Selective beta blockers of the latest generation. Beta blockers

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β-adrenergic receptor blockers, or β-blockers, are a group of drugs that can reversibly block β-adrenergic receptors. They have been used in clinical practice since the early 1960s for the treatment of coronary artery disease and cardiac arrhythmias; later they began to be used for the treatment of hypertension, and later - for the treatment of heart failure. The importance of β-blockers in the secondary prevention of diseases of the cardiovascular system was so high that in 1988 the scientists who took part in the creation of this group of drugs were awarded the Nobel Prize. In recent years, after receiving the results of several large controlled clinical trials and meta-analyzes, the range of use of β-blockers has somewhat narrowed, primarily due to their less active use as drugs for primary prevention in patients with hypertension.

Mechanism of action

The mechanism of action of β-blockers is quite complex, not fully understood, differs significantly for different drugs and consists in preventing the cardiotoxic effect of catecholamines, reducing heart rate, myocardial contractility and blood pressure, which leads to a decrease in myocardial oxygen demand. Improvement in perfusion of ischemic myocardial regions with the use of β-blockers is also due to diastole lengthening and "reverse coronary steal" due to an increase in vascular resistance in non-ischemic areas of the myocardium.

Pharmacokinetics

All β-blockers are capable of blocking β-adrenergic receptors. However, these drugs have differences (Table 1). They are divided depending on the selectivity of action on different types of β-adrenergic receptors, the presence of internal sympathomimetic activity, fat solubility, the ability to be metabolized in the liver, and the duration of action.

Table 1

The main properties of β-blockers used in the clinic

A drug	Presence of β1 -selectivity	Presence of intrinsic sympathomimetic activity	Presence of vasodilating properties	Т1/2
Atenolol Betaxolol bisoprolol Carvedilol metoprolol Nadolol Nebivolol Pindolol Proxodolol propranolol Sotalol Talinolol Timolol Esmolol	Yes Yes Yes Not Yes Not Yes Not There is no data Not Not Yes Not Yes	Not Not Not Not Not Not Not Yes Not Not Yes Yes Not Not	Not Not Not Yes Not Not Yes Not Yes Not Not Not Not Not	6-9 h 16-22 h 7-15 h 6 h 3-7 h 10-24 hours 10 h 2-4 h There is no data 2-5 h 7-15 h 6 h 2-4 h 9 min

Groups of β-blockers depending on the selectivity of action. There are two main types of β-adrenergic receptors: β1- and β2-adrenergic receptors.

• Non-selective. They act equally on both types of β-adrenergic receptors (propranolol).
• selective . They act to a greater extent on β1-adrenergic receptors (metoprolol, atenolol, etc.).

The selectivity of the action of β-blockers can be expressed to varying degrees, it almost always decreases or even disappears with increasing dose.

Groups of β-blockers depending on the presence of internal sympathomimetic activity and blockade of other types of receptors. Allocate β-blockers with internal sympathomimetic activity and without it, with α1 -adrenergic blocking activity and the ability to form nitric oxide.

• β-blockers with intrinsic sympathomimetic activity. They are able to simultaneously have a stimulating effect on the sympathetic nervous system. Previously, this property was considered as useful by reducing the inhibitory effect of drugs on the cardiovascular system. However, the presence of internal sympathomimetic activity worsens the prognosis of the disease.
• β-blockers without internal sympathomimetic activity. It is the severity of the blockade of β1-adrenergic receptors that underlies the favorable effect of drugs on the prognosis of the disease.

The results of clinical studies have confirmed that β1-blockers with intrinsic sympathomimetic activity are much less effective than β-blockers without it, and currently drugs of the first group are rarely used.

• β-blockers with α1-blocking activity. Due to this new effect, the drugs have an additional vasodilating effect (carvedilol).
• β-blockers capable of forming nitric oxide (nebivolol).

Groups of β-blockers depending on fat solubility

• Lipophilic (metoprolol, propranolol, bisoprolol, carvedilol).
• hydrophilic (timolol, sotalol, atenolol).

Previously, parallels were drawn between these properties of β-adrenergic locators and their effectiveness, as well as the ability to have side effects primarily on the central nervous system. However, according to the results of recent studies, in particular a meta-analysis of observational data on 35,000 patients who received β-blockers after myocardial infarction, no relationship was found between the ability of a particular drug to dissolve in fats and have side effects.

Groups of β-blockers depending on metabolism in the liver

• β-blockers metabolized in the liver. They are characterized by the so-called first pass effect.
• β-blockers that are not metabolized in the liver. They are excreted from the body by the kidneys unchanged.

These properties of drugs have practically no clinically significant effect.

Groups of β-blockers depending on the duration of action. It can be indirectly judged by the half-life (in no case should the half-life be considered equal to the duration of the drug!). In accordance with this, drugs of prolonged action, medium and short duration of action are isolated.

• β-blockers of prolonged action. Such drugs can be taken once a day (nadolol, bisoprolol, betaxolol). For some β-blockers (primarily for metoprolol), special dosage forms have been created that can significantly prolong their action and provide a more uniform effect.

Initially, a long-acting form of metoprolol tartrate (the so-called metoprolol SA) was proposed with a duration of effects of about 24 hours. Such dosage forms contain metoprolol tartrate in the form of an insoluble matrix (METO-IM) or in the form of a hydrophilic matrix (METO-HM). These extended release metoprolol tartrate formulations are available in Russia (eg Egilok retard).

In order to make the effect of metoprolol even more uniform, a special sustained release dosage form was proposed (metoprolol CR / ZOK; English controlled release / zero order kinetics, that is, a controlled release drug with zero order kinetics), in which metoprolol was used in the form of succinate .

Pharmacokinetic studies have shown that after taking 1 tablet of metoprolol CR / ZOK at 100 mg, a uniform concentration of metoprolol in the blood was maintained at a level of 100 nmol / l for at least 24 hours, which is significantly less than the peak concentration of the drug after taking conventional tablets (after taking a conventional metoprolol tablet the peak concentration reaches 600 nmol / l), but enough to create the maximum effect of the blockade of β-adrenergic receptors. At the same time, the absence of sharp peaks in the increase in the concentration of metoprolol after taking the sustained release dosage form causes better tolerability of the drug and prevents a number of undesirable effects.

• β-Adrenoblockers of medium duration of action. The effect of regular metoprolol tartrate tablets lasts from 8 to 10 hours, so they must be administered 2 or even 3 times a day.
• β-Adrenoblockers of short action. Esmolol is one of the shortest acting drugs. Its antianginal and antihypertensive effect lasts only 10-20 minutes after the infusion is stopped.

Martsevich S.Yu., Tolpygina S.N.

Beta blockers

Modern cardiology cannot be imagined without drugs from the group of beta-blockers, of which more than 30 names are currently known. The need to include beta-blockers in the treatment program for cardiovascular diseases (CVD) is obvious: over the past 50 years of cardiac clinical practice, beta-blockers have taken a strong position in the prevention of complications and in the pharmacotherapy of arterial hypertension (AH), coronary heart disease (CHD), chronic heart failure (CHF), metabolic syndrome (MS), as well as in some forms of tachyarrhythmias. Traditionally, in uncomplicated cases, drug treatment of hypertension begins with beta-blockers and diuretics, which reduce the risk of myocardial infarction (MI), cerebrovascular accident and sudden cardiogenic death.

The concept of the mediated action of drugs through the receptors of tissues of various organs was proposed by N.? Langly in 1905, and in 1906 H.? Dale confirmed it in practice.

In the 1990s, it was established that beta-adrenergic receptors are divided into three subtypes:

Beta1-adrenergic receptors, which are located in the heart and through which the stimulating effects of catecholamines on the activity of the heart pump are mediated: increased sinus rhythm, improved intracardiac conduction, increased myocardial excitability, increased myocardial contractility (positive chrono-, dromo-, batmo-, inotropic effects) ;

Beta2-adrenergic receptors, which are located mainly in the bronchi, smooth muscle cells of the vascular wall, skeletal muscles, in the pancreas; when stimulated, broncho- and vasodilatory effects, relaxation of smooth muscles and insulin secretion are realized;

Beta3-adrenergic receptors, localized mainly on adipocyte membranes, are involved in thermogenesis and lipolysis.
The idea of ​​using beta-blockers as cardioprotectors belongs to the Englishman J.? W.? Black, who was awarded the Nobel Prize in 1988 together with his colleagues, creators of beta-blockers. The Nobel Committee considered the clinical relevance of these drugs "the greatest breakthrough in the fight against heart disease since the discovery of digitalis 200 years ago."

The ability to block the effect of mediators on myocardial beta1-adrenergic receptors and the weakening of the effect of catecholamines on the membrane adenylate cyclase of cardiomyocytes with a decrease in the formation of cyclic adenosine monophosphate (cAMP) determine the main cardiotherapeutic effects of beta-blockers.

Anti-ischemic effect of beta-blockers due to a decrease in myocardial oxygen demand due to a decrease in heart rate (HR) and the strength of heart contractions that occur when myocardial beta-adrenergic receptors are blocked.

Beta-blockers simultaneously improve myocardial perfusion by reducing end-diastolic pressure in the left ventricle (LV) and increasing the pressure gradient that determines coronary perfusion during diastole, the duration of which increases as a result of slowing the heart rate.

Antiarrhythmic action of beta-blockers, based on their ability to reduce the adrenergic effect on the heart, leads to:

Decrease in heart rate (negative chronotropic effect);

Decreased automatism of the sinus node, AV connection and the His-Purkinje system (negative bathmotropic effect);

Reducing the duration of the action potential and the refractory period in the His-Purkinje system (the QT interval is shortened);

Slowing conduction in the AV junction and increasing the duration of the effective refractory period of the AV junction, lengthening the PQ interval (negative dromotropic effect).

Beta-blockers increase the threshold for ventricular fibrillation in patients with acute myocardial infarction and can be considered as a means of preventing fatal arrhythmias in the acute period of myocardial infarction.

Hypotensive action beta-blockers due to:

A decrease in the frequency and strength of heart contractions (negative chrono- and inotropic effect), which in total leads to a decrease in cardiac output (MOS);

Decrease in secretion and decrease in plasma renin concentration;

Restructuring of the baroreceptor mechanisms of the aortic arch and carotid sinus;

Central inhibition of sympathetic tone;

Blockade of postsynaptic peripheral beta-adrenergic receptors in the venous vascular bed, with a decrease in blood flow to the right heart and a decrease in MOS;

Competitive antagonism with catecholamines for receptor binding;

An increase in the level of prostaglandins in the blood.

Drugs from the group of beta-blockers differ in the presence or absence of cardioselectivity, internal sympathetic activity, membrane-stabilizing, vasodilating properties, solubility in lipids and water, the effect on platelet aggregation, and also in duration of action.

The effect on beta2-adrenergic receptors determines a significant part of the side effects and contraindications to their use (bronchospasm, peripheral vasoconstriction). A feature of cardioselective beta-blockers in comparison with non-selective ones is a greater affinity for beta1-receptors of the heart than for beta2-adrenergic receptors. Therefore, when used in small and medium doses, these drugs have a less pronounced effect on the smooth muscles of the bronchi and peripheral arteries. It should be borne in mind that the degree of cardioselectivity is not the same for different drugs. Index ci/beta1 to ci/beta2, characterizing the degree of cardioselectivity, is 1.8:1 for non-selective propranolol, 1:35 for atenolol and betaxolol, 1:20 for metoprolol, 1:75 for bisoprolol (Bisogamma). However, it should be remembered that selectivity is dose-dependent, it decreases with increasing dose of the drug (Fig. 1).

Currently, clinicians distinguish three generations of drugs with beta-blocking effect.

I generation - non-selective beta1- and beta2-blockers (propranolol, nadolol), which, along with negative ino-, chrono- and dromotropic effects, have the ability to increase the tone of the smooth muscles of the bronchi, vascular wall, myometrium, which significantly limits their use in clinical practice.

II generation - cardioselective beta1-blockers (metoprolol, bisoprolol), due to their high selectivity for myocardial beta1-adrenergic receptors, have more favorable tolerability with long-term use and a convincing evidence base for long-term life prognosis in the treatment of hypertension, coronary artery disease and CHF.

In the mid-1980s, third-generation beta-blockers appeared on the world pharmaceutical market with low selectivity for beta1, 2-adrenergic receptors, but with a combined blockade of alpha-adrenergic receptors.

III generation drugs - celiprolol, bucindolol, carvedilol (its generic analogue with the brand name Carvedigamma®) have additional vasodilating properties due to the blockade of alpha-adrenergic receptors, without internal sympathomimetic activity.

In 1982-1983, the first reports of clinical experience with the use of carvedilol in the treatment of CVD appeared in the scientific medical literature.

A number of authors have revealed the protective effect of third-generation beta-blockers on cell membranes. This is due, firstly, to the inhibition of lipid peroxidation (LPO) of membranes and the antioxidant effect of beta-blockers and, secondly, to a decrease in the effect of catecholamines on beta-receptors. Some authors associate the membrane-stabilizing effect of beta-blockers with a change in sodium conductivity through them and inhibition of lipid peroxidation.

These additional properties expand the prospects for the use of these drugs, since they neutralize the negative effect characteristic of the first two generations on myocardial contractility, carbohydrate and lipid metabolism, and at the same time provide improved tissue perfusion, a positive effect on hemostasis and the level of oxidative processes in the body.

Carvedilol is metabolized in the liver (glucuronidation and sulfation) by the cytochrome P450 enzyme system, using the CYP2D6 and CYP2C9 family of enzymes. The antioxidant effect of carvedilol and its metabolites is due to the presence of a carbazole group in the molecules (Fig. 2).

Carvedilol metabolites - SB 211475, SB 209995 inhibit LPO 40-100 times more actively than the drug itself, and vitamin E - about 1000 times.

The use of carvedilol (Carvedigamma®) in the treatment of coronary artery disease

According to the results of a number of completed multicenter studies, beta-blockers have a pronounced anti-ischemic effect. It should be noted that the anti-ischemic activity of beta-blockers is commensurate with the activity of calcium and nitrate antagonists, but, unlike these groups, beta-blockers not only improve the quality, but also increase the life expectancy of patients with coronary artery disease. According to the results of a meta-analysis of 27 multicenter studies involving more than 27 thousand people, selective beta-blockers without internal sympathomimetic activity in patients with a history of acute coronary syndrome reduce the risk of recurrent myocardial infarction and mortality from a heart attack by 20%.

However, not only selective beta-blockers have a positive effect on the nature of the course and prognosis in patients with coronary artery disease. The non-selective beta-blocker carvedilol has also shown very good efficacy in patients with stable angina. The high anti-ischemic efficacy of this drug is due to the presence of additional alpha1-blocking activity, which contributes to the dilatation of the coronary vessels and collaterals of the post-stenotic region, and hence to the improvement of myocardial perfusion. In addition, carvedilol has a proven antioxidant effect associated with the capture of free radicals released during ischemia, which causes its additional cardioprotective effect. At the same time, carvedilol blocks apoptosis (programmed death) of cardiomyocytes in the ischemic zone, while maintaining the volume of the functioning myocardium. The metabolite of carvedilol (VM 910228) has been shown to have a lesser beta-blocking effect, but is an active antioxidant, blocking lipid peroxidation, "trapping" active free radicals OH-. This derivative preserves the inotropic response of cardiomyocytes to Ca++, the intracellular concentration of which in the cardiomyocyte is regulated by the Ca++ pump of the sarcoplasmic reticulum. Therefore, carvedilol is more effective in the treatment of myocardial ischemia through inhibition of the damaging effect of free radicals on membrane lipids of subcellular structures of cardiomyocytes.

Due to these unique pharmacological properties, carvedilol may be superior to traditional beta1-selective blockers in terms of improving myocardial perfusion and help preserve systolic function in patients with CAD. As shown by Das Gupta et al., in patients with LV dysfunction and heart failure due to coronary artery disease, carvedilol monotherapy reduced filling pressure, and also increased LV ejection fraction (EF) and improved hemodynamic parameters, while not being accompanied by the development of bradycardia.

According to the results of clinical studies in patients with chronic stable angina, carvedilol reduces heart rate at rest and during exercise, and also increases EF at rest. A comparative study of carvedilol and verapamil, in which 313 patients took part, showed that, compared with verapamil, carvedilol to a greater extent reduces heart rate, systolic blood pressure and heart rate ´ blood pressure product during maximally tolerated physical activity. Moreover, carvedilol has a more favorable tolerability profile.
Importantly, carvedilol appears to be more effective in treating angina than conventional beta1-blockers. Thus, during a 3-month randomized, multicenter, double-blind study, carvedilol was directly compared with metoprolol in 364 patients with stable chronic angina. They took carvedilol 25–50 mg twice daily or metoprolol 50–100 mg twice daily. While both drugs showed good antianginal and anti-ischemic effects, carvedilol more significantly increased the time to ST segment depression by 1 mm during exercise than metoprolol. The tolerability of carvedilol was very good and, importantly, there was no marked change in the types of adverse events with increasing doses of carvedilol.

It is noteworthy that carvedilol, which, unlike other beta-blockers, does not have a cardiodepressive effect, improves the quality and life expectancy of patients with acute myocardial infarction (CHAPS) and post-infarction ischemic LV dysfunction (CAPRICORN) . Promising data came from the Carvedilol Heart Attack Pilot Study (CHAPS), a pilot study of the effect of carvedilol on the development of MI. This was the first randomized trial comparing carvedilol with placebo in 151 patients after acute myocardial infarction. Treatment was started within 24 hours of onset of chest pain and the dose was increased to 25 mg twice daily. The main endpoints of the study were LV function and drug safety. Patients were observed for 6 months from the onset of the disease. According to the data obtained, the incidence of serious cardiac events decreased by 49%.

Sonographic data obtained during the CHAPS study of 49 patients with reduced LVEF (< 45%) показали, что карведилол значительно улучшает восстановление функции ЛЖ после острого ИМ, как через 7 дней, так и через 3 месяца. При лечении карведилолом масса ЛЖ достоверно уменьшалась, в то время как у пациентов, принимавших плацебо, она увеличивалась (р = 0,02). Толщина стенки ЛЖ также значительно уменьшилась (р = 0,01). Карведилол способствовал сохранению геометрии ЛЖ, предупреждая изменение индекса сферичности, эхографического индекса глобального ремоделирования и размера ЛЖ. Следует подчеркнуть, что эти результаты были получены при монотерапии карведилолом. Кроме того, исследования с таллием-201 в этой же группе пациентов показали, что только карведилол значимо снижает частоту событий при наличии признаков обратимой ишемии. Собранные в ходе вышеописанных исследований данные убедительно доказывают наличие явных преимуществ карведилола перед традиционными бета-адреноблокаторами, что обусловлено его фармакологическими свойствами.

The good tolerability and anti-remodeling effect of carvedilol indicate that this drug may reduce the risk of death in post-MI patients. The large-scale CAPRICORN (CARvedilol Post InfaRct Survival COntRol in Left Ventricular DysfunctioN) study investigated the effect of carvedilol on survival in patients with left ventricular dysfunction after myocardial infarction. The CAPRICORN study demonstrated for the first time that carvedilol in combination with ACE inhibitors can reduce overall and cardiovascular mortality, as well as the rate of recurrent non-fatal heart attacks in this group of patients. New evidence that carvedilol is at least as effective, if not more effective in reversing remodeling in patients with CHF and CAD, supports the need for earlier carvedilol administration in myocardial ischemia. In addition, the effect of the drug on the “sleeping” (hibernating) myocardium deserves special attention.

Carvedilol in the treatment of hypertension

The leading role of violations of neurohumoral regulation in the pathogenesis of hypertension today is beyond doubt. Both main pathogenetic mechanisms of hypertension - an increase in cardiac output and an increase in peripheral vascular resistance - are controlled by the sympathetic nervous system. Therefore, beta-blockers and diuretics have been the standard of antihypertensive therapy for many years.

In the JNC-VI recommendations, beta-blockers were considered as first-line drugs for uncomplicated forms of hypertension, since only beta-blockers and diuretics have been proven in controlled clinical trials to reduce cardiovascular morbidity and mortality. According to the results of a meta-analysis of previous multicenter studies, beta-blockers did not live up to expectations regarding the effectiveness of reducing the risk of stroke. Negative metabolic effects and features of influence on hemodynamics did not allow them to take a leading place in the process of reducing myocardial and vascular remodeling. However, it should be noted that the studies included in the meta-analysis concerned only representatives of the second generation of beta-blockers - atenolol, metoprolol and did not include data on new drugs of the class. With the advent of new representatives of this group, the danger of their use in patients with impaired cardiac conduction, diabetes mellitus, lipid metabolism disorders, and renal pathology was largely leveled. The use of these drugs allows expanding the scope of beta-blockers in hypertension.

The most promising in the treatment of patients with hypertension of all representatives of the class of beta-blockers are drugs with vasodilating properties, one of which is carvedilol.

Carvedilol has a long-term hypotensive effect. According to the results of a meta-analysis of the hypotensive effect of carvedilol in more than 2.5 thousand patients with hypertension, blood pressure decreases after a single dose of the drug, but the maximum hypotensive effect develops after 1-2 weeks. The same study provides data on the effectiveness of the drug in different age groups: there were no significant differences in the level of blood pressure against the background of a 4-week intake of carvedilol at a dose of 25 or 50 mg in persons younger or older than 60 years of age.

It is important that, unlike non-selective and some beta1-selective blockers, beta-blockers with vasodilating activity not only do not reduce tissue sensitivity to insulin, but even slightly increase it. The ability of carvedilol to reduce insulin resistance is an effect that is largely due to beta1-blocking activity, which increases the activity of lipoprotein lipase in muscles, which in turn increases lipid clearance and improves peripheral perfusion, which contributes to more active absorption of glucose by tissues. Comparison of the effects of various beta blockers supports this concept. Thus, in a randomized study, carvedilol and atenolol were prescribed to patients with type 2 diabetes mellitus and hypertension. It was shown that after 24 weeks of therapy, fasting glycemia and insulin levels decreased with carvedilol treatment, and increased with atenolol treatment. In addition, carvedilol had a more pronounced positive effect on insulin sensitivity (p = 0.02), high-density lipoprotein (HDL) levels (p = 0.04), triglycerides (p = 0.01) and lipid peroxidation (p = 0.04).

Dyslipidemia is known to be one of the four major risk factors for CVD. Its combination with AG is especially unfavorable. However, taking some beta-blockers can also lead to unwanted changes in blood lipid levels. As already mentioned, carvedilol does not adversely affect serum lipid levels. The effect of carvedilol on the lipid profile in patients with mild to moderate hypertension and dyslipoproteinemia was studied in a multicentre, blind, randomized study. The study included 250 patients who were randomized into treatment groups with carvedilol at a dose of 25–50 mg/day or the ACE inhibitor captopril at a dose of 25–50 mg/day. The choice of captopril for comparison was determined by the fact that it either has no effect or has a positive effect on lipid metabolism. The duration of treatment was 6 months. In both compared groups, positive dynamics was noted: both drugs improved the lipid profile comparable. The beneficial effect of carvedilol on lipid metabolism is most likely due to its alpha-adrenergic blocking activity, since blockade of beta1-adrenergic receptors has been shown to cause vasodilation, resulting in improved hemodynamics, as well as a decrease in the severity of dyslipidemia.

In addition to the blockade of beta1-, beta2- and alpha1-receptors, carvedilol also has additional antioxidant and antiproliferative properties, which is important to consider in terms of influencing risk factors for CVD and ensuring protection of target organs in hypertensive patients.

Thus, the metabolic neutrality of the drug allows its widespread use in patients with hypertension and diabetes mellitus, as well as in patients with MS, which is especially important in the treatment of the elderly.

The alpha-blocking and antioxidant actions of carvedilol, which provide peripheral and coronary vasodilation, contribute to the effect of the drug on the parameters of central and peripheral hemodynamics, the positive effect of the drug on the ejection fraction and stroke volume of the left ventricle has been proven, which is especially important in the treatment of hypertensive patients with ischemic and non-ischemic heart failure.

As is known, hypertension is often combined with kidney damage, and when choosing antihypertensive therapy, it is necessary to take into account the possible adverse effects of the drug on the functional state of the kidneys. The use of beta-blockers in most cases may be associated with a decrease in renal blood flow and glomerular filtration rate. Carvedilol's beta-adrenergic blocking effect and the provision of vasodilation have been shown to have a positive effect on renal function.

Thus, carvedilol combines beta-blocking and vasodilating properties, which ensures its effectiveness in the treatment of hypertension.

Beta-blockers in the treatment of CHF

CHF is one of the most unfavorable pathological conditions that significantly worsen the quality and life expectancy of patients. The prevalence of heart failure is very high, it is the most common diagnosis in patients over 65 years of age. Currently, there is a steady upward trend in the number of patients with CHF, which is associated with an increase in survival in other CVDs, primarily in acute forms of coronary artery disease. According to WHO, the 5-year survival rate of patients with CHF does not exceed 30-50%. In the group of patients who have undergone MI, up to 50% die within the first year after the development of circulatory failure associated with a coronary event. Therefore, the most important task of optimizing therapy for CHF is the search for drugs that increase the life expectancy of patients with CHF.

Beta-blockers are recognized as one of the most promising classes of drugs that are effective both for the prevention of development and for the treatment of CHF, since activation of the sympathoadrenal system is one of the leading pathogenetic mechanisms for the development of CHF. Compensatory, at the initial stages of the disease, hypersympathicotonia subsequently becomes the main cause of myocardial remodeling, an increase in the trigger activity of cardiomyocytes, an increase in peripheral vascular resistance, and impaired perfusion of target organs.

The history of the use of beta-blockers in the treatment of patients with CHF has 25 years. Large-scale international studies CIBIS-II, MERIT-HF, US Carvedilol Heart Failure Trials Program, COPERNICUS approved beta-blockers as first-line drugs for the treatment of patients with CHF, confirming their safety and efficacy in the treatment of such patients (Table .). A meta-analysis of the results of major studies on the effectiveness of beta-blockers in patients with CHF showed that the additional appointment of beta-blockers to ACE inhibitors, along with improving hemodynamic parameters and well-being of patients, improves the course of CHF, quality of life indicators, reduces the frequency of hospitalization - by 41 % and the risk of death in patients with CHF by 37%.

According to the 2005 European guidelines, the use of beta-blockers is recommended in all patients with CHF in addition to ACE inhibitor therapy and symptomatic treatment. Moreover, according to the results of the COMET multicenter study, which was the first direct comparative test of the effect of carvedilol and the second-generation selective beta-blocker metoprolol at doses that provide an equivalent antiadrenergic effect on survival with an average follow-up period of 58 months, carvedilol was 17% more effective than metoprolol in reducing the risk of death.

This provided an average life expectancy gain of 1.4 years in the carvedilol group, with a maximum follow-up of up to 7 years. The indicated advantage of carvedilol is due to the absence of cardioselectivity and the presence of an alpha-blocking effect, which helps to reduce the hypertrophic response of the myocardium to noradrenaline, reduce peripheral vascular resistance, and suppress the production of renin by the kidneys. In addition, in clinical trials in patients with CHF, the antioxidant, anti-inflammatory (decrease in the levels of TNF-alpha (tumor necrosis factor), interleukins 6-8, C-peptide), antiproliferative and antiapoptotic effects of the drug have been proven, which also determines its significant advantages in the treatment of this contingent of patients not only among drugs of their own, but also of other groups.

On fig. Figure 3 shows a scheme for titrating doses of carvedilol for various pathologies of the cardiovascular system.

Thus, carvedilol, having beta- and alpha-adrenergic blocking effects with antioxidant, anti-inflammatory, antaptoptic activity, is among the most effective drugs from the class of beta-blockers currently used in the treatment of CVD and MS.

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A. M. Shilov
M. V. Melnik*, Doctor of Medical Sciences, Professor
A. Sh. Avshalumov**

*MMA them. I. M. Sechenov, Moscow
**Clinic of the Moscow Institute of Cybernetic Medicine, Moscow

Beta-blockers: pharmacological properties and clinical use

S. Yu. Shtrygol, Dr. med. Sciences, Professor National Pharmaceutical University, Kharkov

Blockers (antagonists) of β-adrenergic receptors have been successfully used in cardiology and other fields of medicine for about 40 years. The first β-blocker was dichloroisopropylnorepinephrine, which has now lost its importance. More than 80 drugs of similar action have been created, but not all of them have a wide clinical application.

For β-blockers, a combination of the following most important pharmacological effects is characteristic: hypotensive, antianginal and antiarrhythmic. Along with this, β-blockers have other types of action, for example, psychotropic effects (in particular, tranquilizing), the ability to lower intraocular pressure. In arterial hypertension, β-blockers are among the first-line drugs, especially in young patients with a hyperkinetic type of blood circulation.

β-adrenergic receptors play an important role in the regulation of physiological functions. These receptors specifically recognize and bind molecules of the circulating adrenal medulla hormone adrenaline and the neurotransmitter norepinephrine and transmit the molecular signals received from them to effector cells. β-adrenergic receptors are coupled to G-proteins, and through them to the enzyme adenylate cyclase, which catalyzes the formation of cyclic adenosine monophosphate in effector cells.

Since 1967, two main types of β-receptors have been distinguished. β1-adrenergic receptors are localized mainly on the postsynaptic membrane in the myocardium and the conduction system of the heart, in the kidneys and adipose tissue. Their excitation (provided mainly by the mediator norepinephrine) is accompanied by an increase and an increase in heart rate, an increase in the automatism of the heart, facilitation of atrioventricular conduction, and an increase in the heart's need for oxygen. In the kidneys, they mediate the release of renin. Blockade of β1-adrenergic receptors leads to opposite effects.

β2-adrenergic receptors are located on the presynaptic membrane of adrenergic synapses; when they are excited, the release of the norepinephrine mediator is stimulated. There are also extrasynaptic adrenergic receptors of this type, predominantly excited by circulating adrenaline. β2-adrenergic receptors predominate in the bronchi, in the vessels of most organs, in the uterus (when excited, the smooth muscles of these organs relax), in the liver (when excited, glycogenolysis and lipolysis increase), pancreas (control the release of insulin), platelets (reduce the ability to aggregate ). Both types of receptors are present in the CNS. In addition, another subtype of β-adrenergic receptors (β3 -) has been recently discovered, localized mainly in adipose tissue, where their excitation stimulates lipolysis and heat generation. The clinical significance of agents capable of blocking these receptors has yet to be clarified.

Depending on the ability to block both main types of β-adrenergic receptors (β1 - and β2 -) or block predominantly β1-receptors that predominate in the heart, cardio-nonselective (i.e., non-selective) and cardioselective (selective for β1-adrenergic receptors of the heart) are isolated drugs.

The table shows the most important representatives of β-blockers.

Table. The main representatives of β-adrenergic antagonists

Main pharmacological properties
β-blockers

By blocking β-adrenergic receptors, drugs of this group prevent the influence of norepinephrine, a mediator released from sympathetic nerve endings, as well as adrenaline circulating in the blood, on them. Thus, they weaken the sympathetic innervation and the action of adrenaline on various organs.

hypotensive action. Drugs in this group reduce blood pressure due to:

1. Weakening of the influence of the sympathetic nervous system and circulating adrenaline on the heart (decrease in the strength and frequency of heart contractions, and hence the stroke and minute volume of the heart)
2. A decrease in vascular tone due to relaxation of their smooth muscles, but this effect is secondary, occurs gradually (initially, vascular tone may even increase, since β-adrenergic receptors in the vessels, when excited, contribute to the relaxation of smooth muscles, and with blockade of β-receptors, vascular tone increases due to the predominance of effects on α-adrenergic receptors). Only gradually, due to a decrease in the release of noradrenaline from sympathetic nerve endings and due to a decrease in the secretion of renin in the kidneys, as well as due to the central action of β-blockers (a decrease in sympathetic influences), does the total peripheral resistance decrease.
3. Moderate diuretic effect due to inhibition of tubular sodium reabsorption (Shtrygol S. Yu., Branchevsky L. L., 1995).

The hypotensive effect practically does not depend on the presence or absence of selectivity of blockade of β-adrenergic receptors.

Antiarrhythmic action due to the inhibition of automatism in the sinus node and in heterotopic foci of excitation. Most β-blockers also have a moderate local anesthetic (membrane stabilizing) effect, which is important for their antiarrhythmic effect. However, β-blockers slow down atrioventricular conduction, which is the basis of their adverse effect - atrioventricular blockade.

Antianginal action is based mainly on a decrease in the heart's need for oxygen due to a decrease in the frequency and contractility of the myocardium, as well as on a decrease in the activity of lipolysis and a decrease in the content of fatty acids in the myocardium. Consequently, with less work of the heart and a lower level of energy substrates, the myocardium requires less oxygen. In addition, β-blockers increase the dissociation of oxyhemoglobin, which improves myocardial metabolism. β-blockers do not dilate coronary vessels. But due to bradycardia, by lengthening the diastole, during which there is an intense coronary blood flow, they can indirectly improve the blood supply to the heart.

Along with the listed types of action of β-blockers, which are of high relevance in cardiology, it is impossible not to dwell on the antiglaucomatous effect of the drugs in question, which is important in ophthalmology. They reduce intraocular pressure by reducing the production of intraocular fluid; for this purpose, the non-selective drug timolol (okumed, okupres, arutimol) and the β1-blocker betaxolol (betoptik) in the form of eye drops are mainly used.

In addition, β-blockers reduce insulin secretion in the pancreas, increase bronchial tone, increase the blood levels of atherogenic lipoprotein fractions (low and very low density). These properties underlie the side effects, which will be discussed in detail below.

β-blockers are classified not only by the ability to selectively or non-selectively block β-adrenergic receptors, but also by the presence or absence of intrinsic sympathomimetic activity. It is present in pindolol (whisken), oxprenolol (trazikor), acebutolol (sectral), talinolol (cordanum). Due to a special interaction with β-adrenergic receptors (stimulation of their active centers to a physiological level), these drugs at rest practically do not reduce the frequency and strength of heart contractions, and their blocking effect is manifested only with an increase in the level of catecholamines - during emotional or physical stress.

Such adverse effects as a decrease in insulin secretion, an increase in bronchial tone, an atherogenic effect are especially characteristic of non-selective drugs without internal sympathomimetic activity and are almost not manifested in β1-selective drugs in small (medium therapeutic) doses. With increasing doses, the selectivity of action decreases and may even disappear.

β-blockers differ in their ability to dissolve in lipids. Related to this are their features such as penetration into the central nervous system and the ability to be metabolized and excreted from the body in one way or another. Metoprolol (egilok), propranolol (anaprilin, inderal, obzidan), oxprenolol (trazikor) are lipophilic, therefore they penetrate the central nervous system and can cause drowsiness, lethargy, lethargy, and are metabolized by the liver, so they should not be prescribed to patients with impaired liver function. Atenolol (tenormin) and acebutolol (sektral) are hydrophilic, almost do not penetrate the brain and cause practically no side effects from the central nervous system, but are excreted by the kidneys, so they should not be prescribed to patients with renal insufficiency. Pindolol (whisken) occupies an intermediate position.

Drugs such as propranolol and oxprenolol are relatively short-acting (about 8 hours), they are prescribed 3 times a day. It is enough to take metoprolol 2 times a day, and atenolol - 1 time per day. The rest of the drugs listed in the classification can be prescribed 2-3 times a day.

There is conflicting information on the effect of β-blockers on the life expectancy of patients. Some authors have established its increase (Olbinskaya L.I., Andrushchishina T.B., 2001), others point to its decrease due to disorders of carbohydrate and lipid metabolism with long-term use (Mikhailov I. B., 1998).

Indications

β-blockers are used in hypertension and symptomatic arterial hypertension, especially in the hyperkinetic type of circulation (it is manifested by clinically excessive tachycardia and a significant increase in systolic blood pressure during exercise).

They are also prescribed for coronary heart disease (rest and variant angina, especially insensitive to nitrates). Antiarrhythmic action is used for sinus tachycardia, atrial fibrillation, ventricular extrasystole (with arrhythmias, the dose is usually lower than with arterial hypertension and angina pectoris).

In addition, β-blockers are used for hypertrophic cardiomyopathy, thyrotoxicosis (especially for allergies to mercazolil), migraine, parkinsonism. Non-selective drugs can be used to induce labor in women with high blood pressure. In the form of ophthalmic dosage forms, β-blockers, as already noted, are used in glaucoma.

appointment features,
dosing regimen

With arterial hypertension, coronary heart disease and cardiac arrhythmias, β-blockers are usually prescribed in the following dosages.

Propranolol (anaprilin) ​​- is available in tablets of 0.01 and 0.04 g and in ampoules of 1 ml of a 0.25% solution, 0.01-0.04 g is administered orally 3 times a day (daily dose - 0, 03-0.12 g). Oxprenolol (trazicor) - available in tablets of 0.02 g, is prescribed 1-2 tablets 3 times a day. Pindolol (whisken) - available in tablets of 0.005; 0.01; 0.015 and 0.02 g, in the form of a 0.5% solution for oral administration and in 2 ml ampoules of a 0.2% solution for injection. It is prescribed orally at 0.01-0.015 g per day in 2-3 doses, the daily dose can be increased to 0.045 g. It is injected slowly intravenously, 2 ml of a 0.2% solution. Metoprolol (betaloc, metocard) - is available in tablets of 0.05 and 0.1 g. It is administered orally at 0.05-0.1 g 2 times a day, the maximum daily dose is 0.4 g (400 mg). Metocard-retard is a long-acting drug of metoprolol, available in tablets of 0.2 g. It is prescribed 1 tablet 1 time per day (in the morning). Atenolol (tenormin) - is available in tablets of 0.05 and 0.1 g, is administered orally in the morning (before meals) 1 time per day for 0.05-0.1 g. Acebutolol (sectral) - is available in tablets of 0, 2 g, administered orally 0.4 g (2 tablets) once in the morning or in two doses (1 tablet in the morning and evening). Talinolol (cordanum) - available in pills of 0.05 g. It is prescribed 1-2 pills 1-2 times a day 1 hour before meals.

The hypotensive effect reaches a maximum gradually, within 1-2 weeks. The duration of treatment is usually at least 1-2 months, often several months. Cancellation of β-blockers should be done gradually, with a dose reduction within 1-1.5 weeks to half of the minimum therapeutic one, otherwise a withdrawal syndrome may develop. During treatment, it is necessary to control the heart rate (bradycardia at rest - no more than 30% of the initial level; during exercise, tachycardia no more than 100-120 bpm), ECG (PQ interval should increase by no more than 25% ). It makes sense to determine the level of glucose in the blood and urine and low and very low density lipoproteins, especially with prolonged use of β-blockers.

In patients with concomitant arterial hypertension, obstructive pulmonary diseases and metabolic disorders, preference is given to cardioselective drugs (Egilok, Metocard, Tenormin, Sektral, Cordanum) in the minimum effective doses or in combination with other antihypertensive drugs.

Side effects
and the possibility of their correction

For blockers of β-adrenergic receptors, the following side effects are characteristic.

• Severe bradycardia, impaired atrioventricular conduction, development of heart failure (mainly for drugs lacking internal sympathomimetic activity).
• Bronchial obstruction (mainly for drugs that non-selectively block β-adrenergic receptors). This effect is especially dangerous in patients with altered bronchial reactivity suffering from bronchial asthma. Since β-blockers can be absorbed into the bloodstream and cause bronchial obstruction even when used in the form of eye drops, oculists should take this ability into account when prescribing timolol or betaxolol to patients in whom glaucoma is combined with bronchial asthma. After the introduction of eye drops into the conjunctival sac, it is recommended to press the inner corner of the eye for 2-3 minutes to avoid getting the solution into the nasolacrimal canal and nasal cavity, from where the drug can be absorbed into the blood.
• CNS disorders - fatigue, decreased attention, headache, dizziness, sleep disturbances, a state of agitation or, conversely, depression, impotence (especially for lipophilic drugs - metoprolol, propranolol, oxprenolol).
• Deterioration of lipid metabolism - the accumulation of cholesterol in low and very low density lipoproteins, an increase in the atherogenic properties of blood serum, especially in conditions of increased dietary intake of sodium chloride. This property, of course, reduces the therapeutic value of β-blockers in cardiology, since it means an increase in atherosclerotic vascular damage. To correct this side effect, we developed in the experiment and tested in the clinic a method consisting in the use of potassium and magnesium salts, in particular, sanasol in a daily dose of 3 g for adding salt to ready meals against the background of limiting the dietary intake of table salt. (Shtrygol S. Yu., 1995; Shtrygol S. Yu. et al., 1997). In addition, it was found that the atherogenic properties of β-blockers are weakened by the simultaneous administration of papaverine. (Andrianova I.A., 1991).
• Hyperglycemia, impaired glucose tolerance.
• An increase in the level of uric acid in the blood.
• Spasm of the vessels of the lower extremities (intermittent claudication, exacerbation of Raynaud's disease, obliterating endarteritis) - mainly for drugs that can block β2-adrenergic receptors.
• Dyspeptic phenomena - nausea, heaviness in the epigastrium.
• Increased uterine tone and fetal bradycardia during pregnancy (especially for drugs that block β2-adrenergic receptors).
• Withdrawal syndrome (formed 1-2 days after the sudden discontinuation of the drug, lasts up to 2 weeks); to prevent it, as already noted, it is necessary to reduce the dose of β-blockers gradually, over a period of at least 1 week.
• Relatively infrequently, β-blockers cause allergic reactions.
• A rare side effect is oculocutaneous syndrome (conjunctivitis, adhesive peritonitis).
• In rare cases, talinolol can cause sweating, weight gain, decreased tear secretion, alopecia, and increased symptoms of psoriasis; the latter effect is also described with the use of atenolol.

Contraindications

Severe heart failure, bradycardia, sick sinus syndrome, atrioventricular blockade, arterial hypotension, bronchial asthma, obstructive bronchitis, peripheral circulatory disorders (Reynaud's disease or syndrome, obliterating endarteritis, atherosclerosis of the vessels of the lower extremities), diabetes mellitus I and II types.

Interaction with other drugs

rational combinations.β-blockers are well combined with α-blockers (there are so-called "hybrid" α, β-blockers, such as labetalol, proxodolol). These combinations enhance the hypotensive effect, while simultaneously with a decrease in cardiac output, the total peripheral vascular resistance also quickly and effectively decreases.

Combinations of β-blockers with nitrates are successful, especially when arterial hypertension is combined with coronary heart disease; at the same time, the hypotensive effect is enhanced, and the bradycardia caused by β-blockers is leveled by the tachycardia caused by nitrates.

Combinations of β-blockers with diuretics are favorable, since the action of the latter is enhanced and somewhat lengthened due to the inhibition of renin release in the kidneys by β-blockers.

The action of β-blockers and ACE inhibitors, angiotensin receptor blockers is very successfully combined. With drug-resistant arrhythmias, β-blockers can be combined with caution with novocainamide, quinidine.

Allowed combinations. With caution, you can combine β-blockers in low doses with calcium channel blockers belonging to the group of dihydropyridines (nifedipine, fenigidin, cordafen, nicardipine, etc.).

Irrational and dangerous combinations. It is unacceptable to combine β-adrenergic receptor antagonists with calcium channel blockers of the verapamil group (verapamil, isoptin, finoptin, gallopamil), since this potentiates a decrease in the frequency and strength of heart contractions, deterioration of atrioventricular conduction; possible excessive bradycardia and hypotension, atrioventricular blockade, acute left ventricular failure.

It is impossible to combine β-blockers with sympatholytics - reserpine and preparations containing it (raunatin, rauvazan, adelfan, kristepin, brinerdine, trirezide), octadine, since these combinations sharply weaken the sympathetic effects on the myocardium and can lead to similar complications.

Combinations of β-blockers with cardiac glycosides are irrational (the risk of bradyarrhythmias, blockades and even cardiac arrest increases), with direct M-cholinomimetics (aceclidine) and anticholinesterase agents (prozerin, galantamine, amiridine), tricyclic antidepressants (imipramine) for the same reasons.

It cannot be combined with antidepressants - MAO inhibitors (nialamide), since a hypertensive crisis is possible.

The action of such agents as typical and atypical β-adrenergic agonists (izadrin, salbutamol, oxyphedrine, nonahlazine, etc.), antihistamines (diphenhydramine, diprazine, phencarol, diazolin, etc.), glucocorticoids (prednisolone, hydrocortisone, budesonide, ingacort, etc. ) when combined with β-blockers is weakened.

It is irrational to combine β-blockers with theophylline and preparations containing it (eufillin) due to the slowing down of metabolism and accumulation of theophylline.

With the simultaneous administration of β-blockers with insulin and oral hypoglycemic agents, an excessive hypoglycemic effect develops.

β-blockers weaken the anti-inflammatory effect of salicylates, butadione, antithrombotic effect of indirect anticoagulants (neodicoumarin, phenylin).

In conclusion, it should be emphasized that in modern conditions, preference is given to cardioselective β-blockers (β1-blockers) as the safest in relation to bronchial obstruction, lipid and carbohydrate metabolism disorders and peripheral circulation, which have a longer duration of action and therefore are taken in a more convenient mode for the patient. (1-2 times a day).

Literature

1. Avakyan O. M. Pharmacological regulation of the function of adrenoreceptors.- M .: Medicine, 1988.- 256 p.
2. Andrianova I. A. Changes in the structure and chemical composition of the inner membrane of the rabbit aorta during mechanical damage under conditions of normolipidemia, hypercholesterolemia and the introduction of certain pharmacological preparations: Abstract of the thesis. dis. … cand. honey. Sciences. - M., 1991.
3. Gaevyj M. D., Galenko-Yaroshevsky P. A., Petrov V. I. et al. Pharmacotherapy with the basics of clinical pharmacology / Ed. V. I. Petrova. - Volgograd, 1998. - 451 p.
4. Grishina T. R., Shtrygol S. Yu. Vegetotropic agents: Educational and methodological manual. - Ivanovo, 1999. - 56 p.
5. Lyusov V. A., Kharchenko V. I., Savenkov P. M. et al. Potentiation of the hypotensive effect of labetalol in hypertensive patients when exposed to sodium balance in the body // Kardiologiya.— 1987.— No. 2.— P. 71 -77.
6. Mikhailov I. B. Clinical pharmacology.- St. Petersburg: Folio, 1998.- 496 p.
7. Olbinskaya L. I., Andrushchishina T. B. Rational pharmacotherapy of arterial hypertension // Russian medical journal. - 2001. - V. 9, No. 15. - P. 615-621.
8. Register of medicines of Russia: Annual collection. - M .: Remako, 1997-2002.
9. Shtrygol S. Yu. Influence of the mineral composition of the diet on cholesterol metabolism and experimental correction of atherogenic dyslipoproteinemia caused by propranolol // Experiment. and wedge. Pharmacology. - 1995. - No. 1. - S. 29-31.
10. Shtrygol S. Yu., Branchevsky LL The effect of adrenergic agonists and antagonists on kidney function and blood pressure depending on the mineral composition of the diet // Experiment. and wedge. Pharmacology. - 1995. - No. 5. - S. 31-33.
11. Shtrygol S. Yu., Branchevsky L. L., Frolova A. P. Sanasol as a means of correcting atherogenic dyslipoproteinemia in coronary heart disease // Bulletin of Ivanovskaya Med. Academy. - 1997. - No. 1-2. - P. 39-41.

Adrenoblockers or adrenolytics are a group of medications that cause blockade of receptors for norepinephrine and adrenaline. They are used in cardiology and general therapy for the treatment of patients with lesions of the heart and blood vessels. Every year, the list of drugs is replenished, but only a qualified doctor can determine which one should be taken for a particular pathology.

Mechanism of action

In many diseases, there is a need for blockade of adrenergic impulses to eliminate the effects of norepinephrine and epinephrine. For this purpose, adrenoblockers are used, the mechanism of action of which is to block adrenoreceptors (protein molecules to noradrenaline and adrenaline), while the process of producing the hormones themselves is not disturbed.

There are 4 types of adrenergic receptors in the vascular walls and the heart muscle - alpha-1, alpha-2, beta-1 and beta-2. Adrenolytics are able to selectively turn off receptors, for example, only alpha-1 or beta-2, and so on. As a result, adrenoblocking drugs are divided into several groups depending on which adrenoreceptors they turn off.

List

Alpha-1 blockers (selective)

They contribute to a decrease in the tone of the arteries, which leads to their expansion and a decrease in pressure in the bloodstream. In addition, drugs are used in the complex treatment of prostatitis in men.

Dalfaz (Alfuzosin, Dalfaz Retard, Alfuprost MR)

Available in the form of tablets; The active ingredient is alfuzosin hydrochloride.

Blocker of alpha-1-adrenergic receptors (mainly in the area of ​​the prostate gland and urethra). Helps to reduce pressure in the urethra and reduce the resistance of urine flow, helps to facilitate urination and eliminate dysuria, in particular, with prostatic hyperplasia. In a therapeutic dosage, it does not affect alpha-1-adrenergic receptors of blood vessels. It is used to treat functional signs of benign prostatic hyperplasia.

Inside, 5 milligrams are taken twice a day, it is recommended to start therapy with an evening dose. The daily dose should not exceed 10 milligrams. Elderly people and patients receiving antihypertensive treatment are prescribed 5 milligrams per day in the evening, if necessary, the daily dose is adjusted to 10 milligrams.

Side effects: nausea, dry mouth, headache, tachycardia, dizziness, drowsiness, allergic reactions (skin rashes, itching), swelling, tinnitus.

Contraindications: abnormal liver function, orthostatic hypotension, concomitant use of other alpha-blockers, hypersensitivity to the active substance or other components, renal failure, intestinal obstruction.

Doxazosin (Doxazosin-FPO, Kamiren HL, Kamiren, Kardura, Magurol, Doxaprostan, Zokson)

Available in the form of tablets; the active substance is doxazosin.

Reduces blood pressure without the development of tachycardia, increases the coefficient of good cholesterol and reduces the total content of triglycerides and cholesterol. The drug is effective in arterial hypertension, including those accompanied by metabolic disorders (hyperlipidemia, obesity).

Take the tablets in the morning or evening without chewing. The initial dose is 1 milligram per day. After 7-14 days, depending on the patient's condition, the dose can be increased to 2 milligrams per day, then after another 7-14 days - up to 4 milligrams, 8 milligrams or 16 milligrams per day to achieve the desired therapeutic effect.

Side effects: fainting, arrhythmia, tachycardia, nausea, fatigue, headache, drowsiness, irritability, asthenia, rhinitis.

Contraindications: severe liver failure, anuria, urinary tract infections, arterial hypotension in the treatment of benign prostatic hyperplasia, esophageal obstruction, lactose intolerance, intolerance to the components of the drug, age under 18 years, lactation.

Prazosin (Adverzuten, Polpressin, Prazosinbene, Minipress)

Available in the form of tablets; the active substance is prazosin.

A peripheral blocker of postsynaptic alpha-1-adrenergic receptors prevents the vasoconstrictive effect of catecholamines, lowers blood pressure and reduces afterload on the heart muscle. Indications for use are arterial hypertension, Raynaud's disease and syndrome, chronic heart failure, peripheral vascular spasm, pheochromocytoma, prostatic hyperplasia.

The dosage is set by the doctor depending on the condition and illness of the patient. The starting dose is 500 micrograms 2-3 times a day. The average therapeutic dose is 4-6 milligrams per day; maximum - 20 milligrams.

Side effects: tachycardia, arterial hypotension, palpitations, shortness of breath, dizziness, anxiety, hallucinations, emotional disorders, vomiting, dry mouth, frequent urination, darkening of the eyes, hyperemia of the cornea and conjunctiva, rashes, epistaxis, nasal congestion and others .

Contraindications: pregnancy, lactation, age up to 12 years, arterial hypotension, myocardial tamponade, chronic heart failure against the background of constrictive pericarditis, hypersensitivity to drug components.

Terazosin (Terazosin-Teva, Setegis, Kornam)

Available in the form of tablets; The active substance is terazosin hydrochloride dihydrate.

The drug promotes the expansion of venules and arterioles, a decrease in venous return to the myocardium and total peripheral vascular resistance, and also has a hypotensive effect. It is prescribed for the treatment of arterial hypertension and benign prostatic hyperplasia.

Therapy should be started with a minimum dose of 1 milligram, taken at bedtime and after being in bed for 5-6 hours. The dose increase occurs gradually 1 time in 7-10 days. The maintenance dose, depending on the effectiveness of therapy and indications, is 1-10 milligrams 1 time per day. The maximum daily dose is 20 milligrams.

Side effects: asthenia, dizziness, drowsiness, fainting, nausea, palpitations, tachycardia, nasal congestion, peripheral edema, visual disturbances, rarely impotence.

Contraindications: lactation, pregnancy, childhood, hypersensitivity to the active substance. With caution in angina pectoris, hepatic or renal failure, diabetes mellitus, cerebrovascular accident.

Tamsulosin (Omnic, Focusin, Omsulosin, Proflosin)

Available in the form of capsules and granules; The active substance is tamsulosin hydrochloride.

The drug reduces the tone of the smooth muscles of the bladder neck, prostate gland and prostatic part of the urethra, improving the outflow of urine. Simultaneously reduces the symptoms of irritation and obstruction caused by benign prostatic hyperplasia.

For treatment, 0.4 milligrams per day is prescribed after breakfast, drinking plenty of fluids.

Side effects: asthenia, headache, increased heart rate, dizziness, rarely - retrograde ejaculation, decreased libido, constipation, diarrhea, rhinitis.

Contraindications: intolerance to the components of the drug. With caution in arterial hypotension, severe renal failure.

Urapidil Carino (Ebrantil, Tahiben)

Available in the form of a solution; The active substance is urapidil hydrochloride.

It has a hypotensive effect (lowers blood pressure), reduces peripheral vascular resistance. The drug is prescribed for hypertensive crisis and arterial hypertension.

The agent is administered intravenously. In severe and acute forms of pathology, 25 milligrams are administered over 5 minutes. If the desired result has not been achieved, after 2 minutes the dose is repeated, in case of ineffectiveness of the repeated dose, after 2 minutes they switch to slow intravenous administration of 50 milligrams. Then they switch to a slow drip infusion.

Side effects: headache, dry mouth, thrombocytopenia, allergic reactions, orthostatic collapse phenomena.

Contraindications: pregnancy, aortic stenosis, lactation, age under 18, patent ductus arteriosus, hypersensitivity.

Urorek

Available in the form of capsules; the active substance is silodosin.

Indicated for the treatment of urinary disorders caused by benign prostatic hyperplasia.

The recommended starting dose is 8 milligrams once a day, at the same time as meals (preferably at the same time of day). Patients with renal insufficiency for 7 days should take the drug at a dose of 4 milligrams per day, with good tolerance, the dose can be increased to 8 milligrams.

Side effects: dizziness, orthostatic hypotension, diarrhea, nasal congestion, decreased libido, nausea, dry mouth.

Contraindications: severe renal and / or hepatic insufficiency, age under 18 years, hypersensitivity to the drug.

Alpha-2 blockers (non-selective)

Increase pressure by stimulating adrenoreceptors of the hypothalamic-pituitary system.

Dopegyt (Methyldopa, Dopanol)

Available in the form of tablets; The active ingredient is methyldopa sesquihydrate.

An antihypertensive drug that lowers heart rate and reduces total peripheral vascular resistance. It is used to treat mild to moderate hypertension (including hypertension during pregnancy).

In the first 2 days, the drug is recommended to take 250 milligrams in the evening, then in the next 2 days the dose is increased by 250 milligrams and so on until the therapeutic effect is achieved (usually develops when a daily dose of 1 gram divided by 2 is reached). -3 receptions). The maximum daily dose cannot be more than 2 grams.

Side effects: drowsiness, paresthesia, lethargy, staggering when walking, dryness of the oral mucosa, myalgia, arthralgia, decreased libido (potency), fever, pancreatitis, leukopenia, nasal congestion and others.

Contraindications: hemolytic anemia, renal and / or liver failure, liver cirrhosis, acute myocardial infarction, depression, hepatitis, hypersensitivity, severe cerebral atherosclerosis, parkinsonism and others.

Clonidine (Catapresan, Clonidine, Barklid, Chlofazolin)

Available in the form of tablets, solution and eye drops; The active substance is clonidine hydrochloride.

Clonidine is a centrally acting antihypertensive drug. Indications for use are: arterial hypertension, hypertensive crisis, primary open-type glaucoma as monotherapy or in combination with other drugs that reduce intraocular pressure.

The doctor sets the dosage individually. The recommended starting dose is 0.075 milligrams three times a day. Further, the dose can be gradually increased to 0.9 milligrams. The maximum daily dose should not exceed 2.4 milligrams. Elderly patients are prescribed 0.0375 milligrams three times a day. The average course duration is 1-2 months. To stop a hypertensive crisis, the drug is administered intramuscularly or intravenously at a dose of 0.15 milligrams.

Side effects: drowsiness, anxiety, asthenia, sedation, nighttime restlessness, bradycardia, itching, skin rashes, dryness of the conjunctiva, burning or itching in the eyes, swelling and hyperemia of the conjunctiva.

Contraindications: cardiogenic shock, hypersensitivity, arterial hypotension, severe sinus bradycardia, severe cerebral atherosclerosis, depression, sick sinus syndrome, pregnancy, lactation, inflammation of the anterior eye (for drops).

Alpha-1,2-blockers

Dihydroergotamine (Ditamin, Clavigrenin, DG-Ergotamine)

Available in the form of a solution; the active substance is dihydroergotamine.

Reduces the tone of the arteries, has a direct tonic effect on the peripheral veins. It is prescribed for migraine, varicose veins of the lower extremities, orthostatic hypotension, autonomic lability, intestinal atony.

The drug is administered intramuscularly and intravenously, also administered orally (intermittent treatment). Intramuscularly for the relief of an attack, the recommended dose is 1-3 milligrams, for a faster effect, 1 milligram is administered intravenously. Inside, to eliminate migraines, 2.5 milligrams are prescribed 2-3 times a day for several weeks. With varicose veins - 15 milligrams per day three times a day.

Side effects: dizziness, vomiting, diarrhea, arrhythmia, drowsiness, rhinitis, paresthesia of the fingers and toes, pain in the extremities, tachycardia, cardialgia, vasospasm, nasal congestion.

Contraindications: ischemic heart disease, intolerance to drug components, angina pectoris, severe atherosclerosis, myocardial infarction, sepsis, pregnancy, lactation, renal and / or liver failure, arterial hypertension, organic myocardial damage, vasospastic angina pectoris, age up to 16 years.

Dihydroergotoxin (Hidergin, DG-Ergotoxin)

Available in the form of a solution for injection and oral administration; the active substance is dihydroergotoxin.

An antiadrenergic drug that lowers blood pressure and dilates blood vessels, an alpha and alpha-adrenergic blocker. Indications for use: hypertension, endarteritis (disease of the inner lining of the arteries), migraine, Raynaud's disease, retinal vasospasm.

In hypertension and peripheral circulatory disorders, an alpha-blocker is prescribed 5 drops orally three times a day, then the dose is increased by 2-3 drops to 25-40 drops 3 times a day. In case of severe violations of the peripheral circulation, 1-2 milliliters are administered intramuscularly or intravenously.

Side effects: allergic reaction, indigestion.

Contraindications: hypotension, severe atherosclerosis, myocardial infarction, old age, organic lesions of the heart muscle, impaired renal function.

Sermion (Nicergoline, Nicergoline-Ferein)

Available in the form of tablets; the active substance is nicergoline.

Alpha1,2-blocker improves peripheral and cerebral circulation. Indications: chronic and acute cerebral vascular and metabolic disorders (due to arterial hypertension, atherosclerosis, and so on); chronic and acute vascular and peripheral metabolic disorders (Raynaud's disease, arteriopathy of the extremities).

The drug is prescribed orally, depending on the disease and its severity, 5-10 milligrams three times a day or 30 milligrams twice a day, at regular intervals, for a long time.

Side effects: decrease in blood pressure, headache, insomnia or drowsiness, confusion, diarrhea, dyspepsia, skin rash.

Contraindications: acute bleeding, violation of orthostatic regulation, acute myocardial infarction, pregnancy, age up to 18 years, sucrase deficiency, lactation, hypersensitivity.

Beta-1-blockers (selective, cardioselective)

Beta-1 receptors are mainly concentrated in the myocardium, and when they are blocked, a decrease in heart rate is observed.

Bisoprolol (Concor, Concor Cor, Coronal, Niperten)

Available in the form of tablets; The active ingredient is bisoprolol fumarate.

The drug has antiarrhythmic, antihypertensive and antianginal effects. The drug reduces the heart's need for oxygen, reduces the heart rate (during exercise and rest) and cardiac output. Indications: prevention of angina attacks, arterial hypertension, chronic heart failure.

The dosage regimen is determined by the doctor individually. The average dose is 0.005-0.01 grams. The medicine must be taken once a day in the morning during or before breakfast.

Side effects: dizziness, feeling cold, sleep disorders, bradycardia, conjunctivitis, nausea, diarrhea, abdominal pain, muscle weakness, convulsions, skin rashes, hot flashes, impaired potency.

Contraindications: pregnancy, lactation, chronic heart failure in the stage of decompensation, collapse, cardiogenic shock, pronounced decrease in blood pressure, age under 18 years, hypersensitivity and others.

Breviblock

Available in the form of a solution; The active substance is esmolol hydrochloride.

A selective beta-1-blocker is indicated for supraventricular tachyarrhythmia (including atrial flutter and fibrillation) and arterial hypertension after and during surgical interventions.

The agent is administered intravenously, the dose is selected individually and adjusted depending on the clinical result.

Side effects: pronounced decrease in blood pressure, bradycardia, asystole, sweating, dizziness, confusion, bronchospasm, shortness of breath, shortness of breath, nausea, urinary retention, impaired vision and speech, swelling and others.

Contraindications: sinoatrial blockade of 2-3 degrees, severe bradycardia, acute myocardial insufficiency, cardiogenic shock, hypovolemia, lactation, pregnancy, age up to 18 years, hypersensitivity.

Metoprolol (Egilok, Betalok, Metocard, Metoprolol Retard-Akrikhin)

Available in the form of tablets; The active substance is metoprolol tartrate.

A modern selective beta-blocker is taken for arterial hypertension (including hyperkinetic-type tachycardia), coronary artery disease (secondary prevention of myocardial infarction, angina attacks), cardiac arrhythmia, hyperthyroidism (in combination therapy), migraine.

Tablets should be taken with food or immediately after a meal, swallowed whole. Depending on the pathology and its severity, the daily dose can be from 50 to 200 milligrams.

Side effects: fatigue, paresthesia of the extremities, headache, sinus bradycardia, decreased blood pressure, anxiety, allergic reaction (rash, itching, skin flushing), pain in the abdomen, palpitations, nasal congestion and others.

Contraindications: cardiogenic shock, AV blockade of 2-3 degrees, sick sinus syndrome, myocardial insufficiency in the stage of decompensation, severe bradycardia, lactation, pregnancy, age up to 18 years, hypersensitivity.

Beta-1,2-blockers (non-selective)

Drugs regulate blood pressure and affect cardiac conduction.

Anaprilin (Obzidan)

Available in tablets; The active substance is propranolol hydrochloride. A non-selective beta-blocker is indicated for hypertension, unstable angina pectoris, sinus tachycardia, tachysystolic atrial fibrillation, supraventricular tachycardia, ventricular and supraventricular extrasystole, anxiety, essential tremor.

Tablets are taken orally, regardless of food. At the beginning of treatment, 20 milligrams per day are prescribed, then the doctor may increase the dosage.

Side effects: pain and dryness of the eyes, fatigue, depression, nervousness, sinus bradycardia, thrombocytopenia, bronchospasm, increased sweating, and so on.

Contraindications: acute heart failure, cardiogenic shock, bradycardia, sinoatrial blockade, pregnancy, lactation.

Bopindolol (Sandorm)

Available in the form of tablets; the active substance is bopindolol.

A non-selective beta-blocker with antihypertensive and antianginal effects. It is used for arterial hypertension, angina pectoris, arrhythmia, myocardial infarction (secondary prevention).

The drug is prescribed in the initial dosage - 1 milligram per day, according to indications, the dose can be increased to 2 milligrams per day, and when the desired effect is achieved, it is reduced to 0.5 milligrams per day.

Side effects: bradycardia, decreased blood pressure, sleep disturbance, feeling cold, bronchospasm, dyspnea, fatigue, weakness, vomiting, nausea, constipation, flatulence, dry mouth, dizziness.

Contraindications: cardiogenic shock, decompensated heart failure, hypersensitivity, severe bronchial asthma, sick sinus syndrome, angina pectoris, pregnancy, lactation.

Nadolol (Solgol, Betadol)

Available in the form of tablets; active substance - nadolol.

The drug has anti-ischemic (antanginal) activity and is used to treat ischemic myocardial disease. It is also effective in hypertension (persistent high blood pressure). In addition, the drug is indicated for the treatment of migraine, tachyarrhythmia (heart rhythm disorder) and for the elimination of symptoms of hyperthyroidism (increased thyroid function).

Tablets are prescribed inside, regardless of food. With coronary heart disease, the medication is started with 40 milligrams 1 time per day, after 4-7 days the dose is increased to 80-160 milligrams per day. With hypertension, 40-80 milligrams are prescribed 1 time per day, the dose is slowly increased to 240 milligrams (in 1-2 doses). For the treatment of tachyarrhythmia, start with 40 milligrams per day, then increase to 160 milligrams per day.

Side effects: insomnia, fatigue, paresthesia (feeling of numbness in the limbs), bradycardia, dry mouth, gastrointestinal disorders.

Contraindications: bronchial asthma, tendency to bronchospasm, cardiogenic shock, pulmonary hypertension, pregnancy, lactation. With caution in hepatic and / or renal failure, diabetes mellitus.

Oxprenolol (Trazicor)

Available in the form of tablets; the active substance is oxprenolol.

It has antianginal, hypotensive and antiarrhythmic action. It is indicated for arterial hypertension, myocardial infarction (secondary prevention), atrial fibrillation, heart rhythm disturbances. Also, the drug is used as an additional treatment for mitral valve prolapse, pheochromocytoma, tremor.

It is recommended to start taking the medicine with 20 milligrams 4 times a day, gradually increasing the dose to 40-80 milligrams 3-4 times a day. The maximum daily dose should not exceed 480 milligrams. For secondary prevention after a heart attack, 40 milligrams are prescribed twice a day.

Side effects: weakness, drowsiness, dizziness, depression, anxiety, weakening of the contractility of the heart muscle, chest pain, visual impairment and others.

Contraindications: intolerance to the components of the drug, arterial hypotension, bronchial asthma, diabetes mellitus, pregnancy, lactation, cardiomegaly, liver failure, Raynaud's syndrome and others.

Alpha beta blockers

Drugs in this group lower blood pressure and OPSS (total peripheral vascular resistance), and also reduce intraocular pressure in open-angle glaucoma.

Carvedilol (Dilatrend, Carvedilol Sandoz, Carvedilol Zentiva, Vedicardol)

Available in the form of tablets; the active substance is carvedilol.

It has a vasodilating, antihypertensive and antianginal effect. The drug reduces blood pressure, post- and preload on the myocardium, moderately reduces heart rate, without affecting renal blood flow and kidney function. It is used as monotherapy and in combination with other antihypertensive drugs for the treatment of arterial hypertension, stable angina, chronic heart failure.

The medicine is taken orally, regardless of food. The dose is determined by the doctor individually, depending on the disease and clinical response. At the beginning of treatment, the dose is 12.5 milligrams, after 1-2 weeks it can be increased to 25 milligrams. The maximum daily dose is 50 milligrams.

Side effects: bradycardia, headache, depression, diarrhea, vomiting, edema, renal dysfunction, leukopenia, nasal congestion, shortness of breath, bronchospasm, and so on.

Contraindications: severe bradycardia, severe renal failure, heart failure in the stage of decompensation, pregnancy, lactation, age up to 18 years, cardiogenic shock, hypersensitivity.

Proxodolol

Available in the form of eye drops; the active substance is proxodolol. An antiglaucoma agent is used to treat increased intraocular pressure, aphakic glaucoma, open-angle glaucoma and other types of secondary glaucoma. It is also used in complex therapy to reduce intraocular pressure in angle-closure glaucoma.

The medicine should be instilled into the conjunctival sac 1 drop up to 3 times a day.

Side effects: blurred vision, dry mouth, bradycardia, gastralgia, headache, decreased blood pressure, the occurrence of bronchospasm.

Contraindications: sinus bradycardia, cardiogenic shock, chronic insufficiency of the heart muscle in the stage of decompensation, arterial hypotension, insulin-dependent diabetes mellitus, individual intolerance.

During pregnancy

Taking adrenoblockers during pregnancy is not recommended. However, if there is an urgent need, then only a specialist can prescribe and control its intake, select replacements.

During lactation, adrenergic blockers are not prescribed; instead, the doctor recommends that you follow a special diet and reduce physical activity. It is possible to use medical products with a high content of potassium, minerals, magnesium and calcium.

children

It is possible to use adrenoblockers at the age of 16-18 years. In rare cases, and as prescribed by a doctor, drugs are used to treat children under this age.