What should be the normal cardiac ejection fraction? Cardiac output and cardiac ejection fraction: norm, reasons for changes, methods of regulation. Average generally accepted normal value

• How do beta blockers work?
• Modern beta blockers: list

Modern beta-blockers are drugs that are prescribed for the treatment of cardiovascular diseases, in particular hypertension. There is a wide range of drugs in this group. It is extremely important that treatment is prescribed exclusively by a doctor. Self-medication is strictly prohibited!

Beta blockers: purpose

Beta blockers are a very important group of drugs that are prescribed to patients with hypertension and heart disease. The mechanism of action of drugs is to act on the sympathetic nervous system. Medicines in this group are among the most important drugs in the treatment of diseases such as:

Also, the prescription of this group of drugs is justified in the treatment of patients with Marfan syndrome, migraine, withdrawal syndrome, mitral valve prolapse, aortic aneurysm and in the case of vegetative crises. Drugs should be prescribed exclusively by a doctor after a detailed examination, diagnosis of the patient and collection of complaints. Despite the free access to medicines in pharmacies, you should never choose your own medicines. Therapy with beta blockers is a complex and serious undertaking that can either make the patient’s life easier or significantly harm it if administered incorrectly.

Return to contents

Beta blockers: types

The list of drugs in this group is very extensive.

It is customary to distinguish the following groups of beta-adrenaline receptor blockers:

• The heart rate slows down less;
• the pumping function of the heart does not decrease as much;
• Peripheral vascular resistance increases less;
• the risk of developing atherosclerosis is not so great, since the effect on blood cholesterol levels is minimal.

However, both types of medications are equally effective in reducing blood pressure. There are also fewer side effects from taking these medications.

List of drugs that have sympathomimetic activity: Sectral, Cordanum, Celiprolol (from the cardioselective group), Alprenol, Trazicor (from the non-selective group).

The following medications do not have this property: cardioselective drugs Betaxolol (Lokren), Bisoprolol, Concor, Metoprolol (Vazocordin, Engilok), Nebivolol (Nebvet) and non-selective Nadolol (Korgard), Anaprilin (Inderal).

Return to contents

Lipo- and hydrophilic preparations

Another type of blockers. Lipophilic drugs are fat soluble. When these drugs enter the body, they are largely processed by the liver. The effect of drugs of this type is quite short-term, since they are quickly eliminated from the body. At the same time, they are distinguished by better penetration through the blood-brain barrier, through which nutrients pass into the brain and waste products from the nervous tissue are eliminated. In addition, a lower mortality rate has been proven among patients with ischemia who took lipophilic blockers. However, these drugs have side effects on the central nervous system, causing insomnia and depression.

Hydrophilic drugs dissolve well in water. They do not undergo the process of metabolism in the liver, but are excreted to a greater extent through the kidneys, that is, in the urine. In this case, the type of medication does not change. Hydrophilic drugs have a prolonged effect because they are not eliminated from the body very quickly.

Some drugs have both lipo- and hydrophilic properties, that is, they dissolve equally successfully in both fats and water. Bisoprolol has this property. This is especially important in cases where the patient has problems with the kidneys or liver: the body itself “selects” the system that is in a healthier state to remove the medicine.

Typically, lipophilic blockers are taken regardless of meals, and hydrophilic blockers are taken before meals and with a large volume of water.

Selecting a beta blocker is an extremely important and very difficult task, since the choice of a specific medication depends on many factors. All these factors can only be taken into account by a qualified specialist. Modern pharmacology has a wide range of truly effective drugs, so the most important primary task of the patient is to find a good doctor who will competently select the appropriate treatment for a particular patient and determine which drugs will be best for him. Only in this case will drug therapy bring results and literally prolong the patient’s life.

β-blockers block β-adrenergic receptors in various organs and tissues, which limits the effect of catecholamines, providing an organoprotective effect in cardiovascular diseases, making it possible to use them in ophthalmology and gastroenterology. On the other hand, the systemic effect on β-adrenergic receptors causes a number of side effects. To reduce undesirable side effects, selective β-blockers and β-blockers with additional vasodilating properties have been synthesized. The level of selectivity will determine the selectivity of the action. Lipophilicity determines their predominant cardioprotective effect. β-blockers are most widely used in the treatment of patients with coronary heart disease, arterial hypertension, and chronic heart failure.

Keywords:β-blockers, selectivity, vasodilating properties, cardioprotection.

TYPES AND LOCALIZATION OF β-ADRENORESCEPTORS

β-blockers, the action of which is due to blocking effects on β-adrenergic receptors of organs and tissues, have been used in clinical practice since the early 1960s and have hypotensive, antiaginal, anti-ischemic, antiarrhythmic and organoprotective effects.

There are 2 types of β-adrenergic receptors - and β 2 -adrenoreceptors; their ratio is different in different organs and tissues. The effects of stimulation of different types of β-adrenergic receptors are presented in table. 5.1.

PHARMACODYNAMIC EFFECTS OF β-ADRENORESCEPTOR BLOCKade

Pharmacodynamic effects of preferential β blockade l-adrenergic receptors are:

Decrease in heart rate (negative chronotropic, bradycardic effect);

Reduced blood pressure (reduced afterload, hypotensive effect);

Slowing of atrioventricular (AV) conduction (negative dromotropic effect);

Reduced myocardial excitability (negative bathmotropic, antiarrhythmic effect);

Decreased myocardial contractility (negative inotropic, antiarrhythmic effect);

Table 5.1

Localization and ratio of β-adrenergic receptors in organs and tissues

decreased pressure in the portal vein system (due to a decrease in hepatic and mesenteric arterial blood flow);

Reducing the formation of intraocular fluid (reducing intraocular pressure);

Psychotropic effects for beta-blockers that penetrate the blood-brain barrier (weakness, drowsiness, depression, insomnia, nightmares, hallucinations, etc.);

Withdrawal syndrome in case of sudden cessation of taking short-acting beta-blockers (hypertensive reaction, exacerbation of coronary insufficiency, including the development of unstable angina, acute myocardial infarction or sudden death).

Pharmacodynamic effects of partial or complete β blockade 2 -adrenergic receptors are:

Increased tone of the smooth muscles of the bronchi, including the extreme degree of its severity - bronchospasm;

Impaired mobilization of glucose from the liver into the blood due to inhibition of glycogenolysis and gluconeogenesis, the potentiating hypoglycemic effect of insulin and other hypoglycemic drugs;

Increased arterial smooth muscle tone - arterial vasoconstriction, causing an increase in peripheral vascular resistance, coronary spasm, decreased renal blood flow, decreased blood circulation in the extremities, a hypertensive reaction to hypercatecholaminemia during hypoglycemia, pheochromocytoma, after withdrawal of clonidine, during surgery or in the postoperative period.

STRUCTURE OF β-ADRENORESCEPTORS AND EFFECTS OF β-ADRENOBLOCKade

The molecular structure of β-adrenergic receptors is characterized by a specific sequence of amino acids. Stimulation of β-adrenergic receptors promotes the cascade of activity of G-protein, the enzyme adenylate cyclase, the formation of cyclic AMP from ATP under the influence of adenylate cyclase, and the activity of protein kinase. Under the influence of protein kinase, there is an increase in phosphorylation of calcium channels with an increase in the flow of calcium into the cell during the period of voltage-induced depolarization, calcium-induced release of calcium from the sarcoplasmic reticulum with an increase in the level of cytosolic calcium, an increase in the frequency and efficiency of the impulse, the force of contraction and further relaxation.

The action of β-blockers limits β-adrenergic receptors from the influence of β-agonists, providing negative chrono-, dromo-, batmo- and inotropic effects.

SELECTIVITY PROPERTY

The defining pharmacological parameters of β-blockers are β l-selectivity (cardioselectivity) and degree of selectivity, intrinsic sympathomimetic activity (ISA), level of lipophilicity and membrane-stabilizing effect, additional vasodilating properties, duration of action of the drug.

To study cardioselectivity, the degree of drug inhibition of the effect of β-adrenergic receptor agonists on heart rate, finger tremor, blood pressure, and bronchial tone is assessed in comparison with the effects of propranolol.

The degree of selectivity reflects the intensity of the connection with the β-adrenergic receptor and determines the strength and duration of action of the β-blocker. Preferential β blockade l-adrenergic receptors determines the selectivity index of β-blockers, reducing the effects of β 2 -blockade, thereby reducing the likelihood of side effects (Table 5.2).

Long-term use of β-blockers increases the number of β-receptors, which determines a gradual increase in the effects of β-blockade and a much more pronounced sympathomimetic response to catecholamines circulating in the blood in case of sudden withdrawal, especially of short-acting β-blockers (withdrawal syndrome).

1st generation β-blockers, causing blockade and β to the same extent 2 -adrenergic receptors, belong to non-selective β-blockers - propranolol, nadolol. Non-selective β-blockers without BCA have a definite advantage.

The second generation includes selective β l-adrenergic blockers, called cardioselective - atenolol, bisoprolol, betaxolol, metoprolol, nebivolol, talinolol, oxprenolol, acebutolol, celiprolol. At low doses β l-selective drugs have little effect on physiological responses mediated by peripheral β 2 -adrenergic receptors - bronchodilation, insulin secretion, mobilization of glucose from the liver, vasodilation and contractile activity of the uterus during pregnancy, therefore they have advantages in the severity of the hypotensive effect, lower frequency of side effects, compared to non-selective ones.

High level of selectivity β lβ-adrenergic blockade makes it possible to use it in patients with broncho-obstructive diseases, in smokers, due to a less pronounced reaction to catecholamines, in patients with hyperlipidemia, diabetes mellitus type I and II, and peripheral circulatory disorders compared to non-selective and less selective β-blockers.

The level of selectivity of β-blockers determines the effect on total peripheral vascular resistance as one of the determining components of the hypotensive effect. Selective β l-adrenergic blockers do not have a significant effect on peripheral vascular resistance, non-selective β-blockers, due to blockade of β 2 -vascular receptors, can enhance the vasoconstrictor effect and increase

The state of selectivity is dose dependent. An increase in the dose of the drug is accompanied by a decrease in the selectivity of action, clinical manifestations of β blockade 2 -adrenergic receptors, in large doses β l-selective beta blockers lose β l-selectivity.

There are β-adrenergic blockers that have a vasodilating effect, having a combined mechanism of action: labetalol (non-selective blocker and α1-adrenergic receptors), car-

vedilol (non-selective β blocker 1 β 2- and a 1 -adrenergic receptors), dilevalol (non-selective β-adrenergic receptor blocker and partial β agonist 2 -adrenergic receptors), nebivolol (b 1 -adrenergic blocker with activation of endothelial nitric oxide). These drugs have different mechanisms of vasodilating action and belong to the third generation β-blockers.

Depending on the degree of selectivity and the presence of vasodilating properties of M.R. Bristow in 1998 proposed a classification of beta-blockers (Table 5.3).

Table 5.3

Classification of beta-blockers (M. R. Bristow, 1998)

Some β-blockers have the ability to partially activate adrenergic receptors, i.e. partial agonistic activity. These β-blockers are called drugs with intrinsic sympathomimetic activity - alprenolol, acebutalol, oxprenolol, penbutalol, pindolol, talinolol, practolol. Pindolol has the most pronounced sympathomimetic activity.

The intrinsic sympathomimetic activity of β-blockers limits the reduction in resting heart rate, which is useful in patients with a low baseline heart rate.

Non-selective (β 1- + β 2-) β-blockers without BCA: propranolol, nadolol, sotalol, timolol, and with BCA: alprenolol, bopindolol, oxprenolol, pindolol.

Drugs with a membrane-stabilizing effect - propranolol, betaxolol, bisoprolol, oxprenolol, pindolol, talinolol.

LIPOPHILICITY, HYDROPHILICITY, AMPHOPHILICITY

Differences in the duration of action of β-blockers with a low selectivity index depend on the characteristics of the chemical structure, lipophilicity and elimination routes. There are hydrophilic, lipophilic and amphophilic drugs.

Lipophilic drugs are typically metabolized in the liver and have a relatively short elimination half-life (T 1/2). Lipophilicity is combined with the hepatic elimination route. Lipophilic drugs are quickly and completely (more than 90%) absorbed in the gastrointestinal tract, their metabolism in the liver is 80-100%, the bioavailability of most lipophilic β-blockers (propranolol, metoprolol, alprenolol, etc.) due to the “first pass” effect » through the liver is slightly more than 10-40% (Table 5.4).

The state of hepatic blood flow affects the metabolic rate, the size of single doses and the frequency of drug administration. This must be taken into account when treating elderly patients, patients with heart failure, and cirrhosis of the liver. In severe liver failure, the rate of elimination decreases pro-

Table 5.4

Pharmacokinetic parameters of lipophilic β-blockers

proportional to the decrease in liver function. Lipophilic drugs with long-term use can themselves reduce hepatic blood flow, slow down their own metabolism and the metabolism of other lipophilic drugs. This explains the increase in the half-life and the possibility of reducing the single (daily) dose and frequency of taking lipophilic drugs, increasing the effect, and the threat of overdose.

The influence of the level of microsomal oxidation on the metabolism of lipophilic drugs is significant. Drugs that induce microsomal oxidation of lipophilic β-blockers (heavy smoking, alcohol, rifampicin, barbiturates, diphenin) significantly accelerate their elimination and reduce the severity of the effect. The opposite effect is exerted by drugs that slow down hepatic blood flow and reduce the rate of microsomal oxidation in hepatocytes (cimetidine, chlorpromazine).

Among the lipophilic beta-blockers, the use of betaxolol does not require dose adjustment in case of liver failure, however, when using betaxolol, dose adjustment of the drug is required in case of severe renal failure and dialysis. Dose adjustment of metoprolol is carried out in case of severe liver dysfunction.

The lipophilicity of β-blockers facilitates their penetration through the blood-brain and hystero-placental barriers into the chambers of the eye.

Hydrophilic drugs are excreted predominantly by the kidneys unchanged and have a longer duration. Hydrophilic drugs are not completely (30-70%) and unevenly (0-20%) absorbed in the gastrointestinal tract, excreted by the kidneys by 40-70% unchanged or in the form metabolites have a longer half-life (6-24 hours) than lipophilic β-blockers (Table 5.5).

A reduced glomerular filtration rate (in elderly patients, with chronic renal failure) reduces the rate of excretion of hydrophilic drugs, which requires a reduction in dose and frequency of administration. You can navigate by the serum creatinine concentration, the level of which increases when the glomerular filtration rate decreases below 50 ml/min. In this case, the frequency of administration of the hydrophilic β-blocker should be every other day. Of the hydrophilic β-blockers, penbutalol does not require

Table5.5

Pharmacokinetic parameters of hydrophilic β-blockers

Table5.6

Pharmacokinetic parameters of amphophilic β-blockers

dose adjustment for renal impairment. Nadolol does not reduce renal blood flow and glomerular filtration rate, having a vasodilating effect on the renal vessels.

The influence of the level of microsomal oxidation on the metabolism of hydrophilic β-blockers is insignificant.

Ultra-short-acting β-blockers are destroyed by blood esterases and are used exclusively for intravenous infusion. β-blockers, which are destroyed by blood esterases, have a very short half-life; their effect ceases 30 minutes after stopping the infusion. Such drugs are used to treat acute ischemia, control ventricular rhythm during paroxysm of supraventricular tachycardia during surgery or in the postoperative period. The short duration of action makes their use safer in patients with hypotension and heart failure, and the βl-selectivity of the drug (esmolol) makes it safer for bronchial obstruction.

Amphophilic β-blockers are soluble in fats and water (acebutolol, bisoprolol, pindolol, celiprolol) and have two elimination routes - hepatic metabolism and renal excretion (Table 5.6).

The balanced clearance of these drugs determines the safety of their use in patients with moderate renal and hepatic insufficiency and a low likelihood of interaction with other drugs. The rate of drug elimination decreases only in severe renal and hepatic impairment. In this case, daily doses of β-blockers with balanced clearance must be reduced by 1.5-2 times.

The amphophilic β-blocker pindol in chronic renal failure can increase renal blood flow.

Doses of β-blockers must be selected individually, focusing on the clinical effect, heart rate, and blood pressure levels. The initial dose of the β-blocker should be 1/8-1/4 of the average therapeutic single dose; if the effect is insufficient, the dose is increased every 3-7 days to the average therapeutic single dose. Heart rate at rest in an upright position should be in the range of 55-60 per minute, systolic blood pressure - not lower than 100 mm Hg. The maximum severity of the β-blocker effect is observed after 4-6 weeks of regular use of the β-blocker; lipophilic β-blockers, which can

able to slow down their own metabolism. The frequency of dosing depends on the frequency of anginal attacks and the duration of action of the β-blocker.

It should be taken into account that the duration of the bradycardic and hypotensive effects of β-blockers significantly exceeds their half-life periods, and the duration of the antianginal effect is less than the duration of the negative chronotropic effect.

MECHANISMS OF ANTIANGINAL AND ANTIISCHEMIC ACTION OF β-ADRENOBLOCKERS IN THE TREATMENT OF ANGINA PARDIA

Improving the balance between myocardial oxygen demand and its delivery through the coronary arteries can be achieved by increasing coronary blood flow and by reducing myocardial oxygen demand.

The antianginal and anti-ischemic action of β-blockers is based on their ability to influence hemodynamic parameters - to reduce myocardial oxygen consumption by reducing heart rate, myocardial contractility and systemic blood pressure. β-blockers, by reducing heart rate, increase the duration of diastole. Oxygen delivery to the myocardium of the left ventricle is carried out mainly in diastole, since in systole the coronary arteries are compressed by the surrounding myocardium and the duration of diastole determines the level of coronary blood flow. A decrease in myocardial contractility, along with an extension of the time of distolic relaxation with a decrease in heart rate, contributes to an extension of the period of diastolic perfusion of the myocardium. A decrease in diastolic pressure in the left ventricle due to a decrease in myocardial contractility with a decrease in systemic blood pressure contributes to an increase in the pressure gradient (the difference between dastolic pressure in the aorta and diastolic pressure in the left ventricular cavity), providing coronary perfusion in diastole.

A decrease in systemic blood pressure is determined by a decrease in myocardial contractility with a decrease in cardiac output by

15-20%, inhibition of central adrenergic effects (for drugs that penetrate the blood-brain barrier) and antirenin (up to 60%) action of β-blockers, which causes a decrease in systolic and then diastolic pressure.

A decrease in heart rate and a decrease in myocardial contractility as a result of blockade of β-adrenergic receptors of the heart leads to an increase in volume and end-diastolic pressure in the left ventricle, which is corrected by a combination of β-blockers with drugs that reduce venous return of blood to the left ventricle (nirovasodilators).

Lipophilic beta-adrenergic receptor blockers, which do not have intrinsic sympathomimetic activity, regardless of selectivity, have a greater cardioprotective effect in patients who have suffered acute myocardial infarction with long-term use, reducing the risk of recurrent myocardial infarction, sudden death and overall mortality in this group of patients. Such properties were noted in metoprolol, propranolol (BHAT study, 3837 patients), timolol (Norwegian MSG, 1884 patients). Lipophilic drugs with intrinsic sympathomimetic activity have less prophylactic antianginal effectiveness. The effects of carvedilol and bisoprolol in terms of cardioprotective properties are comparable to the effects of the retardated form of metoprolol. Hydrophilic β-blockers - atenolol, sotalol did not affect overall mortality and the incidence of sudden death in patients with coronary heart disease. Data from a meta-analysis of 25 controlled studies are presented in Table. 5.8.

For secondary prevention, β-blockers are indicated in all patients who have had a Q-wave myocardial infarction for at least 3 years in the absence of absolute contraindications to the use of drugs of this class, especially in patients over 50 years of age with an infarction of the anterior wall of the left ventricle, early post-infarction angina, high heart rate, ventricular arrhythmias, symptoms of stable heart failure.

Table 5.7

β-blockers in the treatment of angina pectoris

Note,- selective drug; # - currently the original drug is not registered in Russia; the original drug is highlighted in bold;

* - single dose.

Table 5.8

Cardioprotective efficacy of β-blockers in patients who have suffered myocardial infarction

EFFECTS OF β-ADRENOBLOCKERS IN CHF

The therapeutic effect of β-blockers in CHF is associated with a direct antiarrhythmic effect, a positive effect on the function of the left ventricle, a decrease in chronic ischemia of the dilated ventricle even in the absence of coronary artery disease, and suppression of the processes of apoptosis of myocardiocytes activated under conditions of βl-adrenergic stimulation.

In CHF, there is an increase in the level of basal norepinephrine in the blood plasma, associated with its increased production by the endings of adrenergic nerves, the rate of entry into the blood plasma and a decrease in the clearance of norepinephrine from the blood plasma, accompanied by an increase in dopamine and often adrenaline. The concentration of basal plasma norepinephrine level is an independent predictor of death in CHF. The initial increase in the activity of the sympathetic-adrenal system in CHF is compensatory in nature and contributes to an increase in cardiac output, redistribution of regional blood flow towards the heart and skeletal muscles; renal vasoconstriction helps improve perfusion of vital organs. Subsequently, an increase in the activity of the sympathetic-adrenal

ovary system leads to increased oxygen demand by the myocardium, increased ischemia, cardiac arrhythmia, and a direct effect on cardiomyocytes - remodeling, hypertrophy, apoptosis and necrosis.

With prolonged elevated levels of catecholamines, myocardial β-adrenergic receptors enter a state of reduced sensitivity to neurotransmitters (desinitization state) due to a decrease in the number of receptors on the plasma membrane and disruption of the coupling of receptors with adenylate cyclase. The density of myocardial β-adrenergic receptors is reduced by half, the degree of receptor reduction is proportional to the severity of CHF, myocardial contractility and ejection fraction. The ratio and β change 2 -adrenergic receptors in the direction of increasing β 2 -adrenoreceptors. Disruption of the coupling of β-adrenergic receptors with adenylate cyclase leads to direct cardiotoxic effects of catecholamines, overload of cardiomyocyte mitochondria with calcium ions, disruption of ADP rephosphorylation processes, depletion of creatine phosphate and ATP reserves. Activation of phospholipases and proteases contributes to the destruction of the cell membrane and the death of cardiomyocytes.

A decrease in the density of adrenergic receptors in the myocardium is combined with depletion of local reserves of norepinephrine, disruption of adequate load of adrenergic support of the myocardium, and progression of the disease.

The positive effects of β-blockers in CHF are: a decrease in sympathetic activity, a decrease in heart rate, an antiarrhythmic effect, an improvement in diastolic function, a decrease in myocardial hypoxia and regression of hypertrophy, a decrease in necrosis and apoptosis of cardiomyocytes, a decrease in the severity of congestion due to blockade of the renin-angiotensin-aldosterone system.

Based on research data from the USCP - American program for carvedilol, CIBIS II with bisoprolol and MERIT HF with metoprolol succinate with sustained release of the drug, COPERNICUS, CAPRICORN about a significant reduction in overall, cardiovascular, sudden death, a reduction in the frequency of hospitalizations, a reduction in the risk of death by 35 % in the severe category of patients with CHF, the above β-blockers occupy one of the leading positions in the pharmacotherapy of patients with CHF of all functional classes. β-blockers along with ACE inhibitors

are the main means in the treatment of CHF. Their ability to slow the progression of the disease, the number of hospitalizations and improve the prognosis of decompensated patients is beyond doubt (evidence level A). β-blockers should be used in all patients with CHF who do not have the usual contraindications for this group of drugs. The severity of decompensation, gender, age, initial pressure level (SBP not less than 85 mm Hg) and initial heart rate do not play an independent role in determining contraindications to the use of β-blockers. Prescription of β-blockers begins with 1 /8 therapeutic dose for patients with achieved stabilization of CHF. β-blockers in the treatment of CHF are not “emergency medicine” and cannot relieve patients from a state of decompensation and overhydration. Possible appointment β l-selective β-blocker bisoprolol as an initial treatment drug in patients over 65 years of age with NYHA class II - III CHF, left ventricular ejection fraction<35% с последующим присоединением ингибитора АПФ (степень доказанности В). Начальная терапия βl A -selective β-blocker may be justified in clinical situations where severe tachycardia predominates at low blood pressure, followed by the addition of an ACE inhibitor.

The tactics for prescribing β-blockers in patients with CHF are presented in Table. 5.9.

In the first 2-3 months, the use of even small doses of β-blockers causes an increase in peripheral vascular resistance and a decrease in myocardial systolic function, which requires titration of the dose of the β-blocker prescribed to a patient with CHF and dynamic monitoring of the clinical course of the disease. In these cases, it is recommended to increase the doses of diuretics, ACE inhibitors, the use of positive inotropic drugs (small doses of cardiac glycosides or calcium sensitizers - levosimendan), and a slower titration of the beta-blocker dose.

Contraindications to the use of β-blockers for heart failure are:

Bronchial asthma or severe bronchial pathology, accompanied by an increase in symptoms of bronchial obstruction when a beta-blocker is prescribed;

Symptomatic bradycadia (<50 уд/мин);

Symptomatic hypotension (<85 мм рт.ст.);

Table 5.9

Initial, target doses and dosing schedules of beta-blockers in heart failure based on large-scale placebo-controlled studies

research

A-V blockade of the second degree and higher;

Severe obliterating endarteritis.

The administration of β-blockers to patients with CHF and type 2 diabetes is absolutely indicated. All the positive properties of drugs of this class are completely preserved in the presence of diabetes mellitus. Use of non-cardioselective and adrenoblocker with additional properties 0 4 The β-blocker carvedilol may be the drug of choice in such patients by improving the sensitivity of peripheral tissues to insulin (evidence level A).

Results of the SENIORS study using β l-selective β-blocker nebivolol, which demonstrated a small but significant overall reduction in the frequency of hospitalizations and deaths in patients with CHF over 75 years of age, allowed us to recommend nebivolol for the treatment of patients with CHF over 70 years of age.

Doses of β-arenoblockers for the treatment of patients with CHF, established by the National Recommendations of GFCI and OSHF, are presented in Table 5.10.

Table 5.10

Doses of beta-blockers for the treatment of patients with CHF

left ventricle<35%, была выявлена одинаковая эффективность и переносимость бетаксолола и карведилола.

The use of the non-selective β-blocker bucindolol, which has moderate intrinsic sympathomimetic activity and additional vasodilating properties (BEST study), did not significantly reduce overall mortality and the frequency of hospitalizations due to CHF; there was a worsening prognosis and an increase in the risk of death by 17% in the group of black patients.

Further clarification of the effectiveness of drugs in this group in certain demographic groups of patients, in elderly patients, and in patients with atrial fibrillation is required.

MAIN MECHANISMS OF HYPOTENSIVE ACTION OF β-ADRENOB LOCATORS

β-blockers are initial therapy drugs in the treatment of arterial hypertension. β-blockers are first-line drugs in the treatment of hypertension in patients after myocardial infarction, suffering from stable angina, heart failure, in people intolerant to ACE inhibitors and/or ATII receptor blockers, in women of childbearing age planning pregnancy.

As a result of blockade of β-adrenergic receptors of the heart, the heart rate and myocardial contractility decrease, and cardiac output decreases. Blockade of β-adrenergic receptors in the cells of the juxtaglomerular apparatus of the kidneys leads to a decrease in the secretion of renin, a decrease in the formation of angiotensin, and a decrease in peripheral vascular resistance. Reducing aldosterone production helps reduce fluid retention. The sensitivity of the baroreceptors of the aortic arch and carotid sinus changes, and the release of norepinephrine from the endings of postganglionic sympathetic nerve fibers is inhibited. Central adrenergic effects are inhibited (for β-blockers that penetrate the blood-brain barrier).

The use of β-adrenor blockers helps reduce systolic and diastolic blood pressure, control blood pressure in the early morning hours, and normalize

daily blood pressure profile. Left ventricular hypertrophy is today considered one of the most significant risk factors for the development of cardiovascular complications.

β-blockers, as a result of reducing the activity of the sympathetic and renin-angiothesin system, are the optimal class of drugs for the prevention and reversal of left ventricular hypertrophy. Indirect reduction of aldosterone levels limits the simulation of myocardial fibrosis, improving left ventricular diastolic function.

The level of selectivity of β-blockers determines the effect on total peripheral vascular resistance as one of the determining components of the hypotensive effect. Selective β l-adrenergic blockers do not have a significant effect on peripheral vascular resistance, non-selective, due to β blockade 2 -vascular receptors, can enhance the vasoconstrictor effect and increase peripheral vascular resistance.

β-blockers in combination with vasodilators or labetolol are the drugs of choice when there is a threat of aortic aneurysm dissection due to increased blood pressure. This is the only clinical situation of high blood pressure that requires a rapid decrease in blood pressure within 5-10 minutes. The administration of a beta-blocker should precede the administration of a vasodilator to prevent increases in cardiac output that may aggravate the situation.

Labetolol is the drug of choice in the treatment of hypertensive crisis complicated by acute coronary insufficiency; parenteral administration of a non-selective β-blocker is indicated for the development of tachycardia or rhythm disturbances.

Labetolol and esmolol are the drugs of choice for the management of patients with traumatic brain injuries complicated by hypertensive crises.

Labetolol and oxprenalol are the drugs of choice for controlling blood pressure in pregnant women in case of intolerance to methyldopa. The effectiveness of pindolol is comparable to oxprenolol and labetolol. With long-term use of atenolol, a decrease in the weight of the newborn and the placenta was found, which is associated with a decrease in feto-placental blood flow.

In table Table 5.11 presents the main doses and frequency of administration of β-blockers for the treatment of hypertension.

Table 5.11

Daily doses and frequency of use of β-blockers for the treatment of hypertension

MONITORING THE EFFECTIVENESS OF THERAPY WITH β-ADRENOBLOCKERS

The effective heart rate at the maximum expected effect of the next dose of beta-blocker (usually 2 hours after administration) is 55-60 beats per minute. A stable hypotensive effect occurs after 3-4 weeks of regular use of the drug. Given the possibility of slowing atrioventricular conduction, electrocardiographic monitoring is necessary, especially in cases of a more significant decrease in heart rate. Patients with symptoms of latent circulatory failure require attention; such patients require a longer titration of the dose of the β-blocker due to the threat of the development of decompensation phenomena (the appearance of fatigue, weight gain, shortness of breath, wheezing in the lungs).

Age-related features of the pharmacodynamics of β-adrenergic blockers are due to changes in the interaction between β-adrenergic receptors and stimulation of alanine aminotransferase production and binding of the receptor to adenylate cyclase. The sensitivity of β-adrenergic receptors to β-blockers changes and becomes distorted. This determines the multidirectional and difficult to predict nature of the pharmacodynamic response to the drug.

Pharmacokinetic parameters also change: the protein capacity of the blood, water and muscle mass of the body decrease, the volume of adipose tissue increases, and tissue perfusion changes. The volume and speed of hepatic blood flow decreases by 35-45%. The number of hepatocytes and the level of their enzymatic activity decreases - liver weight decreases by 18-25%. The number of functioning glomeruli of the kidneys, the rate of glomerular filtration (by 35-50%) and tubular secretion decrease.

SELECTED β-ADRENOBLOCKER DRUGS

Non-selectiveβ - adrenergic blockers

Propranolol- a non-selective beta-blocker without its own sympathomimetic activity with a short-term effect. The bioavailability of propranolol after oral administration is less than 30%, T 1/2 - 2-3 hours. Due to the high rate of metabolism of the drug during the first passage through the liver, its concentrations in the blood plasma after taking the same dose can vary from person to person by 7-20 times. 90% of the dose taken is eliminated in the urine in the form of metabolites. The distribution of propranolol and, apparently, other β-blockers in the body is influenced by a number of drugs. At the same time, beta-blockers themselves can alter the metabolism and pharmacokinetics of other drugs. Propranolol is prescribed orally, starting with small doses - 10-20 mg, gradually (especially in older people and in cases of suspected heart failure) over 2-3 weeks, bringing the daily dose to an effective dose (160-180-240 mg). Given the short half-life of the drug, to achieve a constant therapeutic concentration it is necessary to take propranolol 3-4 times a day. Treatment can be lengthy. It should be remembered that high

Doses of propranolol may result in increased side effects. To select the optimal dose, regular measurement of heart rate and blood pressure is necessary. It is recommended to discontinue the drug gradually, especially after long-term use or after using large doses (reduce the dose by 50% within one week), since abrupt cessation of its use can cause withdrawal syndrome: increased frequency of angina attacks, development of gastric tachycardia or myocardial infarction, and AH - a sharp rise in blood pressure.

Nadolol- a non-selective β-blocker without internal sympathomimetic and membrane-stabilizing activity. It differs from other drugs in this group in its long-lasting action and ability to improve kidney function. Nadolol has antianginal activity. Has less cardiodepressive effect, possibly due to the lack of membrane-stabilizing activity. When taken orally, about 30% of the drug is absorbed. Only 18-21% binds to plasma proteins. Peak concentration in the blood after oral administration is reached after 3-4 hours, T 1/2

From 14 to 24 hours, which allows the drug to be prescribed once a day in the treatment of patients with both angina and hypertension. Nadolol is not metabolized in the body and is excreted unchanged by the kidneys and intestines. Complete release is achieved only 4 days after a single dose. Nadolol is prescribed 40-160 mg once a day. A stable level of its concentration in the blood is achieved after 6-9 days of administration.

Pindolol is a non-selective β-adrenergic receptor blocker with sympathomimetic activity. It is well absorbed when taken orally. Features high bioavailability, T 1/2

3-6 hours, the beta-blocking effect lasts for 8 hours. About 57% of the dose taken is combined with protein. 80% of the drug is excreted in the urine (40% unchanged). Its metabolites are presented in the form of glucuronides and sulfates. CRF does not significantly change the elimination constant and half-life. The rate of drug elimination is reduced only in severe renal and hepatic impairment The drug penetrates the blood-brain barrier and the placenta. Compatible with diuretics, antiadrenergic drugs, methyldopa, reserpine, barbiturates, digitalis. In terms of β-adrenergic blocking action, 2 mg of pindolol is equivalent to 40 mg of propranolol. Pindolol is used 5 mg 3-4 times a day, and in severe cases - 10 mg 3 times a day.

If necessary, the drug can be administered intravenously in a dose of 0.4 mg; the maximum dose for intravenous administration is 1-2 mg. The drug causes a less pronounced negative inotropic effect at rest than propranolol. It has a weaker effect on β than other non-selective β-blockers. 2 -adrenergic receptors and therefore in normal doses is safer for bronchospasm and diabetes mellitus. In hypertension, the hypotensive effect of pindolol develops more slowly than that of propranolol: the onset of action is after a week, and the maximum effect is after 4-6 weeks.

Selectiveβ - adrenergic blockers

Nebivolol- highly selective third-generation β-blocker. The active substance of nebivolol is a racemate, consisting of two enantiomers. D-nebivolol is a competitive and highly selective β l-blocker. L-nebivolol has a mild vasodilating effect by modulating the release of relaxing factor (NO) from the vascular endothelium, which maintains normal basal vascular tone. After oral administration, it is quickly absorbed. Highly lipophilic drug. Nebivolol is actively metabolized, partially with the formation of active hydroxymetabolites. The time to reach a stable equilibrium concentration in individuals with rapid metabolism is achieved within 24 hours, for hydroxymetabolites - after several days.

The level of the hypothetical effect and the number of patients responding to therapy increases in proportion to the 2.5-5 mg daily dose of the drug, therefore the average effective dose of nebivolol is taken to be 5 mg per day; in case of renal failure, as well as in persons over 65 years of age, the initial dose should not exceed 2.5 mg.

The hypotensive effect of nebivolol develops after the first week of treatment, increases by the 4th week of regular use, and with long-term treatment up to 12 months, the effect is stably maintained. After discontinuation of nebivolol, blood pressure slowly returns to its original level over 1 month; withdrawal syndrome in the form of exacerbation of hypertension is not observed.

Due to the presence of vasodilating properties, nebivolol does not affect renal hemodynamic parameters (renal artery resistance, renal blood flow, glomerular filtration,

filtration fraction) both in patients with normal and impaired renal function against the background of arterial hypertension.

Despite its high lipophilicity, nebivolol is practically free of side effects from the central nervous system: it did not cause sleep disturbances or nightmares, which are characteristic of lipophilic β-blockers. The only neurological disorder is paresthesia - their frequency is 2-6%. Sexual dysfunction occurred at a rate not different from placebo (less than 2%).

Carvedilol has β- and a 1 -adrenergic blocking as well as antioxidant properties. It reduces the effects of stress on the heart through arteriolar vasodilation and inhibits neurohumoral vasoconstrictor activation of blood vessels and the heart. Carvedilol has a prolonged antihypertensive effect. It has an antianginal effect. It does not have its own sympathomimetic activity. Carvedilol inhibits the proliferation and migration of smooth muscle cells, apparently acting on specific mitogenic receptors. Carvedilol has lipophilic properties. T 1/2 is 6 hours. During the first passage through the liver, it is metabolized. In blood plasma, carvedilol is 95% protein bound. The drug is excreted through the liver. Used for hypertension - 25-20 mg once a day; for angina pectoris and chronic heart failure - 25-50 mg twice a day.

Bisoprolol- a highly selective, long-acting β-blocker without internal sympathomimetic activity and does not have a membrane-stabilizing effect. It has amphophilic properties. Due to its prolonged action, it can be prescribed once a day. The peak effect of bisoprolol occurs 2-4 hours after administration, the antihypertensive effect lasts 24 hours. Bioavailability is 65-75% for bisoprolol hydrochloride and 80% for bisoprolol fumarate. The bioavailability of the drug increases in the elderly. Food intake does not affect the bioavailability of bisoprolol. Low binding to plasma proteins (30%) ensures safety when used together with most drugs. 20% of bisoprolol is metabolized into 3 inactive metabolites. There is a linear dependence of the pharmacokinetics of the drug on the dose within the range of 2.5-20 mg. T s is 7-15 hours for bisoprolol fumarate and 4-10 hours for bisoprolol hydrochloride. Bisoprolol fumarate binds to blood proteins by 30%,

bisoprolol hydrochloride - by 40-68%. Accumulation of bisoprolol in the blood is possible in case of impaired liver and kidney function. Excreted equally by the liver and kidneys. The rate of drug elimination decreases only in cases of severe renal and hepatic insufficiency, which is why bisoprolol can accumulate in the blood if liver and kidney function are impaired.

Penetrates the blood-brain barrier. Used for arterial hypertension, angina pectoris, heart failure. The initial dose for hypertension is 5-10 mg per day, it is possible to increase the dose to 20 mg per day; in case of insufficiency of liver and kidney function, the daily dose should not exceed 10 mg. Bisoprolol does not affect the level of glucose in the blood in patients with diabetes and the level of thyroid hormones, and has virtually no effect on potency in men.

Betaxolol- a cardioselective β-blocker without its own sympathomimetic activity and with weakly expressed membrane-stabilizing properties. The potency of β-adrenergic receptor blockade is 4 times greater than the effects of propranolol. It has high lipophilicity. Well (more than 95%) absorbed from the gastrointestinal tract. After a single dose, it reaches maximum concentrations in the blood plasma after 2-4 hours. Food intake does not affect the degree and rate of absorption. Unlike other lipophilic drugs, the bioavailability of betaxolol when taken orally is 80-89%, which is explained by the absence of a “first pass” effect through the liver. Individual metabolic features do not affect the variability of drug concentrations in the blood serum, which allows us to expect a more stable response to the action of the drug when used. The degree of heart rate reduction is proportional to the dose of betaxolol. There is a correlation of the antihypertensive effect with the peak concentration of betaxolol in the blood 3-4 hours after administration and then for 24 hours, the effect is dose dependent. With regular use of betaxolol, the antihypertensive effect reaches its maximum after 1-2 weeks. Betaxolol is metabolized in the liver by microsomal oxidation, however, cimetidine does not change the concentration of the drug when used together and does not lead to a prolongation of T1/2. T1/2 is 14-22 hours, which allows you to take the drug once a day. In older people, T1/2 increases to 27 hours.

Binds to plasma proteins by 50-55%, of which to albumin by 42%. Liver and kidney disease does not affect the degree of protein binding; it does not change when taking digoxin, aspirin, or diuretics at the same time. Betaxolol and its metabolites are excreted in the urine. The rate of drug elimination decreases only in severe renal and hepatic insufficiency. The pharmacokinetics of betaxolol do not require changes in the dosage regimen for severe hepatic and moderate renal failure. Dose adjustment of the drug is necessary only in cases of severe renal failure and in patients on dialysis. For patients with significant renal impairment requiring hemodialysis, the initial dose of betaxolol is 5 mg per day, the dose can be increased by 5 mg every 14 days, the maximum dose is 20 mg. The initial dose for hypertension and angina pectoris is 10 mg once a day; if necessary, the dose can be doubled after 7-14 days. To enhance the effect, betaxalol can be combined with thiazide diuretics, vasodilators, imdazoline receptor agonists, and o 1 -blockers. The advantage over other selective β 1 -adrenergic receptors is the absence of a decrease in HDL concentration. Betaxolol does not affect the process of glucose metabolism and compensatory mechanisms during hypoglycemia. In terms of the degree of reduction in heart rate, blood pressure, and increase in exercise tolerance in patients with angina pectoris, the effects of betaxolol did not differ from those of nadolol.

Metoprolol- selective blocker of β 1-adrenergic receptors. The bioavailability of metoprolol is 50%, TS is 3-4 hours for the regular release dosage form. About 12% of the drug is bound to blood proteins. Metoprolol quickly dissolves in tissues, penetrates the blood-brain barrier, and is found in breast milk in higher concentrations than in plasma. The drug undergoes intensive hepatic metabolism in the cytochrome P4502D6 system and has two active metabolites - α-hydroxymetoprolol and o-dimethylmetoprolol. Age does not affect the concentration of metoprolol; cirrhosis increases bioavailability to 84% and half-life to 7.2 hours. In chronic renal failure, the drug does not accumulate in the body. In patients with hyperthyroidism, the level of maximum concentration achieved and the area under the kinetic curve are reduced. The drug exists in the form of metoprolol tartrate (regular and delayed release forms).

nia), metoprolol succinate with prolonged controlled release. Sustained release forms have a maximum peak concentration of the active substance 2.5 times lower than regular release forms, which is advantageous in patients with circulatory insufficiency. Pharmacokinetic parameters for metoprolol of various releases at a dose of 100 mg are presented in table. 5.12.

Table 5.12

Pharmacokinetics of dosage forms of metoprolol

Metoprolol succinate in controlled release form has a constant rate of release of the active substance, absorption in the stomach does not depend on food intake.

For hypertension and angina pectoris, metoprolol is prescribed 2 times a day, 50-100-200 mg. The hypotensive effect occurs quickly, systolic blood pressure decreases after 15 minutes, maximum after 2 hours. Diastolic pressure decreases after several weeks of regular use. Sustained release forms are the drugs of choice in the treatment of circulatory failure. The clinical effectiveness of ACE inhibitors in heart failure increases significantly with the addition of a β-blocker (ATLAS, MERIT HF, PRECISE, MOCHA studies).

Atenolol- selective β l- an adrenergic blocker that does not have its own sympathomimetic and membrane-stabilizing activity. Absorbed from the gastrointestinal tract by approximately 50%. The peak plasma concentration occurs after 2-4 hours. It is almost not metabolized in the liver and is eliminated mainly by the kidneys. About 6-16% binds to plasma proteins. T 1/2 is 6-7 hours for both single and long-term

destination. After oral administration, a decrease in cardiac output occurs within an hour, the maximum effect is between 2 and 4 hours and lasts at least 24 hours. The hypotensive effect, like all β-blockers, does not correlate with plasma levels and increases after continuous use for several weeks For hypertension, the initial dose is 25-50 mg; if there is no effect within 2-3 weeks, the dose is increased to 100-200 mg, divided into 2 doses. In elderly patients with chronic renal failure, dose adjustment is recommended when glomerular filtration rate is below 35 ml/min.

DRUG INTERACTIONS WITH β-ADRENOBLOCKERS

Table 5.13

Drug interactions

SIDE EFFECTS AND CONTRAINDICATIONS TO THE USE OF β-ADRENOBLOCKERS

Side effects of β-blockers are determined by their predominant blocking effect on one or another type of receptor; the level of lipophilicity determines the presence of side effects from the central nervous system (Table 5.14).

The main side effects of β-blockers are: sinus bradycardia, development or increase in the degree of atrioventricular block, manifestation of latent congestive heart failure, exacerbation of bronchial asthma or other obstructive pulmonary diseases, hypoglycemia, impaired

Table 5.14

Characteristics of side effects of β-blockers

function in men, various manifestations of vasospasm, general weakness, drowsiness, depression, dizziness, decreased reaction speed, the possibility of developing withdrawal syndrome (mainly for drugs with a short duration of action).

Contraindications to the use of β-blockers. The drugs should not be used for severe bradycardia (less than 48 beats/min), arterial hypotension (systolic blood pressure below 100 mm Hg), bronchial asthma, sick sinus syndrome, and high-grade atrioventricular conduction disorders. Relative contraindications are diabetes mellitus in the stage of decompensation, severe peripheral circulatory disorders, severe circulatory failure in a state of decompensation, pregnancy (for β-blockers that do not have a vasodilating effect).

PLACE OF β-ADRENOBLOCKERS

IN COMBINED THERAPY

Monotherapy with β-blockers is effective for the prevention of anginal attacks in angina pectoris of functional class I-III and in 30-50% of patients with mild and moderate hypertension to maintain target blood pressure values.

According to the HOT study, to achieve a target diastolic blood pressure below 85-80 mm Hg. 68-74% of patients require combination antihypertensive therapy. Combination therapy to achieve target blood pressure values ​​is indicated for the vast majority of patients with diabetes and chronic renal failure.

The undeniable advantages of rational combinations are the potentiation of the hypotensive effect due to the impact on various parts of the pathogenesis of arterial hypertension, improving drug tolerability, reducing the number of side effects, limiting counter-regulatory mechanisms (bradycardia, increased total peripheral resistance, arteriospasm, excessive decrease in myocardial contractility and others), including at the initial stages of prescribing antihypertensive drugs (Table 5.15). Combined antihypertensive therapy is indicated for patients with moderate arterial hypertension, in the presence of proteinuria, diabetes mellitus, and renal failure.

An effective combination is the combined use of a β-blocker and a diuretic. The diuretic and vasodilating effect of the diuretic limits sodium retention and increased peripheral vascular tone characteristic of beta-blockers. β-blockers, in turn, suppress the activity of the sympathoadrenal and renin-angiotensin systems, characteristic of a diuretic. It is possible to inhibit the development of diuretic hypokalemia with a β-blocker. The low cost of such combinations is attractive.

There are combined dosage forms: tenoretic (50-100 mg atenolol and 25 mg chlorthalidone), lopressor HGT (50-100 mg metoprolol and 25-50 mg hydrochlorothiazide), corzoid (40-80 mg nadolol and 5 mg bendroflumetazide), viscaldix (10 mg pindolol and 5 mg clopamide), Ziac (2.5-5-10 mg bisoprolol and 6.25 mg gyrochlorothiazide).

When combined with dihydropyridine antagonists of slow calcium channels, β-blockers have an additive effect, counteracting the development of tachycardia and activation of the sympathetic nervous system, characteristic of initial therapy with dihydropyridines. This combination therapy is indicated for patients with hypertension and coronary artery disease, patients with severe refractory arterial hypertension. Logimax is a fixed combination with a long-term release system of active components of 50-100 mg of metoprolol and 5-10 mg of felodipine, which selectively acts on precapillary resistive vessels. 50 mg of atenolol and 5 mg of amlodipine are included in the drug tenochek.

The combination of β-blockers and calcium antagonists - verapamil or diltiazem - is dangerous in terms of significant slowdown of atrioventricular conduction.

The combination of β-blockers and a1-adrenergic receptor blockers is beneficial. β-blockers inhibit the development of tachycardia, which is typical when α-blockers are prescribed. Blockers of a 1 -adrenergic receptors reduce the effects of β-blockers, such as increased peripheral vascular resistance and effects on lipid and carbohydrate metabolism.

Drugs beta-blockers and ACE inhibitors, by reducing the activity of the renin-angiotensin system, can have a synergistic hypotensive effect. The administration of an ACE inhibitor does not completely suppress the formation of angiotensin II, since there are alternative pathways for its formation. Hyperreninemia resulting from ACE inhibitor inhibition can be reduced by the direct suppressive effect of β-blockers on renin secretion by the juxtaglomerular apparatus of the kidneys. Suppression of renin secretion will reduce the production of angiotensin I and, indirectly, angiotensin II. The vasodilating properties of ACEIs may reduce the vasoconstrictor effects of β-blockers. The organoprotective effect of this combination has been proven in patients with congestive heart failure.

The combination of a β-blocker and an imidazoline receptor agonist (a centrally acting drug) may be rational in the combination therapy of arterial hypertension to achieve target blood pressure values ​​in patients with metabolic disorders (up to 80% of patients with arterial hypertension suffer from metabolic disorders). Additive

the hypotensive effect is combined with the correction of insulin resistance, impaired glucose tolerance, and dyslipidemia, characteristic of the class of β-blockers.

Table 5.15

Combined antihypertensive therapy with β-blockers

Catecholamines: adrenaline and norepinephrine play an important role in regulating body functions. They are released into the blood and act on special sensitive nerve endings - adrenergic receptors. The latter are divided into two large groups: alpha and beta adrenergic receptors. Beta adrenergic receptors are located in many organs and tissues and are divided into two subgroups.

When β1-adrenergic receptors are activated, the frequency and strength of heart contractions increases, the coronary arteries dilate, the conductivity and automaticity of the heart improves, and the breakdown of glycogen in the liver and energy production increases.

When β2-adrenergic receptors are excited, the walls of blood vessels and the muscles of the bronchi relax, the tone of the uterus decreases during pregnancy, the secretion of insulin and the breakdown of fat increase. Thus, stimulation of beta-adrenergic receptors with the help of catecholamines leads to the mobilization of all the body’s forces for active life.

Beta-adrenergic blockers (BAB) are a group of drugs that bind beta-adrenergic receptors and prevent the action of catecholamines on them. These drugs are widely used in cardiology.

BBs reduce the frequency and strength of heart contractions and lower blood pressure. As a result, oxygen consumption by the heart muscle decreases.

Diastole lengthens - a period of rest and relaxation of the heart muscle, during which the coronary vessels are filled with blood. Improvement of coronary perfusion (blood supply to the myocardium) is also facilitated by a decrease in intracardiac diastolic pressure.

There is a redistribution of blood flow from normally blood-supplied areas to ischemic areas, as a result of which physical exercise tolerance improves.

Beta blockers have an antiarrhythmic effect. They suppress the cardiotoxic and arrhythmogenic effects of catecholamines, and also prevent the accumulation of calcium ions in the heart cells, which worsen energy metabolism in the myocardium.

Classification

BAB is a broad group of medicines. They can be classified according to many criteria.
Cardioselectivity is the ability of the drug to block only β1-adrenergic receptors, without affecting β2-adrenergic receptors, which are located in the wall of the bronchi, blood vessels, and uterus. The higher the selectivity of the beta blocker, the safer it is to use for concomitant diseases of the respiratory tract and peripheral vessels, as well as for diabetes mellitus. However, selectivity is a relative concept. When prescribing the drug in large doses, the degree of selectivity decreases.

Some beta blockers have intrinsic sympathomimetic activity: the ability to stimulate beta-adrenergic receptors to some extent. Compared to conventional beta blockers, such drugs slow down the heart rate and the force of its contractions less, less often lead to the development of withdrawal syndrome, and have less negative effects on lipid metabolism.

Some beta blockers are capable of further dilating blood vessels, that is, they have vasodilating properties. This mechanism is realized through pronounced internal sympathomimetic activity, blockade of alpha-adrenergic receptors, or direct action on the vascular walls.

The duration of action most often depends on the characteristics of the chemical structure of the biologically active substance. Lipophilic agents (propranolol) act for several hours and are quickly eliminated from the body. Hydrophilic drugs (atenolol) are effective for a longer period of time and may be prescribed less frequently. Currently, long-acting lipophilic substances (metoprolol retard) have also been created. In addition, there are beta blockers with a very short duration of action - up to 30 minutes (esmolol).

Scroll

1. Non-cardioselective beta blockers:

A. Without intrinsic sympathomimetic activity:

• propranolol (anaprilin, obzidan);
• nadolol (korgard);
• sotalol (sotahexal, tenzol);
• timolol (blocarden);
• nipradilol;
• flestrolol.

• oxprenolol (Trazicor);
• pindolol (wisken);
• alprenolol (aptin);
• penbutolol (betapressin, levatol);
• bopindolol (Sandorm);
• bucindolol;
• dilevalol;
• carteolol;
• labetalol.

2. Cardioselective beta blockers:

A. Without internal sympathomimetic activity:

B. With internal sympathomimetic activity:

• acebutalol (acecor, sectral);
• talinolol (cordanum);
• celiprolol;
• epanolol (vasacor).

3. Beta blockers with vasodilating properties:

A. Non-cardioselective:

B. Cardioselective:

• carvedilol;
• nebivolol;
• Celiprolol.

4. Long-acting beta blockers:

A. Non-cardioselective:

• bopindolol;
• nadolol;
• penbutolol;
• sotalol.

B.
Cardioselective:

• atenolol;
• betaxolol;
• bisoprolol;
• epanolol.

5. Ultra-short-acting beta blockers, cardioselective:

• esmolol.

Use for diseases of the cardiovascular system

Angina pectoris

In many cases, beta blockers are one of the leading means for treating and preventing attacks. Unlike nitrates, these agents do not cause tolerance (drug resistance) with long-term use. BAs are capable of cumulating (accumulating) in the body, which makes it possible to reduce the dosage of the drug after some time. In addition, these drugs protect the heart muscle itself, improving the prognosis by reducing the risk of recurrent myocardial infarction.

The antianginal activity of all beta blockers is approximately the same.
Their choice is based on the duration of the effect, severity of side effects, cost and other factors.

Begin treatment with a small dose, gradually increasing it until it is effective. The dosage is selected in such a way that the resting heart rate is not lower than 50 per minute, and the systolic blood pressure level is not less than 100 mmHg. Art. After the onset of a therapeutic effect (cessation of angina attacks, improvement of exercise tolerance), the dose is gradually reduced to the minimum effective.

Long-term use of high doses of beta blockers is not advisable, since this significantly increases the risk of side effects. If these drugs are insufficiently effective, it is better to combine them with other groups of drugs.

BAB should not be abruptly discontinued, as this may result in withdrawal syndrome.

Beta blockers are especially indicated if angina pectoris is combined with sinus tachycardia, glaucoma, constipation and gastroesophageal reflux.

Myocardial infarction

Early use of beta blockers helps to limit the area of ​​cardiac muscle necrosis. This reduces mortality and reduces the risk of recurrent myocardial infarction and cardiac arrest.

This effect is exerted by beta blockers without internal sympathomimetic activity; it is preferable to use cardioselective agents. They are especially useful when myocardial infarction is combined with arterial hypertension, sinus tachycardia, post-infarction angina and tachysystolic form.

BAB can be prescribed immediately upon admission of the patient to the hospital to all patients in the absence of contraindications. In the absence of side effects, treatment with them continues for at least a year after myocardial infarction.

Chronic heart failure

The use of beta blockers in heart failure is being studied. It is believed that they can be used for a combination of heart failure (especially diastolic) and angina pectoris. Rhythm disturbances, arterial hypertension, tachysystolic form of atrial fibrillation in combination with are also grounds for prescribing this group of drugs.

Hypertonic disease

Beta blockers are indicated in the treatment of complicated hypertension. They are also widely used in young patients leading an active lifestyle. This group of drugs is prescribed for the combination of arterial hypertension with angina pectoris or heart rhythm disturbances, as well as after a myocardial infarction.

Heart rhythm disturbances

BBs are used for cardiac arrhythmias such as atrial fibrillation and flutter, supraventricular arrhythmias, and poorly tolerated sinus tachycardia. They can also be prescribed for ventricular arrhythmias, but their effectiveness in this case is usually less pronounced. BABs in combination with potassium preparations are used to treat diseases caused by glycoside intoxication.

Side effects

The cardiovascular system

BBs inhibit the ability of the sinus node to produce impulses that cause contractions of the heart and cause sinus bradycardia - a slowdown in heart rate to less than 50 per minute. This side effect is much less pronounced in beta blockers with intrinsic sympathomimetic activity.

Drugs in this group can cause atrioventricular block of varying degrees. They also reduce the strength of heart contractions. The latter side effect is less pronounced in beta blockers with vasodilating properties. BBs reduce blood pressure.

Medicines in this group cause spasm of peripheral vessels. Coldness of the extremities may appear, and Raynaud's syndrome worsens. Drugs with vasodilating properties are almost free of these side effects.

BBs reduce renal blood flow (except for nadolol). Due to the deterioration of peripheral circulation during treatment with these drugs, severe general weakness sometimes occurs.

Respiratory system

BBs cause bronchospasm due to concomitant blockade of β2-adrenergic receptors. This side effect is less pronounced with cardioselective drugs. However, their effective doses against angina or hypertension are often quite high, and cardioselectivity is significantly reduced.
The use of high doses of beta blockers can provoke apnea, or temporary cessation of breathing.

BAs worsen the course of allergic reactions to insect bites, medicinal and food allergens.

Nervous system

Propranolol, metoprolol and other lipophilic beta blockers penetrate from the blood into brain cells through the blood-brain barrier. Therefore, they can cause headaches, sleep disturbances, dizziness, memory impairment and depression. In severe cases, hallucinations, convulsions, and coma occur. These side effects are much less pronounced with hydrophilic biologically active agents, in particular atenolol.

Treatment with beta blockers may be accompanied by impaired neuromuscular conduction. This leads to muscle weakness, decreased endurance and fatigue.

Metabolism

Non-selective beta blockers suppress insulin production in the pancreas. On the other hand, these drugs inhibit the mobilization of glucose from the liver, contributing to the development of prolonged hypoglycemia in patients with diabetes mellitus. Hypoglycemia promotes the release of adrenaline into the blood, acting on alpha-adrenergic receptors. This leads to a significant increase in blood pressure.

Therefore, if it is necessary to prescribe beta blockers to patients with concomitant diabetes mellitus, preference should be given to cardioselective drugs or replaced with calcium antagonists or drugs from other groups.

Many blockers, especially non-selective ones, reduce the level of “good” cholesterol (high-density alpha lipoproteins) in the blood and increase the level of “bad” cholesterol (triglycerides and very low-density lipoproteins). Drugs with β1-intrinsic sympathomimetic and α-blocking activity (carvedilol, labetolol, pindolol, dilevalol, celiprolol) do not have this drawback.

Other side effects

Treatment with beta blockers is in some cases accompanied by sexual dysfunction: erectile dysfunction and loss of sexual desire. The mechanism of this effect is unclear.

BBs can cause skin changes: rash, itching, erythema, symptoms of psoriasis. In rare cases, hair loss and stomatitis are reported.

One of the serious side effects is inhibition of hematopoiesis with the development of agranulocytosis and thrombocytopenic purpura.

Withdrawal syndrome

If beta blockers are used for a long time in high dosages, then sudden cessation of treatment can provoke the so-called withdrawal syndrome. It is manifested by an increase in angina attacks, the occurrence of ventricular arrhythmias, and the development of myocardial infarction. In milder cases, withdrawal syndrome is accompanied by tachycardia and increased blood pressure. Withdrawal syndrome usually manifests itself a few days after stopping the use of beta blockers.

To avoid the development of withdrawal syndrome, you must follow the following rules:

• discontinue beta blockers slowly, over two weeks, gradually reducing the dosage per dose;
• during and after discontinuation of beta blockers, it is necessary to limit physical activity and, if necessary, increase the dosage of nitrates and other antianginal drugs, as well as medications that lower blood pressure.

Contraindications

BABs are absolutely contraindicated in the following situations:

• pulmonary edema and cardiogenic shock;
• severe heart failure;
• bronchial asthma;
• atrioventricular block II – III degree;
• systolic blood pressure level 100 mm Hg. Art. and below;
• heart rate less than 50 per minute;
• poorly controlled insulin-dependent diabetes mellitus.

A relative contraindication to the use of beta blockers is Raynaud's syndrome and atherosclerosis of peripheral arteries with the development of intermittent claudication.

A.Ya.Ivleva
Polyclinic No. 1 of the Medical Center of the Administration of the President of the Russian Federation, Moscow

Beta-blockers were first introduced into clinical practice 40 years ago as antiarrhythmic drugs and for the treatment of angina pectoris. Currently, they are the most effective means for secondary prevention after acute myocardial infarction (AMI). Their effectiveness has been proven as a means for the primary prevention of cardiovascular complications in the treatment of hypertension. In 1988, the creators of beta-blockers were awarded the Nobel Prize. The Nobel Committee assessed the importance of drugs of this group for cardiology as comparable to digitalis. Interest in the clinical study of beta-blockers turned out to be justified. Beta-adrenergic receptor blockade has become a therapeutic strategy for AMI, aimed at reducing mortality and reducing the infarct area. Over the past decade, it has been found that beta-blockers reduce mortality in chronic heart failure (CHF) and prevent cardiac complications during non-cardiac surgery. Controlled clinical studies have confirmed the high effectiveness of beta-blockers in special groups of patients, in particular those with diabetes mellitus and the elderly.

However, recent large-scale epidemiological studies (IMPROVEMENT, EUROASPIRE II and Euro Heart Failure survey) have shown that beta-blockers are used less frequently than they should in situations where they could be beneficial, so efforts are required to introduce modern preventive medicine strategies into medical practice from leading clinicians and scientists to explain the pharmacodynamic advantages of individual representatives of the group of beta-blockers and to substantiate new approaches to solving complex clinical problems, taking into account differences in the pharmacological properties of drugs.

Beta-blockers are competitive inhibitors of the binding of the transmitter of the sympathetic nervous system to beta-adrenergic receptors. Norepinephrine plays a critical role in the genesis of hypertension, insulin resistance, diabetes mellitus and atherosclerosis. The level of norepinephrine in the blood increases with stable and unstable angina, AMI and during the period of cardiac remodeling. In CHF, the level of norepinephrine varies over a wide range and increases as the NYHA functional class increases. With a pathological increase in sympathetic activity, a chain of progressive pathophysiological changes is initiated, the culmination of which is cardiovascular mortality. Increased sympathetic tone can provoke arrhythmias and sudden death. In the presence of a beta blocker, a higher concentration of norepinephrine agonist is required for the specific receptor to respond.

For the clinician, the most clinically accessible marker of increased sympathetic activity is a high resting heart rate (HR). In 20 large epidemiological studies involving more than 288,000 people, completed over the past 20 years, data have been obtained that a fast heart rate is an independent risk factor for cardiovascular mortality in the population as a whole and a prognostic marker for the development of coronary artery disease, hypertension, and diabetes mellitus . A generalized analysis of epidemiological observations made it possible to establish that in a cohort with a heart rate in the range of 90-99 beats/min, the mortality rate from complications of coronary heart disease and sudden death is 3 times higher compared to the population group with a heart rate less than 60 beats/min. It has been established that a high rhythm of cardiac activity is significantly more often recorded in arterial hypertension (AH) and ischemic heart disease. After an AMI, heart rate becomes an independent prognostic criterion for mortality both in the early post-infarction period and for mortality 6 months after AMI. Many experts consider the optimal heart rate to be up to 80 beats/min at rest, and the presence of tachycardia is stated when the heart rate is above 85 beats/min.

Studies of the level of norepinephrine in the blood, its metabolism and the tone of the sympathetic nervous system in normal and pathological conditions using high experimental technologies with the use of radioactive substances, microneurography, spectral analysis made it possible to establish that beta-blockers eliminate many of the toxic effects characteristic of catecholamines :

• oversaturation of the cytosol with calcium and protect myocytes from necrosis,
• stimulating effect on cell growth and apoptosis of cardiomyocytes,
• progression of myocardial fibrosis and left ventricular myocardial hypertrophy (LVMH),
• increased automatism of myocytes and fibrillatory action,
• hypokalemia and proarrhythmic effect,
• increased oxygen consumption by the myocardium in hypertension and LVMH,
• hyperreninemia,
• tachycardia.

There is a misconception that, with proper dosing, any beta blocker can be effective for angina, hypertension and arrhythmia. However, there are clinically important pharmacological differences between drugs in this group, such as selectivity for beta-adrenergic receptors, differences in lipophilicity, the presence of partial beta-adrenergic agonist properties, as well as differences in pharmacokinetic properties that determine the stability and duration of action in clinical settings . Pharmacological properties of beta-blockers, presented in table. 1 may have clinical significance both when choosing a drug at the initial stage of use, and when switching from one beta-blocker to another.

The strength of binding to a specific receptor, or the strength of the binding of the drug to the receptor, determines the concentration of the mediator norepinephrine, which is required to overcome the competitive connection at the receptor level. As a result, the therapeutic doses of bisoprolol and carvedilol are lower than those of atenolol, metoprolol and propranolol, which have a less strong connection with the beta-adrenoreceptor.

The selectivity of blockers to beta-adrenergic receptors reflects the ability of drugs to varying degrees to block the effect of adrenomimetics on specific beta-adrenergic receptors in different tissues. Selective Beta-adrenergic locators include bisoprolol, betaxolol, nebivolol, metoprolol, atenolol, as well as the currently rarely used talinolol, oxprenolol and acebutolol. When used in low doses, Beta-adrenergic blockers exhibit the effects of blocking adrenergic receptors, which belong to the “Pj” subgroup, therefore their effect is manifested in organs in the tissue structures of which Beta-adrenergic receptors are predominantly represented, in particular in the myocardium, and have little effect on beta 2 - adrenergic receptors in the bronchi and blood vessels. However, at higher doses they also block beta-adrenergic receptors. In some patients, even selective beta-blockers can provoke bronchospasm, so the use of beta-blockers is not recommended for bronchial asthma. Correction of tachycardia in patients with bronchial asthma receiving beta-adrenergic agonists is clinically one of the most pressing and at the same time difficult to solve problems, especially with concomitant coronary heart disease (CHD), therefore, increasing the selectivity of beta-blockers is a particularly important clinical property for this group of patients . There is evidence that metoprolol succinate CR/XL has higher selectivity for beta-adrenergic receptors than atenolol. In a clinical experimental study, it had a significantly less effect on the forced expiratory volume in patients with bronchial asthma, and when using formaterol, it provided a more complete restoration of bronchial patency than atenolol.

Table 1.
Clinically important pharmacological properties of beta-blockers

Note. Relative selectivity (after Wellstern et al., 1987, cited in); * - carvedilol additionally has the property of a beta-blocker; ** - labetolol additionally has the property of an α-adrenergic blocker and the intrinsic property of a beta-adrenergic receptor agonist; *** - sotalol has additional antiarrhythmic properties

Selectivity for Beta-adrenergic receptors has important clinical significance not only for broncho-obstructive diseases, but also when used in patients with hypertension, with peripheral vascular diseases, in particular with Raynaud's disease and intermittent claudication. When using selective Beta-blockers, beta 2-adrenergic receptors, while remaining active, respond to endogenous catecholamines and exogenous adrenergic mimetics, which is accompanied by vasodilation. In special clinical studies, it was found that highly selective Beta-blockers do not increase the resistance of the vessels of the forearm, the femoral artery system, as well as the vessels of the carotid region and do not affect the tolerability of the step test for intermittent claudication.

Metabolic effects of beta blockers

With long-term (from 6 months to 2 years) use of non-selective beta-blockers, triglycerides in the blood increase in a wide range (from 5 to 2 5%) and cholesterol in the high-density lipoprotein fraction (HDL-C) decreases by an average of 13%. The effect of non-selective beta-adrenergic blockers on the lipid profile is associated with inhibition of lipoprotein lipase, since beta-adrenoreceptors, which reduce the activity of lipoprotein lipase, are without counter-regulation by beta 2-adrenoceptors, which are their antagonists in relation to this enzymatic system. At the same time, there is a slowdown in the catabolism of very low density lipoproteins (VLDL) and triglycerides. The amount of HDL cholesterol decreases because this fraction of cholesterol is a product of VLDL catabolism. Convincing information about the clinical significance of the effect of non-selective beta-adrenergic locators on the lipid profile has not yet been obtained, despite the huge number of observations of varying duration presented in the specialized literature. An increase in triglycerides and a decrease in HDL cholesterol are not typical for highly selective Beta-blockers; moreover, there is evidence that metoprolol slows down the process of atherogenesis.

Effect on carbohydrate metabolism mediated through beta 2 adrenergic receptors, since the secretion of insulin and glucagon, glycogenolysis in muscles and glucose synthesis in the liver are regulated through these receptors. The use of non-selective beta-blockers for type 2 diabetes mellitus is accompanied by an increase in hyperglycemia, and when switching to selective beta-blockers, this reaction is completely eliminated. Unlike non-selective beta-blockers, selective beta-blockers do not prolong insulin-induced hypoglycemia, since glycogenolysis and glucagon secretion are mediated through beta 2 -adrenergic receptors. In a clinical study, it was found that metoprolol and bisoprolol do not differ from placebo in their effect on carbohydrate metabolism in type 2 diabetes mellitus and no adjustment of hypoglycemic agents is required. However, insulin sensitivity is reduced when using all beta-blockers, and more significantly under the influence of non-selective beta-blockers.

Membrane stabilizing activity of beta-blockers caused by blockade of sodium channels. It is characteristic only of some beta-blockers (in particular, it is present in propranolol and some others that currently have no clinical significance). When using therapeutic doses, the membrane-stabilizing effect of beta-blockers has no clinical significance. It manifests itself as rhythm disturbances during intoxication due to overdose.

Presence of partial beta-adrenergic receptor agonist properties deprives the drug of its ability to reduce heart rate during tachycardia. As evidence accumulated of a reduction in mortality in patients who had suffered an AMI when treated with beta-blockers, the correlation between their effectiveness and a decrease in tachycardia became increasingly reliable. It was found that drugs with partial beta-adrenergic receptor agonist properties (oxprenolol, practolol, pindolol) had little effect on heart rate and mortality, in contrast to metoprolol, timolol, propranolol and atenolol. Subsequently, in the process of studying the effectiveness of beta-blockers in CHF, it was found that bucindolol, which has the properties of a partial agonist, did not change heart rate and did not have a significant effect on mortality, unlike metoprolol, carvedilol and bisoprolol.

Vasodilating effect present only in some beta-blockers (carvedilol, nebivolol, labetolol) and may have important clinical significance. For labetalol, this pharmacodynamic effect determined the indications and limitations for its use. However, the clinical significance of the vasodilatory effect of other beta-blockers (in particular, carvedilol and nebivalol) has not yet been fully clinically assessed.

Table 2.
Pharmacokinetic parameters of the most commonly used beta-blockers

Lipophilicity and hydrophilicity of beta-blockers determines their pharmacokinetic characteristics and ability to influence vagal tone. Water-soluble beta-blockers (atenolol, sotalol and nodalol) are eliminated from the body primarily through the kidneys and are little metabolized in the liver. Moderately lipophilic (bisoprolol, betaxolol, timolol) have a mixed elimination pathway and are partially metabolized in the liver. Highly lipophilic propranolol is metabolized in the liver by more than 60%, metoprolol is metabolized by the liver by 95%. The pharmacokinetic characteristics of the most commonly used beta-blockers are presented in table. 2. Specific pharmacokinetic properties of drugs may be clinically important. Thus, for drugs with very rapid metabolism in the liver, only a small part of the drug absorbed in the intestine enters the systemic circulation, therefore, when taken orally, the doses of such drugs are much higher than those used parenterally intravenously. Fat-soluble beta-blockers, such as propranolol, metoprolol, timolol and carvedilol, have genetically determined variability in pharmacokinetics, which requires more careful selection of the therapeutic dose.

Lipophilicity increases the penetration of beta-blocker through the blood-brain barrier. It has been experimentally proven that blockade of central Beta-adrenergic receptors increases vagal tone, and this is important in the mechanism of antifibrillatory action. There is clinical evidence that the use of drugs that are lipophilic (clinically proven for propranolol, timolol and metoprolol) is accompanied by a more significant reduction in the incidence of sudden death in high-risk patients. The clinical significance of lipophilicity and the ability of the drug to penetrate the blood-brain barrier cannot be considered fully established in relation to such central effects as drowsiness, depression, hallucinations, since it has not been proven that water-soluble beta 1 adrenergic blockers, such as atenolol, cause fewer such undesirable effects .

It is clinically important that:

• in case of impaired liver function, in particular due to heart failure, as well as when used together with drugs that compete with lipophilic beta-blockers in the process of metabolic biotransformation in the liver, the dose or frequency of taking lipophilic fS-blockers should be reduced.
• in case of severe renal impairment, dose reduction or adjustment of the frequency of taking hydrophilic beta-blockers is required.

Stability of action of the drug, the absence of pronounced fluctuations in blood concentration is an important pharmacokinetic characteristic. Improvements in the dosage form of metoprolol have led to the creation of a drug with controlled slow release. Metoprolol succinate CR/XL provides a stable concentration in the blood for 24 hours without sudden increases in content. At the same time, the pharmacodynamic properties of metoprolol also change: metoprolol CR/XL has been clinically shown to increase selectivity to Beta-adrenergic receptors, since in the absence of peak fluctuations in concentration, less sensitive beta 2-adrenergic receptors remain completely intact.

Clinical value of beta blockers in AMI

The most common cause of death in AMI is rhythm disturbances. However, the risk remains elevated, and in the post-infarction period most deaths occur suddenly. For the first time, in the randomized clinical trial MIAMI (1985), it was found that the use of the beta-blocker metoprolol in AMI reduces mortality. Metoprolol was administered intravenously against the background of AMI, followed by oral administration of this drug. Thrombolysis was not performed. There was a 13% decrease in mortality over 2 weeks compared to the group of patients receiving placebo. Later, in the controlled trial TIMI P-V, intravenous metoprolol was used against the background of thrombolysis and achieved a reduction in recurrent infarctions in the first 6 days from 4.5 to 2.3%.

When using beta-blockers for AMI, the frequency of life-threatening ventricular arrhythmias and ventricular fibrillation is significantly reduced, and the syndrome of prolongation of the Q-T interval that precedes fibrillation develops less frequently. As shown by the results of randomized clinical trials - VNAT (propranolol), the Norwegian study (timolol) and the Gothenburg study (metoprolol) - the use of a beta-blocker can reduce the mortality rate from repeated AMI and the frequency of repeated non-fatal myocardial infarction (MI) in the first 2 weeks on average by 20-25%.

Based on clinical observations, recommendations have been developed for the intravenous use of beta-blockers in the acute period of MI in the first 24 hours. Metoprolol, the most studied clinically in AMI, is recommended to be used intravenously at a dose of 5 mg over 2 minutes with a break of 5 minutes, for a total of 3 doses. Then the drug is prescribed orally at 50 mg every 6 hours for 2 days, and subsequently at 100 mg 2 times a day. In the absence of contraindications (heart rate less than 50 beats/min, SAP less than 100 mm Hg, blockade, pulmonary edema, bronchospasm, or if the patient received verapamil before the development of AMI), treatment is continued for a long time.

It was found that the use of drugs that are lipophilic (proven for timolol, metoprolol and propranolol) is accompanied by a significant reduction in the incidence of sudden death in AMI in high-risk patients. In table Table 3 presents data from controlled clinical studies assessing the clinical effectiveness of lipophilic beta-blockers for coronary artery disease in reducing the incidence of sudden death in AMI and in the early post-infarction period.

Clinical value of beta-blockers as agents for secondary prevention in ischemic heart disease

In the post-infarction period, the use of beta-blockers provides a significant, on average 30%, reduction in cardiovascular mortality in general. According to the Gothenburg study and meta-analysis, the use of metoprolol reduces mortality in the post-infarction period by 36-48%, depending on the level of risk. beta-blockers are the only group of drugs for drug prevention of sudden death in patients who have suffered AMI. However, not all beta blockers are created equal.

Table 3.
Controlled clinical trials showing a reduction in sudden death with the use of lipophilic beta-blockers in AMI

In Fig. Table 1 presents generalized data on the reduction in mortality in the post-infarction period recorded in randomized clinical trials using beta-blockers with grouping depending on the presence of additional pharmacological properties.

A meta-analysis of data from placebo-controlled clinical trials showed a significant reduction in mortality by an average of 22% with long-term use of beta-blockers in patients who had previously suffered an AMI, the incidence of reinfarction by 27%, and a reduction in the incidence of sudden death, especially in the early morning hours, by an average of 30 %. Mortality after AMI in patients treated with metoprolol in the Gothenburg study who had symptoms of heart failure was reduced by 50% compared with the placebo group.

The clinical effectiveness of beta-blockers has been established both after transmural MI and in persons who have suffered AMI without Q on the ECG. The effectiveness is especially high in patients from a high-risk group: smokers, the elderly, with CHF, diabetes mellitus.

The differences in the antifibrillatory properties of beta-blockers are more convincing when comparing the results of clinical studies using lipophilic and hydrophilic drugs, in particular the results recorded with the use of water-soluble sotalol. Clinical data suggest that lipophilicity is an important property of the drug, which at least partly explains the clinical value of beta-blockers in the prevention of sudden arrhythmic death in AMI and in the post-infarction period, since their vagotropic antifibrillatory effect is of central origin.

With long-term use of lipophilic beta-blockers, a particularly important property is the weakening of stress-induced suppression of vagal tone and increased vagotropic effect on the heart. The preventive cardioprotective effect, in particular the reduction of sudden death in the long-term post-infarction period, is largely due to this effect of beta-blockers. In table Table 4 presents data on lipophilicity and cardioprotective properties established in controlled clinical studies in ischemic heart disease.

The effectiveness of beta-blockers in ischemic heart disease is explained by both their antifibrillatory, antiarrhythmic, and anti-ischemic actions. beta-blockers have a beneficial effect on many mechanisms of myocardial ischemia. It is also believed that beta-blockers can reduce the likelihood of rupture of atheromatous formations with subsequent thrombosis.

In clinical practice, the doctor should focus on changes in heart rate during therapy with beta-blockers, the clinical value of which is largely due to their ability to reduce heart rate during tachycardia. In current international expert recommendations for the treatment of coronary artery disease with the use of beta-blockers, the target heart rate is from 55 to 60 beats/min, and in accordance with the recommendations of the American Heart Association, in severe cases, the heart rate can be reduced to 50 beats/min or less.

The work of Hjalmarson et al. The results of a study of the prognostic value of heart rate in 1807 patients admitted with AMI are presented. The analysis included both patients with subsequently developing CHF and those without hemodynamic impairment. Mortality was assessed for the period from the second day of hospitalization to 1 year. It was found that a frequent heart rhythm has an unfavorable prognosis. At the same time, the following mortality rates were recorded during the year depending on the heart rate at admission:

• at heart rate 50-60 beats/min - 15%;
• with heart rate above 90 beats/min - 41%;
• with heart rate above 100 beats/min - 48%.

In the large-scale GISSI-2 study with 8915 patients over a 6-month follow-up period, 0.8% of deaths were reported in the group with a heart rate less than 60 beats/min during the thrombolysis period and 14% in the group with a heart rate above 100 beats/min. The results of the GISSI-2 study confirm observations from the 1980s. about the prognostic value of heart rate in AMI, which was treated without thrombolysis. The project coordinators proposed including heart rate as a prognostic criterion in the clinical characteristics and considering beta-blockers as first-choice drugs for preventive treatment of patients with coronary artery disease and high heart rate.

In Fig. Figure 2 shows the dependence of the incidence of recurrent myocardial infarction when using beta-blockers with different pharmacological properties for the secondary prevention of complications of coronary artery disease, according to randomized controlled trials.

Clinical value of beta-blockers in the treatment of hypertension

A number of large-scale randomized clinical trials (SHEP Cooperative Research Group, 1991; MRC Working Party, 1992; IPPPSH, 1987; HAPPHY, 1987; MAPHY, 1988; STOP Hypertension, 1991) found that the use of beta-blockers as antihypertensive drugs is accompanied by a decrease in the incidence of cardiovascular mortality in both young and older age groups. International expert recommendations classify beta-blockers as first-line drugs for the treatment of hypertension.

Ethnic differences in the effectiveness of beta-blockers as antihypertensive agents have been identified. In general, they are more effective in controlling blood pressure in young white patients and at high heart rates.

Rice. 1.
Reduction of mortality when using beta-blockers after myocardial infarction, depending on additional pharmacological properties.

Table 4.
Lipophilicity and cardioprotective effect of beta-blockers to reduce mortality during long-term use for the purpose of secondary prevention of cardiac complications in coronary artery disease

Rice. 2.
The relationship between a decrease in heart rate when using various beta-blockers and the incidence of reinfarction (according to randomized clinical trials: Pooling Project).

The results of the multicenter randomized comparative study MAPHY, which was devoted to the study of primary prevention of atherosclerotic complications in the treatment of hypertension with metoprolol and a thiazide diuretic in 3234 patients for an average of 4.2 years, proved the advantage of therapy with the selective beta-blocker metoprolol. Overall mortality and mortality from coronary complications was significantly lower in the group receiving metoprolol. Non-CVD mortality was similar in the metoprolol and diuretic groups. In addition, in the group of patients receiving lipophilic metoprolol as the main antihypertensive agent, the incidence of sudden death was significantly 30% lower than in the group receiving a diuretic.

In a similar comparative study, HAPPHY, most patients received the selective hydrophilic beta-blocker atenolol as an antihypertensive agent, and no significant benefit was established with beta-blockers or diuretics. However, in a separate analysis and in this study, in the subgroup receiving metoprolol, its effectiveness in preventing cardiovascular complications, both fatal and non-lethal, was significantly higher than in the group receiving diuretics.

In table Table 5 presents the effectiveness of beta-blockers that have been documented in controlled clinical trials when used for the primary prevention of cardiovascular complications in the treatment of hypertension.

Until now, there is no complete understanding of the mechanism of the antihypertensive action of beta-blockers. However, the observation that the average heart rate in the population of people with hypertension is higher than that of the normotensive population is practically important. A comparison of 129,588 normotensive and hypertensive individuals in the Framingham Study revealed that not only was the mean heart rate higher in the hypertensive group, but mortality during follow-up increased as heart rate increased. This pattern is observed not only in young patients (18-30 years old), but also in the middle age group up to 60 years old, as well as in patients over 60 years old. An increase in sympathetic tone and a decrease in parasympathetic tone is recorded on average in 30% of patients with hypertension and, as a rule, in association with metabolic syndrome, hyperlipidemia and hyperinsulinemia, and for such patients the use of beta-blockers can be considered pathogenetic therapy.

Hypertension itself is only a weak predictor of the risk of developing coronary artery disease for a particular patient, but the association with blood pressure, especially systolic blood pressure, is independent of the presence of other risk factors. The relationship between blood pressure level and the risk of coronary artery disease is linear. Moreover, in patients whose blood pressure decreases at night by less than 10% (non-dippers), the risk of coronary artery disease increases 3 times. Among the numerous risk factors for the development of IHD, hypertension acquires a major role due to its prevalence, as well as due to the common pathogenetic mechanisms of cardiovascular complications in hypertension and IHD. Many risk factors, such as dyslipidemia, insulin resistance, diabetes mellitus, obesity, sedentary lifestyle, and some genetic factors, are important in the development of both coronary artery disease and hypertension. In general, patients with hypertension have a higher number of risk factors for the development of coronary artery disease than those with normal blood pressure. Among the 15% of the general adult population with hypertension, ischemic heart disease is the most common cause of death and disability. An increase in sympathetic activity in hypertension contributes to the development of LVMH and the vascular wall, stabilization of high blood pressure levels and a decrease in coronary reserve with an increased tendency to coronary spasm. Among patients with coronary artery disease, the frequency of hypertension is 25% and an increase in pulse pressure is a highly aggressive risk factor for coronary death.

Reducing blood pressure in hypertension does not completely eliminate the increased risk of mortality from coronary artery disease in patients with hypertension. A meta-analysis based on the results of treatment for 5 years in 37,000 patients with moderate hypertension who did not suffer from coronary artery disease showed that with blood pressure correction, coronary mortality and non-fatal complications of coronary artery disease are reduced by only 14%. In a meta-analysis that included data on the treatment of hypertension in people over 60 years of age, a 19% reduction in the incidence of coronary events was found.

Treatment of hypertension in patients with coronary artery disease should be more aggressive and more individualized than in its absence. The only group of drugs that have a proven cardioprotective effect against coronary artery disease when used for secondary prevention of coronary complications are beta-blockers, regardless of the presence of concomitant hypertension in patients.

Prognostic criteria for the high effectiveness of beta-blockers in ischemic heart disease are high heart rate before drug use and low rhythm variability. As a rule, in such cases there is also low tolerance to physical activity. Despite the favorable changes in myocardial perfusion due to a decrease in tachycardia under the influence of beta-blockers in ischemic heart disease and hypertension, in severe patients with concomitant hypertension and LVMH, a decrease in myocardial contractility may be the most important element in the mechanism of their antianginal action.

Among antihypertensive drugs, the reduction of myocardial ischemia is a property inherent only to beta-blockers, therefore their clinical value in the treatment of hypertension is not limited to the ability to correct blood pressure, since many patients with hypertension are also patients with coronary artery disease or at high risk of developing it. The use of beta-blockers is the most reasonable choice of pharmacotherapy to reduce coronary risk in hypertension in patients with sympathetic hyperactivity.

The clinical value of metoprolol has been fully proven (level A) as a means for the primary prevention of cardiovascular complications in hypertension, its antiarrhythmic effect and a reduction in the incidence of sudden death in hypertension and coronary heart disease have been documented (Gothenburg study; Norwegian study; MAPHY; MRC; IPPPSH; VNAT) .

Drugs for the treatment of hypertension are currently required to have a stable hypotensive effect when taken once a day. The pharmacological properties of the lipophilic selective Beta-blocker metoprolol succinate (CR/XL) in a new dosage form with a daily hypotensive effect fully meet these requirements. The dosage form of metoprolol succinate (CR/XL) is a tablet developed on the basis of high pharmaceutical technology, containing several hundred capsules of metoprolol succinate. After entering the stomach, each

Table 5.
Cardioprotective effect of beta-blockers during long-term use for the prevention of cardiovascular complications in hypertension

The capsule, under the influence of gastric contents, disintegrates in the mode specified for it to penetrate the gastric mucosa and works as an independent system for delivering the drug into the bloodstream. The absorption process occurs within 20 hours and does not depend on the pH in the stomach, its motility and other factors.

Clinical value of beta-blockers as antiarrhythmic agents

Beta-blockers are the drugs of choice for the treatment of supraventricular and ventricular arrhythmias, as they do not have the proarrhythmic effect characteristic of most specific antiarrhythmic drugs.

Supraventricular arrhythmias in hyperkinetic conditions, such as sinus tachycardia during excitement, thyrotoxicosis, mitral valve stenosis, ectopic atrial tachycardia and paroxysmal supraventricular tachycardia, often provoked by emotional or physical stress, are eliminated by beta-blockers. In new-onset atrial fibrillation and flutter, beta blockers may restore sinus rhythm or slow heart rate without restoring sinus rhythm due to an increase in the AV node refractory period. beta-blockers effectively control heart rate in patients with a permanent form of atrial fibrillation. In the placebo-controlled METAFER trial, metoprolol CR/XL was shown to be effective in stabilizing rhythm after cardioversion in patients with atrial fibrillation. The effectiveness of beta-blockers is not inferior to the effectiveness of cardiac glycosides for atrial fibrillation; in addition, cardiac glycosides and beta-blockers can be used in combination. For rhythm disturbances resulting from the use of cardiac glycosides, beta-blockers are the drugs of choice.

Ventricular arrhythmias, such as ventricular extrasystoles, as well as paroxysms of ventricular tachycardia, developing with ischemic heart disease, physical activity, and emotional stress, are usually eliminated with beta-blockers. Of course, ventricular fibrillation requires cardioversion, but for recurrent ventricular fibrillation provoked by physical exertion or emotional stress, especially in children, beta-blockers are effective. Post-infarction ventricular arrhythmias can also be treated with beta-blockers. Ventricular arrhythmias due to mitral valve prolapse and long QT syndrome are effectively treated with propranolol.

Rhythm disturbances during surgical operations and in the postoperative period are usually transient in nature, but if they are long-lasting, the use of beta-blockers is effective. In addition, beta blockers are recommended for the prevention of such arrhythmias.

Clinical value of beta-blockers in CHF

New recommendations from the European Society of Cardiology for the diagnosis and treatment of CHF and the American Heart Association were published in 2001. The principles of rational treatment of heart failure are summarized by leading cardiologists in our country. They are based on evidence-based medicine and highlight for the first time the important role of beta-blockers in combination pharmacotherapy for the treatment of all patients with mild, moderate and severe heart failure with reduced ejection fraction. Long-term treatment with beta-blockers is also recommended for left ventricular systolic dysfunction after AMI, regardless of the presence or absence of clinical manifestations of CHF. The officially recommended drugs for the treatment of CHF are bisoprolol, metoprolol in slow-release dosage form CR/XL and carvedilol. All three beta-blockers (metoprolol CR/XL, bisoprolol and carvedilol) were found to reduce the risk of mortality in CHF, regardless of the cause of death, by an average of 32-34%.

In patients enrolled in the MERIT-HE study who received slow-release metoprolol, mortality from cardiovascular causes decreased by 38%, the incidence of sudden death decreased by 41%, and mortality from increasing CHF decreased by 49%. All this data was highly reliable. Tolerability of metoprolol in the slow-release dosage form was very good. Drug withdrawal occurred in 13.9%, and in the placebo group - in 15.3% of patients. Due to side effects, 9.8% of patients stopped taking metoprolol CR/XL, 11.7% stopped taking placebo. Discontinuation due to worsening CHF occurred in 3.2% of the group receiving extended-release metoprolol and 4.2% of those receiving placebo.

The effectiveness of metoprolol CR/XL for CHF was confirmed in patients younger than 69.4 years (average age in the subgroup was 59 years) and in patients older than 69.4 years (average age in the older subgroup was 74 years). The effectiveness of metoprolol CR/XL has also been demonstrated in CHF with concomitant diabetes mellitus.

In 2003, data from the CO-MET trial were published in 3029 patients with CHF comparing carvedilol (target dose 25 mg twice daily) with immediate-release and low-dose metoprolol tartrate (50 mg twice daily). not corresponding to the required therapy regimen to ensure sufficient and stable concentrations of the drug throughout the day. The study, as would be expected under such circumstances, showed the superiority of carvedilol. However, its results are not of clinical value, since the MERIT-HE study demonstrated the effectiveness of metoprolol succinate in a slow-release dosage form for a single daily dose of 159 mg/day in reducing mortality in CHF (with a target dose of 200 mg /day).

Conclusion

The purpose of this review is to emphasize the importance of a thorough physical examination of the patient and assessment of his condition when choosing pharmacotherapy tactics. To use beta-blockers, emphasis should be placed on identifying hypersympathicotonia, which often accompanies the most common cardiovascular diseases. Currently, there is insufficient data to validate heart rate as a primary target for pharmacological correction in ischemic heart disease, hypertension and heart failure. However, the hypothesis about the importance of reducing heart rate in the treatment of hypertension and coronary artery disease has already been scientifically substantiated. The use of beta-blockers allows you to balance the increased energy consumption during tachycardia, accompanying hypersympathicotonia, correct pathological remodeling of the cardiovascular system, delay or slow down the progression of functional failure of the myocardium due to dysfunction of the beta-adrenergic receptors themselves (down-regulation) and a decrease in the response to catecholamines with a progressive decrease contractile function of cardiomyocytes. In recent years, it has also been established that an independent prognostic risk factor, especially in patients who have suffered an AMI with indicators of reduced left ventricular contractility, is reduced heart rate variability. It is believed that the initiating factor in the development of ventricular tachycardia in this category of patients is an imbalance of sympathetic and parasympathetic regulation of the heart. The use of the beta-blocker metoprolol in patients with coronary artery disease leads to an increase in rhythm variability mainly due to an increase in the influence of the parasympathetic nervous system.

The reasons for excessive caution in prescribing beta-blockers are often concomitant diseases (in particular, left ventricular dysfunction, diabetes mellitus, old age). However, it was found that the maximum effectiveness of the selective Beta-blocker metoprolol CR/XL was registered precisely in these groups of patients.

Literature
1. EUROASP1REII Study Group Lifestyle and risk factor management and use of dnig therapies in coronary patients from 15 countries. Eur Heart J 2001; 22: 554-72.
2. Mapee BJO. Journal heart missing items 2002; 4 (1): 28-30.
3. Task Force of the European Society of Cardiology and the North American Sod - ety of Pacing and Electrophysiology. Circulation 1996; 93: 1043-65. 4. Kannel W, Kannel C, Paffenbarger R, Cupples A. Am Heart J 1987; 113: 1489-94.
5. Singh BN.J Cardiovascular Pharmacol Therapeutics 2 001; 6 (4): 313 -31.
6. Habib GB. Cardiovascular Med 2001; 6:25-31.
7. CndckshankJM, Prichard BNC. Beta-blockers in clinical practice. 2nd edition. Edinburgh: Churchill-Livingstone. 1994;p. 1-1204.
8. Lofdahl C-G, Daholf C, Westergren G et aL EurJ Clin Pharmacol 1988; 33 (SllppL): S25-32.
9. Kaplan JR, Manusk SB, Adams MR, Clarkson TV. Eur Heart J 1987; 8: 928-44.
1 O.Jonas M, Reicher-Reiss H, Boyko Vetal.Fv) Cardiol 1996; 77: 12 73-7.
U. Kjekshus J. Am J Cardiol 1986; 57:43F-49F.
12. ReiterMJ, ReiffelJAAmJ Cardiol 1998; 82(4A):91-9-
13- Head A, Kendall MJ, Maxwell S. Clin Cardiol 1995; 18: 335-40.
14- Lucker P.J Clin Pharmacol 1990; 30 (siippl.): 17-24-
15- The MIAMI Trial Research Group. 1985. Metoprolol in acute myocardial infarction (MIAMI). A randomized placebo controlled international trial. Eur Heart J 1985; 6: 199-226.
16. RobertsR, Rogers WJ, MuellerHS et al. Circulation 1991; 83: 422-37.
17. Norwegian Study Group. Timolol-induced reduction in mortality and rein-farction in patients surviving acute myocardial infarction. NEngl J Med 1981; 304:801-7.
18. Beta-blockers Heart Attack Trial Research Group. A randomized trial of pro-pranolol in patients with acute myocardial infarction: mortality resuUs. JAMA 1982; 247:1707-13. 19- Olsson G, Wikstrand J, Warnoldl et al. Eur HeartJ 1992; 13:28-32.
20. Kennedy HL, Brooks MM, Barker AH et al Am J Cardiol 1997; 80:29J-34J.
21. Kendall MJ, Lynch KP, HjalmarsonA, Kjekshus J.Ann Intern Med 1995; 123: 358-67.
22. Frishman WH. Postinfarction survival: Role of beta-adrenergic blockade, in Fuster V (ed): Atherosclerosis and Coronary Artery Disease. Philadelphia, Lip-pencott, 1996; 1205-14-
23. YusufS, WittesJ, Friedman L.J Am Med Ass 1988; 260:2088-93. 24.Julian DG, Prescott RJJackson FS. Lancet 1982; i: 1142-7.
25. KjekshusJ. Am J Cardiol 1986; 57: 43F-49F.
26. Soriano JB, Hoes AW, Meems L Prog Cardiovasc Dis 199 7; XXXIX: 445-56. 27.AbladB, Bniro T, BjorkmanJA etalJAm Coll Cardiol 1991; 17 (Suppl): 165.
28. HjalmarsonA, ElmfeldtD, HerlitzJ et al. Lancet 1981; ii: 823-7.
29. HjalmarsonA, Gupin E, Kjekshus J etal. AmJ Cardiol 1990; 65: 547-53.
30. Zuanetti G, Mantini L, Hemandesz-Bemal F et al. Eur Heart J 1998; 19 (Suppl): F19-F26.
31. Beta-Blocker Pooling Project Research Group (BBPP). Subgroup findings from randomized trials in post infarction patients. Eur Heart J 1989; 9: 8-16. 32.2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension.) Hypertension 2003; 21: 1011-53.
33.HolmeI, Olsson G, TuomilehtoJ et alJAMA 1989; 262:3272-3.
34. Wtthelmsen L, BerghmdG, ElmfeldtDetalJHypertension 1907; 5: 561-72.
35- The IPPPSH Collaborative Group. Cardiovascular risk and risk factors in a randomized trial of treatment based on the beta blocker oxprenololj Hyperten - sion 1985; 3:379-92.
36. Medical Research Council Working Party trial of treatment of hypertension in older adults: principal results. BMJ 1992; 304:405-12.
37- Velenkov YN., Mapeee VYu. Principles of rational treatment of heart failure M: Media Medica. 2000; pp. 149-55-
38. Wikstrand J, Warnoldl, Olsson G et al. JAMA 1988; 259: 1976-82.
39. Gillman M, Kannel W, Belanger A, D"Agostino R. Am Heart J1993; 125: 1148-54.
40. Julius S. Eur HeartJ 1998; 19 (suppLF): F14-F18. 41. Kaplan NMJ Hypertension 1995; 13 (suppl.2): S1-S5. 42.McInnesGT.JHypertens 1995; 13 (suppl.2):S49-S56.
43. Kannel WB J Am Med Ass 1996;275:1571-6.
44. Franklin SS, Khan SA, Wong ND, Larson MG. Circulation 1999; 100: 354-460.
45. Verdecchia P, Porcellatti C, Schilatti C et al. Hypertension 1994; 24:967-78.
46. ​​Collins R, McMahon S. Br Med Bull 1994; 50:272 -98.
47. Collins R, Peto R, McMahon S et al. Lancet 1990; 335: 82 7-38.
48. McMahon S, Rodgers A Clin Exp Hypertens 1993; 15: 967-78.
49. First international study of infarct survival collaborative group. Lancet 1986; 2: 57-66.
50. The beta-blocker pooling project research group. Eur Heart J 1988; 9: 8-16.
51. Patatini P, Casiglia E, Julius S, Pesina AC. Arch Int Med 1999; 159: 585 -92.
52. Kueblkamp V, Schirdewan A, Stangl K et al. Circulation 1998; 98 Suppl. I: 1-663.
53.Remme WJ, Swedberg K. Eur HeartJ 2001; 22: 1527-260.
54. HuntSA.ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary. Circulation 2001; 104:2996-3007.
55.Andersson B, Aberg J.J Am Coy Cardiol 1999; 33: 183A-184A.
56. BouzamondoA, HulotJS, Sanchez P et al. Eur J Heart failure 2003; 5: 281-9.
57. Keeley EC, Page RL, Lange RA et al. AmJ Cardiol 1996; 77: 557-60.
Medicines Index
Metoprolol succinate: BETALOK ZOK (AstraZeneca)

Adrenergic blockers play an important role in the treatment of heart and vascular diseases. These are drugs that inhibit the functioning of adrenergic receptors, which helps prevent narrowing of the venous walls, reduce high blood pressure and normalize heart rhythm.

Adrenergic blockers are used to treat heart and vascular diseases

What are adrenergic blockers?

Adrenergic blockers (adrenolytics)– a group of medications that affect adrenergic impulses in the vascular walls and tissues of the heart, responding to adrenaline and norepinephrine. Their mechanism of action is that they block these very adrenergic receptors, due to which the therapeutic effect necessary for cardiac pathologies is achieved:

• blood pressure decreases;
• the lumen in the vessels expands;
• blood sugar decreases;

Adrenolytics produce the opposite effect of adrenaline and norepinephrine, that is, they are their antagonists. This allows you to prevent critical pressure levels in hypertension and the aggravation of cardiac pathologies (arrhythmia, atherosclerosis, hypertension, ischemia, heart attack, failure, defects).

Classification of adrenolytic drugs

Receptors located in the blood vessels and smooth muscles of the heart are divided into alpha 1, alpha 2 and beta 1, beta 2.

Depending on which adrenergic impulses need to be blocked, there are 3 main groups of adrenergic drugs:

• alpha blockers;
• beta blockers;
• alpha-beta blockers.

Each group inhibits only those manifestations that arise as a result of the work of specific receptors (beta, alpha, or simultaneously alpha-beta).

Alpha adrenergic blockers

Alpha blockers can be of 3 types:

• drugs that block alpha-1 receptors;
• medications that affect alpha-2 impulses;
• combination drugs that simultaneously block alpha-1,2 impulses.

Main groups of alpha-blockers

Pharmacology of group drugs (mainly alpha-1 blockers) - increasing the lumen in the veins, arteries and capillaries.

This allows:

• reduce the resistance of vascular walls;
• reduce pressure;
• minimize the load on the heart and facilitate its work;
• reduce the degree of thickening of the walls of the left ventricle;
• normalize fat;
• stabilize carbohydrate metabolism (increases insulin sensitivity, normalizes plasma sugar).

Alpha-2 receptor blockers are less effective in treating heart pathologies, as they produce a weak therapeutic effect. They have proven themselves well in urology. Such drugs are often prescribed for problems with sexual function in men.

Table “List of the best alpha adrenergic blockers”

Among the new generation alpha adrenergic blockers, Tamsulosin is highly effective. It is used for prostatitis, as it effectively reduces the tone of the soft tissues of the prostate gland, normalizes the outflow of urine and reduces unpleasant symptoms in benign prostate lesions.

The medicine is well tolerated by the body, but side effects are possible:

• vomiting, diarrhea;
• dizziness, migraine;
• rapid heartbeat, chest pain;
• allergic rash, runny nose.

Beta blockers

The pharmacology of drugs from the beta blocker group is that they interfere with the stimulation of beta1 or beta1,2 impulses by adrenaline. This action inhibits the increase in heart contractions and inhibits the large increase in blood, and also prevents a sharp expansion of the lumen of the bronchi.

All beta blockers are divided into 2 subgroups - selective (cardioselective, beta-1 receptor antagonists) and non-selective (blocking adrenaline in two directions at once - beta-1 and beta-2 impulses).

Mechanism of action of beta blockers

The use of cardioselective drugs in the treatment of cardiac pathologies allows achieving the following therapeutic effect:

• the level of heart rate decreases (the risk of tachycardia is minimized);
• the frequency of angina attacks is reduced, the unpleasant symptoms of the disease are smoothed out;
• the resistance of the cardiac system to emotional, mental and physical stress increases.

Taking beta blockers can normalize the general condition of a patient suffering from cardiac disorders, as well as reduce the risk of hypoglycemia in diabetics, and prevent severe bronchospasm in asthmatics.

Non-selective adrenergic blockers reduce the overall vascular resistance of the peripheral blood flow and affect the tone of the walls, which contributes to:

• decreased heart rate;
• normalization of pressure (for hypertension);
• reducing myocardial contractile activity and increasing resistance to hypoxia;
• preventing arrhythmia by reducing excitability in the conduction system of the heart;
• avoiding acute disorders of blood circulation in the brain.

The use of non-selective beta blockers makes it possible to stop the development of blood clots in blood vessels and reduce the likelihood of a heart attack by increasing the body's resistance to external stimuli (physical and emotional). In addition, such drugs increase the tone of the uterus, intestines, esophagus and have a relaxing effect on the bladder (relax the sphincter).

Table “List of the most effective drugs that block the effect of adrenaline on beta impulses”

In addition to synthetic beta-blockers, there are also natural substitutes. Passionflower is considered the most effective. The drug is a natural muscle tissue relaxant, a good pain reliever and tranquilizer for patients with sleep disorders and increased anxiety and irritability.

All medications must be selected by a doctor, taking into account the individual characteristics of the patient’s body and the severity of the disease. Uncontrolled use of arena blockers can aggravate the patient's condition, even leading to cardiac arrest.

Alpha-beta blockers

Drugs in this group act simultaneously on all types of receptors in the walls of blood vessels, the heart and the soft tissues of other organs.

The use of such drugs makes it possible to achieve a high therapeutic effect in the treatment of severe disorders of the heart and blood vessels:

• pressure decreases (arterial and intraocular);
• lipid metabolism is normalized;
• the contractility of the heart improves (the size of the organ decreases, its rhythm improves, and the patient’s condition with heart failure or defects is alleviated).

Hybrid alpha-beta blockers

New generation drugs are Carvedilol, Labetalol and Methyloxadiazole.

They are prescribed for conditions such as:

• hypertension;
• arrhythmia;
• glaucoma (open angle);
• congenital and acquired heart defects;
• chronic cardiac dysfunction.

In addition to the contraindications that all groups of adrenergic drugs have, alpha-beta blockers should not be used by insulin-dependent diabetics, patients with obstructive pulmonary disease, as well as people who suffer from ulcerations in the duodenum.

Among the side effects caused by subgroup medications are:

• blockade of heart impulses or serious abnormalities in their conduction;
• disruptions in peripheral blood flow;
• changes in blood counts upward (bilirubin, glucose, cholesterol increases);
• a decrease in plasma white blood cells (leukocytes) and anucleated cells (platelet);
• the appearance of blood impurities in the urine.

When using alpha-beta blockers, the number of leukocytes in the blood decreases

To prevent negative reactions or reduce them as much as possible, you need to comply with the dosage and duration of therapy. Adrenergic blockers are serious medications, the uncontrolled use of which can lead to serious consequences.

All adrenergic blockers are cardiac drugs that are aimed at normalizing a person’s condition after serious illness. They help block the increased effect of adrenaline and norepinephrine on cardiac receptors, which facilitates the functioning of the main organ, stabilizes blood circulation and increases resistance to external irritants. Adrenalytics are also used in urology to treat prostatic hyperplasia, gynecology to prevent large blood losses, and improve blood circulation in the pelvic organs.