mg 2 times / day, the heart rate at rest is consistently more than 60 beats / min, the dose of the drug can be increased.

If the heart rate is not more than 50 beats/min or the patient continues to have symptoms of bradycardia, the use of the drug should be discontinued.

U patients aged 75 years and older The recommended initial dose of Coraxan ® is 2.5 mg (1/2 tablet of 5 mg) 2 times a day. In the future, it is possible to increase the dose of the drug.

Patients with renal dysfunction with CC more than 15 ml/min The recommended initial dose of Coraxan ® is 10 mg/day (1 tablet 5 mg 2 times/day). Depending on the therapeutic effect, after 3-4 weeks of use, the dose of the drug can be increased to 15 mg (1 tablet 7.5 mg 2 times a day).

Due to the lack of clinical data on the use of the drug Coraxan ® in patients with CC less than 15 ml/min, the drug should be used with caution.

For patients with mild hepatic insufficiency (up to 7 points on the Child-Pugh scale) The usual dosing regimen is recommended. The recommended initial dose of Coraxan ® is 10 mg/day (1 tablet 5 mg 2 times/day). Depending on the therapeutic effect, after 3-4 weeks of use, the dose of the drug can be increased to 15 mg (1 tablet 7.5 mg 2 times a day).

Caution should be exercised when using the drug in patients with moderate liver failure (7-9 points on the Child-Pugh scale).

Coraxan ® is contraindicated in patients with severe liver failure (more than 9 points on the Child-Pugh scale), since the use of the drug in such patients has not been studied (a significant increase in the concentration of the drug in the blood plasma can be expected).

Consequences of incorrect dosage

Symptoms:
Severe and prolonged bradycardia.

Treatment:
Severe bradycardia should be symptomatic and treated in specialized departments. In case of development of bradycardia in combination with hemodynamic disturbances, symptomatic treatment with intravenous administration of beta-adrenergic agonists, such as isoprenaline, is indicated. If necessary, an artificial pacemaker can be installed.

Combination with other medications

The simultaneous use of ivabradine and drugs that prolong the QT interval should be avoided since a decrease in heart rate may cause further prolongation of the QT interval. If it is necessary to prescribe these drugs together, ECG readings should be carefully monitored:

Ivabradine is metabolized in the liver with the participation of isoenzymes of the cytochrome P450 system and is a very weak inhibitor of this isoenzyme. Ivabradine does not have a significant effect on the metabolism and plasma concentrations of other cytochrome CYP3A4 substrates. At the same time, inhibitors and inducers of the CYP3A4 isoenzyme can interact with ivabradine and have a clinically significant effect on its metabolism and pharmacokinetic properties. It has been found that inhibitors of the CYP3A4 isoenzyme increase, and inducers of the CYP3A4 isoenzyme reduce, plasma concentrations of ivabradine:

Increasing the concentration of ivabradine in blood plasma may increase the risk of developing severe bradycardia.

Contraindicated combinations of drugs:

Concomitant use of ivabradine with potent inhibitors of the CYP3A4 isoenzyme, such as azole antifungals, macrolide antibiotics, HIV protease inhibitors and nefazodone is contraindicated. Potent inhibitors of the CYP3A4 isoenzyme - ketoconazole or josamycin - increase the average concentrations of ivabradine in blood plasma by 7-8 times.

Undesirable drug combinations:

The combined use of ivabradine and moderate inhibitors of the CYP3A4 isoenzyme diltiazem or verapamil in healthy volunteers and patients was accompanied by an increase in the AUC of ivabradine by 2-3 times and an additional decrease in heart rate by 5 beats/min. This use is not recommended:

Combinations of drugs that require caution:

Inducers of the CYP3A4 isoenzyme, such as rifampicin, barbiturates, phenytoin and herbal remedies containing St. John's wort, with joint use may lead to a decrease in the blood concentration and activity of ivabradine and require the selection of a higher dose of ivabradine. With the combined use of ivabradine and preparations containing St. John's wort, a twofold decrease in the AUC of ivabradine was noted. During therapy with Coraxan ®, you should, if possible, avoid the use of drugs and products containing St. John's wort:

Combined use with other drugs:

Clinically shown to be absent significant impact on the pharmacodynamics and pharmacokinetics of ivabradine with the simultaneous use of the following drugs: proton pump inhibitors, PDE5 inhibitors, HMG-CoA reductase inhibitors, slow calcium channel blockers - dihydropyridine derivatives, digoxin and warfarin. It has been shown that ivabradine does not have a clinically significant effect on the pharmacokinetics of simvastatin, amlodipine, lacidipine, the pharmacokinetics and pharmacodynamics of digoxin, warfarin and the pharmacodynamics of acetylsalicylic acid.

Ivabradine was used in combination with ACE inhibitors, angiotensin II receptor antagonists, beta-blockers, diuretics, aldosterone antagonists, short- and long-acting nitrates, HMG-CoA reductase inhibitors, fibrates, proton pump inhibitors, oral hypoglycemic agents, acetylsalicylic acid and other antiplatelet agents. The use of the above drugs was not accompanied by a change in the safety profile of the therapy.

Other interactions requiring caution when used together:

When taking grapefruit juice, there was a 2-fold increase in the concentration of ivabradine in the blood. During therapy with Coraxan ®, you should avoid drinking grapefruit juice if possible:

Modern research has established a clear correlation between heart rate and overall mortality - a chronic increase in heart rate increases the risk of developing cardiovascular diseases, and vice versa, a decrease in heart rate, respectively, prolongation of diastole, increases perfusion time blood vessels, reducing metabolic costs of the myocardium, improving myocardial blood flow. Given the importance of this fact, experts continue to study the mechanisms of formation and control of heart rhythm.

Relatively recently, in the 80s of the last century, an ion f-channel was discovered in the cells of the sinoatrial node, which is activated during depolarization; later it was called pacemaker, since its properties were confirmed by a direct correlation between the degree of its expression and heart rate (the development of bradycardia during its blockade).

First drug ivabradine(coraxan), related to f-channel blockade, was developed in 1999.

The mechanism of action of ivabradine is to suppress I f channels of the sinus node, which control spontaneous diastolic depolarization in the sinus node and regulate heart rate. The drug acts selectively; taking 20 mg of ivabradine twice a day reduces the heart rate by 10 beats/minute, resulting in a decrease in heart function and a decrease in myocardial oxygen demand.

Ivabradine does not affect intracardiac conduction, myocardial contractility and ventricular repolarization processes. After oral administration, the drug is quickly and completely absorbed from the gastrointestinal tract, the maximum concentration in the blood is observed 1.5 hours after oral administration on an empty stomach. Bioavailability - 40%. Eating increases the absorption time of the drug by 1 hour, increases the concentration in the blood by 10% (up to 30%). Communication with blood proteins - 70%. Ivabradine is metabolized in the liver and intestines. The half-life of the drug is 2 hours. Ivabradine is excreted mainly in the form of metabolites and a small amount of unchanged substance through the kidneys and gastrointestinal tract.

Indications for use of ivabradine:

• treatment of stable angina in patients with normal sinus rhythm with intolerance or contraindications to the use of beta-blockers;
• heart failure.

Contraindications:

• hypersensitivity to the drug;
• Heart rate at rest is below 60 beats/min;
• cardiogenic shock;
• acute MI;
• severe arterial hypotension (blood pressure below 90/50 mm Hg);
• severe liver failure;
• sick sinus syndrome;
• sinoatrial block, unstable angina, third degree AV block;
• simultaneous use with cytochrome P4503A4 inhibitors;
• Coraxan is contraindicated during pregnancy and breastfeeding;
• not recommended for use under the age of 18 years.

• with meals in the morning and evening, 5 mg;
• the dose can be adjusted after 3-4 weeks (depending on the therapeutic effect) to 15 mg;
• if bradycardia develops during drug therapy (heart rate less than 50 beats/min), the dose of the drug is reduced.

Side effect:

• disturbances in visual perception associated with changes in lighting brightness (transient);
• blurred vision;
• bradycardia develops in 3.3% of patients in the first 2-3 months of treatment, 0.5% of patients develop a severe degree with a heart rate below 40 beats/min;
• 1st degree AV block;
• ventricular extrasystole;
• Coraxan is not effective for the treatment and prevention of cardiac arrhythmias;
• Coraxan is not recommended for atrial fibrillation (atrial fibrillation), other types of arrhythmias that are associated with the function of the sinus node;
• Coraxan is not recommended in combination with blockers of slow calcium channels that slow down heart rate (verapamil, diltiazem).

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Catad_tema Heart rhythm and conduction disorders - articles

Pulse-sparing pharmacotherapy for sinus rhythm

Heart rate is an independent risk factor for overall and cardiovascular mortality. The review examines the favorable prognosis-modifying effect of selective deceleration of sinus rhythm using a modern arsenal of pharmacological groups.

Keywords: heart rate, pharmacological correction, β-blockers, calcium antagonists, ivabradine.

Heart rate lowering pharmacotherapy in sinus rhythm
Professor V. Oleinikov, MD; A. Kulyutsin, Candidate of Medical Sciences; M. Lukyanova
Medical Institute, Penza State University

Heart rate is an independent risk factor for overall and cardiovascular mortality. The review considers the favorable prognosis-modifying impact of selective sinus rhythm lowering, by applying the current arsenal of pharmacological groups.

Key words: heart rate, pharmacological correction, β-adrenoblockers, calcium antagonists, ivabradine.

In recent decades, the role of the sympathetic nervous system(SNS) in the pathogenesis of cardiovascular diseases, in particular in arterial hypertension (AH), coronary disease heart disease (CHD), chronic heart failure syndrome (CHF), metabolic syndrome(MS). The most accessible manifestation of hypersympathicotonia for physical diagnosis is an increased heart rate (HR). Over the past 20 years, the results of more than 20 epidemiological studies involving more than 280 thousand people have been published, assessing the clinical significance of heart rate in sinus rhythm.

The negative prognosis associated with increased heart rate applies to different categories of patients. Thus, a prospective observation of patients with hypertension showed that each increase in resting heart rate by 10 per minute is associated with an increase in overall and cardiovascular mortality by 20 and 14%, respectively. A number of researchers point to the relationship between resting heart rate and mortality in patients with hypertension, MS and the elderly. C. Pepine et al. The international INVEST study analyzed data from 22,192 patients with hypertension and stable coronary artery disease who were randomized to verapamil SR and atenolol. An increase in baseline resting heart rate was associated with an increased risk of adverse outcomes (death from all causes, non-fatal myocardial infarction - MI, non-fatal stroke) during 2.7 years of follow-up; in patients with a resting heart rate of more than 100 per minute, the risk was 2 times higher than at a lower heart rate.

Heart rate statistically significantly correlates with the severity and progression of atherosclerosis, which was confirmed by A. Perski et al. when performing coronary angiography in men who have had a myocardial infarction at a young age. A recent study found that high heart rate was associated with an increased risk of coronary atherothrombosis. Some studies have shown that an increase in heart rate at rest is associated with increased arterial stiffness, decreased vascular distensibility and high pulse wave propagation speed. Finally, a high heart rate may indicate an imbalance of the autonomic nervous system, being a marker of sympathetic hyperactivity.

It has been established that increased heart rate is accompanied by an increase in cardiovascular morbidity and mortality not only among patients, but also in the general population. According to the Framingham study, an increase in resting heart rate is associated with an increase in mortality from all causes (coronary, sudden, cerebrovascular) regardless of other risk factors. As a result of analysis of available information, most researchers consider an increase in office heart rate to be an independent risk factor for cardiovascular disease and death.

In connection with the above, in 2007, a working group on heart rate was created at the European Society of Cardiology (ESC). Consensus Published working group"Resting heart rate in cardiovascular diseases." Analysis of the evidence base on the role of heart rate as a risk factor led to the following conclusion: studies in recent years demonstrate a continuous increase in risk with a heart rate exceeding 60 per minute. Also in 2007, the ESC Guideline “Prevention of Cardiovascular Diseases in Clinical Practice” was published, where resting heart rate was for the first time recognized as an independent risk factor for both overall and cardiovascular mortality.

The BEAUTIFUL study, completed in 2008, was the first to analyze the relationship between heart rate and prognosis in a group of patients (5438 examined) who received placebo in addition to standard therapy; analysis showed that heart rate >70 per minute identifies individuals at higher risk of cardiovascular events.

The hypothesis about the role of heart rate as a modifiable risk factor is convincingly confirmed by studies devoted to pharmacological correction of heart rate, which show a direct relationship between a decrease in heart rate and mortality during therapy with β-blockers (BB) in patients who have had a MI or suffer from CHF.

A systematic meta-analysis examining the long-term effects of beta-blocker treatment convincingly demonstrated that a reduction in heart rate of 10.7 beats per minute was associated with a 17.4% reduction in cardiovascular mortality in post-MI patients and an 18% reduction in non-fatal MI. Along with left ventricular wall tension and contractility, heart rate is one of the main factors in myocardial oxygen consumption.

In patients with stable coronary artery disease, an increase in heart rate naturally precedes the occurrence of myocardial ischemia during exercise. The incidence of angina while walking in patients receiving treatment for coronary artery disease depends on the average heart rate: in patients with a sinus rhythm frequency >80 per minute, angina attacks occur 2 times more often than in patients with a heart rate of 60 per minute. The likelihood of developing myocardial ischemia is proportional to the initial level, amplitude and duration of the increase in heart rate.

Data clinical trials indicate that in chronic ischemic heart disease, a decrease in heart rate not only provides more complete control of symptoms, but also improves the survival of this category of patients.

The effect of reducing heart rate in hypertension is not so clear. Thus, in a systematic review and meta-analysis performed at Columbia University (USA), it was shown that (in contrast to patients with MI and CHF), a decrease in heart rate with the help of a beta-blocker in patients with hypertension is accompanied by an increase in the risk of adverse cardiovascular outcomes and overall mortality . As a possible explanation, a violation of synchronization between the outgoing and reflected pulse waves, when the latter returns to systole (instead of diastole), thereby increasing central pressure in the aorta and afterload on the left ventricle.

Information about the importance of heart rate in clinical practice is reflected in the principles of sinus rhythm frequency control and target limits for reducing office heart rate in certain diseases and CHF syndrome, presented in European and national recommendations. Oddly enough, other currently available clinically adapted instrumental methods for monitoring pulse-lowering therapy have not yet been considered at all.

Target limits for heart rate reduction
Effective doses of pulse-lowering pharmacological agents, even with the same mechanism of action, can vary significantly in different patients, therefore in clinical practice it is necessary to use not fixed doses of drugs, but those that cause a distinct effect of reducing heart rate. R. Gorlin wrote back in 1976 that in order to reduce the rhythm frequency, “... it is necessary in all cases to look for an effective dose of β-blockers, and the real way for this is to monitor the degree of reduction in heart rate at rest.”

Historically, the greatest development in research and clinical practice has been the determination of heart rate in conditions of physical and emotional rest - the so-called office heart rate. This is explained by the simplicity of studying this indicator and its fairly high prognostic significance. The first attempt to systematize epidemiological data on the effect of resting heart rate on life expectancy was made in 1945. At that time, a heart rate of 99 per minute was considered the starting point above which the risk of cardiovascular complications arose. The evolution of attitudes towards the heart rate threshold in studies devoted to this issue is visible from the data presented in the table.

The value of the threshold heart rate value in studies of different years

There is an obvious trend towards a decrease in the conditional critical level, which gradually led to the office value of 65 per minute.

Despite the large arsenal of methods for both discrete and permanent assessment of the chronotropic function of the heart, primarily Holter ECG monitoring, until now there have been no controlled studies verifying target heart rate levels using more informative indicators than office ones. At the same time, the use of accessible equipment that allows you to quickly process any arrays of frequency indicators of heart rate could fundamentally change our ideas about the permissible limits of heart rate reduction during various diseases. So, according to H. Copie et al. , Heart rate estimated at daily ECG monitoring, has an even higher prognostic value than the determination of left ventricular ejection fraction, which is usually used as a prognostic index. The lack of epidemiological data on threshold heart rate values ​​determined by methods other than resting counting makes it urgent to search for new approaches to in-depth frequency analysis of sinus rhythm.

Pharmacological agents Pulse-lowering heart rate correction
There are 3 most common groups of drugs that modulate the frequency of sinus rhythm due to their effect on the function of the sinoatrial node: BB, calcium antagonists (CA), mainly of the non-dihydropyridine series, and F-channel inhibitors of the sinus node.

There are other classes of drugs that affect heart rate indirectly - through the vasomotor center or sympathovagal interactions. These include centrally acting drugs, cardiac glycosides, acetylcholinesterase inhibitors, and psychotropic modulators. However, their effect on heart rate is nonspecific, often does not reach clinical significance and is difficult to control, so the use of these classes of drugs to correct heart rate in practical work is irrational.

β-blockers.
Since heart rate is a clinical marker of sympathetic activity, it is most logical to correct heart rate using drugs that can prevent activation of the SNS or eliminate the pathophysiological effects of hypersympathicotonia that has already occurred. The latter mechanism underlies the pharmacological effects of BB, introduced into clinical practice more than 40 years ago. Initially they were used as antiarrhythmic drugs and for the treatment of angina pectoris; subsequently, the range of indications was significantly expanded. Currently, BBs are used to treat stable angina of all functional classes; the effectiveness of these drugs has been proven in acute forms IHD, they are used in the treatment of hypertension, supraventricular and ventricular arrhythmias, to control heart rate in patients atrial fibrillation, they increase the life expectancy of patients with CHF.

Without going into the nuances of the mechanism of action, we note that the basis for the positive clinical effect of all BBs is their ability to weaken the physiological and pathophysiological effects of norepinephrine and adrenaline, which are mediated by α- and β-adrenergic receptors.

Studies of the level of norepinephrine in the blood using high experimental technologies (microneurography, spectral analysis) made it possible to establish that BB eliminates many of the toxic effects characteristic of catecholamines: