The main contraindication for the appointment of beta-blockers. Beta-blockers for hypertension and heart disease - a list of the latest generation of drugs and the mechanism of action

Arterial hypertension requires mandatory treatment with medication. New drugs are constantly being developed to bring blood pressure back to normal and prevent dangerous consequences such as stroke and heart attack. Let us consider in more detail what alpha and beta-blockers are - a list of drugs, indications and contraindications for use.

Adrenolytics are drugs that are united by one pharmacological effect - the ability to neutralize the adrenaline receptors of the heart and blood vessels. They turn off the receptors that normally respond to norepinephrine and adrenaline. The effects of adrenolytics are opposite to those of norepinephrine and adrenaline and are characterized by a decrease in pressure, vasodilation and narrowing of the bronchial lumen, and a decrease in blood glucose. Drugs affect receptors localized in the heart and vascular walls.

Alpha-blockers have an expanding effect on the vessels of organs, especially on the skin, mucous membranes, kidneys and intestines. Due to this, an antihypertensive effect occurs, a decrease in peripheral vascular resistance, an improvement in blood flow and blood supply to peripheral tissues.

Consider what beta blockers are. This is a group of drugs that bind to beta-adrenergic receptors and block the effects of catecholamines (norepinephrine and adrenaline) on them. They are considered essential medicines in the treatment of essential arterial hypertension and increased pressure. They have been used for this purpose since the 60s of the 20th century.

The mechanism of action is expressed in the ability to block beta-adrenergic receptors of the heart and other tissues. This results in the following effects:

Beta-blockers have not only an antihypertensive effect, but also a number of other properties:

• Antiarrhythmic activity due to the inhibition of the effects of catecholamines, a decrease in the speed of impulses in the region of the atrioventricular septum and a slowing of the sinus rhythm;
• antianginal activity. Beta-1 adrenergic receptors of vessels and myocardium are blocked. Because of this, heart rate, myocardial contractility, blood pressure decrease, the duration of diastole increases, coronary blood flow becomes better. In general, the need of the heart for oxygen decreases, tolerance to physical loads increases, periods of ischemia decrease, the frequency of anginal attacks decreases in patients with postinfarction angina and exertional angina;
• antiplatelet ability. Platelet aggregation slows down, prostacyclin synthesis is stimulated, blood viscosity decreases;
• Antioxidant activity. free is inhibited fatty acids that are caused by catecholamines. The need for obtaining oxygen for the purpose of further metabolism decreases;
• Decreased venous blood flow to the heart, the volume of circulating plasma;
• Decreases insulin secretion due to inhibition of glycogenolysis;
• There is a sedative effect, the contractility of the uterus increases during pregnancy.

Indications for admission

Alpha-1 blockers are prescribed for the following pathologies:

Alpha-1,2 blockers are used in the following conditions:

• pathology of cerebral circulation;
• migraine;
• dementia, which is due to the vascular component;
• pathology of peripheral circulation;
• problems with urination due to a neurogenic bladder;
• diabetic angiopathy;
• dystrophic diseases of the cornea of ​​the eye;
• vertigo and pathologies of the functioning of the vestibular apparatus associated with the vascular factor;
• neuropathy optic nerve associated with ischemia;
• prostatic hypertrophy.

Important: Alpha-2-blockers are prescribed only for the treatment of impotence in males.

Non-selective beta-1,2 blockers are used in the treatment of the following pathologies:

• arterial;
• increase in intraocular pressure;
• migraine (prophylactic purposes);
• hypertrophic cardiomyopathy;
• heart attack;
• sinus tachycardia;
• tremor;
• bigeminia, supraventricular and ventricular arrhythmia, trigeminia (prophylactic purposes);
• angina pectoris;
• prolapse mitral valve.

Selective beta-1 blockers are also called cardioselective because of their effects on the heart and less on blood pressure and blood vessels. They are issued in the following states:

Alpha-beta-blockers are prescribed in the following cases:

• arrhythmia;
• stable angina;
• CHF (combined treatment);
• elevated arterial pressure;
• glaucoma (eye drops);
• hypertensive crisis.

Classification of drugs

There are four types of adrenergic receptors in the walls of blood vessels (alpha 1 and 2, beta 1 and 2). Drugs from the group of adrenergic blockers can block different types of receptors (for example, only beta-1-adrenergic receptors). Drugs are divided into groups depending on the deactivation of certain types of these receptors:

Alpha blockers:

• alpha-1-blockers (silodosin, terazosin, prazosin, alfuzosin, urapidil, tamsulosin, doxazosin);
• alpha-2 blockers (yohimbine);
• alpha-1, 2-blockers (dihydroergotamine, dihydroergotoxin, phentolamine, nicergoline, dihydroergocristine, proroxan, alpha-dihydroergocriptine).

Beta-blockers are divided into the following groups:

• non-selective blockers (timolol, metipranolol, sotalol, pindolol, nadolol, bopindolol, oxprenolol, propranolol);
• selective (cardioselective) blockers (acebutolol, esmolol, nebivolol, bisoprolol, betaxolol, atenolol, talinolol, esatenolol, celiprolol, metoprolol).

The list of alpha-beta-blockers (they include alpha and beta-adrenergic receptors at the same time):

• labetalol;
• proxodolol;
• carvedilol.

Please note: The classification shows the names active substances, which are part of drugs in a certain group of blockers.

Beta-blockers also come with and without intrinsic sympathomimetic activity. This classification is considered auxiliary, as it is used by specialists to select the necessary drug.

List of drugs

Common names for alpha-1 blockers:

• Alfuzosin;
• Dalphaz;
• Artezin;
• Zokson;
• Urocard;
• Prazosin;
• Urorek;
• Miktosin;
• Tamsulosin;
• Cornam;
• Ebrantil.

Alpha-2 blockers:

• Yohimbine;
• Yohimbine hydrochloride.

Alpha-1,2-blockers:

• Redergin;
• Ditamine;
• Nicergoline;
• Pyrroxane;
• Phentolamine.

• Atenol;
• Atenova;
• Athenolan;
• Betacard;
• Tenormin;
• Sektral;
• Betoftan;
• Xonef;
• Optibetol;
• Bisogamma;
• bisoprolol;
• Concor;
• Tirez;
• Betaloc;
• Serdol;
• Binelol;
• Cordanum;
• Breviblock.

Non-selective beta-blockers:

• Sandonorm;
• trimepranol;
• Whisken;
• Inderal;
• obzidan;
• Darob;
• Sotalol;
• Glaumol;
• Thymol;
• Timoptic.

Alpha-beta-blockers:

• Proxodolol;
• Albetor;
• Bagodilol;
• Carvenal;
• Credex;
• Labetol;
• Abetol.

Side effects

Common side effects from taking adrenergic blockers:

Side effects from taking alpha-1 blockers:

• puffiness;
• a strong decrease in pressure;
• arrhythmia and tachycardia;
• dyspnea;
• runny nose;
• dryness of the oral mucosa;
• pain in the chest area;
• decreased libido;
• erection pain;
• urinary incontinence.

Side effects when using alpha-2 receptor blockers:

• increase in pressure;
• anxiety, excessive excitability, irritability and physical activity;
• tremor;
• decreased frequency of urination and fluid volume.

Side effects from alpha-1 and -2 blockers:

• loss of appetite;
• sleep problems;
• excessive sweating;
• cold hands and feet;
• increased acidity in the stomach.

Common side effects of beta-blockers:

Non-selective beta-blockers can lead to the following conditions:

• vision pathology (blurring, feeling that something has got into the eye foreign body, tearfulness, bifurcation, burning);
• ischemia of the heart;
• colitis;
• cough with possible attacks of suffocation;
• a sharp decrease in pressure;
• impotence;
• fainting;
• runny nose;
• an increase in blood uric acid, potassium and triglycerides.

Alpha-beta blockers have the following side effects:

• decrease in blood platelets and leukocytes;
• the formation of blood in the urine;
• increase in cholesterol, sugar and bilirubin;
• pathology of the conduction of heart impulses, sometimes it comes to blockade;
• impaired peripheral circulation.

Interaction with other drugs

Favorable compatibility with alpha-blockers in the following drugs:

Favorable combination of beta-blockers with other drugs:

1. A combination with nitrates is successful, especially if the patient suffers not only from hypertension, but also from coronary heart disease. There is an increase in the hypotensive effect, bradycardia is leveled by tachycardia, which is caused by nitrates.
2. Combination with diuretics. The effect of diuretics increases and lengthens due to the inhibition of renin release from the kidneys by beta-blockers.
3. ACE inhibitors and angiotensin receptor blockers. If there are drug-resistant arrhythmias, you can carefully combine the reception with quinidine and novocainamide.
4. Calcium channel blockers of the dihydropyridine group (cordafen, nikirdipine, fenigidin). You can combine with caution and in small dosages.

Dangerous combinations:

1. Calcium channel blockers that belong to the verapamil group (isoptin, gallopamil, finoptin). The frequency and strength of heart contractions decrease, atrioventricular conduction becomes worse, hypotension, bradycardia, acute left ventricular failure and atrioventricular blockade increase.
2. Sympatholytics - octadine, reserpine and preparations with it in the composition (rauvazan, brinerdine, adelfan, raunatin, kristepin, trirezide). There is a sharp weakening of sympathetic influences on the myocardium, and complications associated with this may form.
3. Cardiac glycosides, direct M-cholinomimetics, anticholinesterase drugs and tricyclic antidepressants. The likelihood of blockade, bradyarrhythmia and cardiac arrest increases.
4. Antidepressants-MAO inhibitors. There is a possibility of a hypertensive crisis.
5. Typical and atypical beta-agonists and antihistamines. There is a weakening of these drugs when used together with beta-blockers.
6. Insulin and sugar-lowering drugs. There is an increase in the hypoglycemic effect.
7. salicylates and butadione. There is a weakening of the anti-inflammatory effect;
8. Indirect anticoagulants. There is a weakening of the antithrombotic effect.

Contraindications to taking alpha-1 blockers:

Contraindications to taking alpha-1,2 blockers:

• arterial hypotension;
• acute bleeding;
• lactation;
• pregnancy;
• myocardial infarction that occurred less than three months ago;
• organic lesions of the heart;
• atherosclerosis of peripheral vessels in severe form.

Contraindications for alpha-2-blockers:

• excessive sensitivity to the components of the drug;
• severe pathologies of the functioning of the kidneys or liver;
• jumps in blood pressure;
• uncontrolled hypertension or hypotension.

General contraindications to taking non-selective and selective beta-blockers:

• excessive sensitivity to the components of the drug;
• cardiogenic shock;
• sinoatrial blockade;
• weakness of the sinus node;
• hypotension (BP less than 100 mm);
• acute heart failure;
• atrioventricular blockade of the second or third degree;
• bradycardia (pulse less than 55 beats / min.);
• CHF in the stage of decompensation;

Contraindications to taking non-selective beta-blockers:

• bronchial asthma;
• obliterating vascular diseases;
• Prinzmetal's angina.

Selective beta-blockers:

• lactation;
• pregnancy;
• pathology of the peripheral circulation.

The considered drugs for hypertensive patients should be used strictly according to the instructions and at the dose prescribed by the doctor. Self-medication can be dangerous. At the first appearance side effects you need to contact a medical facility immediately.

Do you have any questions? Ask them in the comments! They will be answered by a cardiologist.

Content

One of Nobel Prizes 1988 belongs to D. Black, a scientist who developed and conducted clinical trials of the first beta-blocker - propranolol. This substance began to be used in medical practice in the 60s of the 20th century. Modern cardiology practice is impossible without the use of beta-blockers for hypertension and heart disease, tachycardia and stroke, arterial disease and other dangerous pathologies. circulatory system. Of the 100 stimulants developed, 30 are used for therapeutic purposes.

What are beta blockers

large group pharmaceuticals, which protect the beta receptors of the heart from the effects of adrenaline, are called beta-blockers (BBs). The names of medicines containing these active substances end in "lol". They can easily be chosen among medicines for the treatment of cardiovascular diseases. As active ingredient atenolol, bisoprolol, propranolol, timolol and others are used.

Mechanism of action

In the human body there is a large group of catecholamines - biologically active substances that have a stimulating effect on internal organs and systems, triggering adaptive mechanisms. The action of one of the representatives of this group - adrenaline is well known, it is also called a stress substance, the hormone of fear. The action of the active substance is carried out through special structures - β-1, β-2 adrenoreceptors.

The mechanism of action of beta-blockers is based on the inhibition of the activity of β-1-adrenergic receptors in the heart muscle. The organs of the circulatory system respond to this effect as follows:

• changes heartbeat in the direction of decreasing the frequency of contractions;
• the force of heart contractions decreases;
• decreased vascular tone.

In parallel, beta-blockers inhibit the action of the nervous system. So it is possible to restore the normal functioning of the heart, blood vessels, which reduces the frequency of angina attacks, arterial hypertension, atherosclerosis, ischemic disease. Reduces the risk of sudden death from a heart attack, heart failure. Advances have been made in the treatment of hypertension and conditions associated with high blood pressure.

• Pressure drugs - a list of the latest generation of drugs with minimal side effects
• Drugs for hypertension without side effects - the main groups according to the mechanism of action, composition and treatment regimen
• Popular remedies for high blood pressure and the rules for their appointment

Indications for use

Beta-blockers are prescribed for hypertension and heart disease. it general characteristics their therapeutic effect. The most common diseases for which they are used are:

• Hypertension. Beta-blockers for hypertension reduce the load on the heart, its oxygen demand decreases and blood pressure normalizes.
• Tachycardia. With a heart rate of 90 beats per minute or more, beta-blockers are the most effective.
• Myocardial infarction. The action of the substances is aimed at reducing the affected area of ​​the heart, preventing relapse, and protecting the muscle tissue of the heart. In addition, drugs reduce the risk of sudden death, increase physical endurance, reduce the development of arrhythmias, and contribute to myocardial oxygen saturation.
• Diabetes mellitus with cardiac pathologies. Highly selective beta-blockers improve metabolic processes, increase tissue susceptibility to insulin.
• Heart failure. Drugs are prescribed according to a scheme that involves a gradual increase in dosage.

The list of diseases for which beta-blockers are prescribed includes glaucoma, different types arrhythmias, mitral valve prolapse, tremor, cardiomyopathy, acute aortic dissection, hyperhidrosis, complications of hypertension. The drugs are prescribed for the prevention of migraine, varicose bleeding, for the treatment of arterial pathologies, depression. Therapy of these diseases involves the use of only some BB, as they pharmacological properties different.

Classification of drugs

The classification of beta-blockers is based on the specific properties of these active substances:

1. Adrenaline receptor blockers are able to simultaneously act on both β-1 and β-2 structures, which causes side effects. Based on this feature, two groups of drugs are distinguished: selective (acting only on β-1 structures) and non-selective (acting on both β-1 and β-2 receptors). Selective BBs have a peculiarity: with increasing dosage, the specificity of their action is gradually lost, and they begin to block β-2 receptors as well.
2. Solubility in certain substances distinguishes groups: lipophilic (soluble in fat) and hydrophilic (soluble in water).
3. BB, which are able to partially stimulate adrenoreceptors, are combined into a group of drugs with internal sympathomimetic activity.
4. Adrenaline receptor blockers are divided into short-acting and long-acting drugs.
5. Pharmacologists have developed three generations of beta-blockers. All of them are still used in medical practice. Preparations of the last (third) generation have the least number of contraindications and side effects.

Cardioselective beta-blockers

The higher the selectivity of the drug, the stronger the therapeutic effect it has. Selective beta-blockers of the first generation are called non-cardioselective, these are the earliest representatives of this group of drugs. In addition to therapeutic, they have strong side effects (for example, bronchospasm). II generation BBs are cardioselective drugs, they have a directed effect only on type 1 cardiac receptors and have no contraindications for people with diseases respiratory system.

Talinolol, Acebutanol, Celiprolol have internal sympathomimetic activity, Atenolol, Bisoprolol, Carvedilol do not have this property. These medicines have proven themselves in the treatment of atrial fibrillation, sinus tachycardia. Talinolol is effective in hypertensive crisis, angina attacks, heart attack, in high concentrations it blocks type 2 receptors. Bisoprolol can be taken continuously for hypertension, ischemia, heart failure, and is well tolerated. It has a pronounced withdrawal syndrome.

Internal sympathomimetic activity

Alprenolol, Karteolol, Labetalol - the 1st generation of beta-blockers with internal sympathomimetic activity, Epanolol, Acebutanol, Celiprolol - the 2nd generation of drugs with such an effect. Alprenolol is used in cardiology for the treatment of coronary heart disease, hypertension, a non-selective beta-blocker with a large number of side effects and contraindications. Celiprolol has proven itself in the treatment of hypertension, is the prevention of angina attacks, but the interaction of the drug with a lot of medicines has been revealed.

Lipophilic drugs

Lipophilic adrenaline receptor blockers include Propranolol, Metoprolol, Retard. These drugs are actively processed by the liver. In hepatic pathologies or in elderly patients, an overdose may occur. Lipophilicity determines the side effects that appear through nervous system such as depression. Propranolol is effective in thyrotoxicosis, cardiomyalgia, myocardial dystrophy. Metoprolol inhibits the action of catecholamines in the heart during physical and emotional stress, is indicated for use in cardiac pathologies.

Hydrophilic drugs

Beta-blockers for hypertension and heart disease, which are hydrophilic drugs, are not processed by the liver, they are excreted through the kidneys. In patients with renal insufficiency accumulate in the body. They have a prolonged action. It is better to take medicines before meals and drink plenty of water. Atenolol belongs to this group. It is effective in the treatment of hypertension, the hypotensive effect persists for about a day, while the peripheral vessels remain in good shape. The use of beta-blockers is dangerous in the following conditions and pathologies:

• diabetes;
• depression;
• lung diseases;
• elevated levels of lipids in the blood;
• violation of peripheral circulation;
• asymptomatic sinus node dysfunction.

Side effects

Numerous side effects of beta-blockers do not always appear, among them:

• chronic fatigue;
• decrease in heart rate;
• exacerbation bronchial asthma;
• heart block;
• decrease in the concentration of "good" cholesterol and sugar;
• after discontinuation of drugs, there is a threat of increased pressure;
• heart attacks;
• increased fatigue with physical activity;
• effect on potency in patients with vascular pathologies;
• toxic action.

Video

Attention! The information provided in the article is for informational purposes only. The materials of the article do not call for self-treatment. Only a qualified doctor can make a diagnosis and make recommendations for treatment, based on individual features specific patient.

β-blockers block β-adrenergic receptors in various organs and tissues, which limits the effect of catecholamines, providing an organ-protective effect when cardiovascular diseases, makes it possible to use them in ophthalmology, 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, β-blockers with additional vasodilatory 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 ischemic disease heart, arterial hypertension, chronic heart failure.

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

TYPES AND LOCALIZATION OF β-ADRENORECEPTORS

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

There are 2 types of β-adrenergic receptors - and β 2 -adrenergic receptors; their ratio is not the same in different organs and tissues. Stimulation effects different typesβ-adrenergic receptors are presented in table. 5.1.

PHARMACODYNAMIC EFFECTS OF β-ADRENORECEPTOR BLOCK

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

Decreased heart rate (negative chronotropic, bradycardic effect);

Lowering blood pressure (reducing afterload, hypotensive effect);

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

Decreased 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

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

Reducing the formation of intraocular fluid (decrease in 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 discontinuation of 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 blockade of β 2 -adrenergic receptors are:

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

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

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

STRUCTURE OF β-ADRENORECEPTORS AND EFFECTS OF β-ADRENOBLOCKade

The molecular structure of β-adrenergic receptors is characterized by a certain sequence of amino acids. Stimulation of β-adrenergic receptors contributes to the cascade of G-protein activity, the enzyme adenylate cyclase, the formation of cyclic AMP from ATP under the action of adenylate cyclase, and protein kinase activity. Under the action of protein kinase, there is an increase in phosphorylation of calcium channels with an increase in calcium current 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 impulse conduction, the strength 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, internal sympathomimetic activity (ISA), lipophilicity level and membrane stabilizing effect, additional vasodilating properties, duration of drug action.

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

The degree of selectivity reflects the intensity of communication with the β-adrenergic receptor and determines the severity of the strength and duration 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 contributes to an increase in the number of β-receptors, which determines the gradual increase in the effects of β-blockade and a much more pronounced sympathomimetic response to circulating catecholamines in the blood in case of sudden withdrawal, especially short-acting β-blockers (withdrawal syndrome).

β-blockers of the 1st generation, equally causing blockade and β 2 -adrenergic receptors, belong to non-selective β-blockers - propranolol, nadolol. Non-selective β-blockers without ICA have a certain advantage.

The II generation includes selective β l- adrenoblockers 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 time, therefore, they have advantages in terms of the severity of the hypotensive effect, the lower frequency of side effects, compared with non-selective ones.

High selectivity β l- adrenoblockade makes it possible to use in patients with broncho-obstructive diseases, in smokers, due to a less pronounced reaction to catecholamines, patients with hyperlipidemia, diabetes I and II types, peripheral circulatory disorders compared with non-selective and less selective β-blockers.

The level of selectivity of β-blockers determines the effect on the total peripheral vascular resistance as one of the determining components of the hypotensive effect. Selective β l-blockers do not have a significant effect on OPSS, non-selective β-blockers, due to the 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 blockade of β 2 -adrenergic receptors, in high doses β l-selective beta-blockers lose β l- selectivity.

There are β-blockers that have a vasodilating effect, having a combined mechanism of action: labetalol (non-selective blocker and a1-adrenergic receptors), car-

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

Depending on the degree of selectivity and the presence of vasodilating properties, 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 adrenoreceptors, i.e. partial agonistic activity. These β-blockers are called drugs with internal sympathomimetic activity - alprenolol, acebutalol, oxprenolol, penbutalol, pindolol, talinolol, practolol. Pindolol's own sympathomimetic activity is most pronounced.

The intrinsic sympathomimetic activity of β-blockers limits the decrease in heart rate at rest, which is used in patients with initially low heart rate.

Non-selective (β 1- + β 2-) β-blockers without ICA: propranolol, nadolol, sotalol, timolol, and with ICA: 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 pathways. Allocate hydrophilic, lipophilic and amphophylic drugs.

Lipophilic drugs are usually metabolized in the liver and have a relatively short elimination half-life (T 1/2). Lipophilicity is combined with the hepatic route of elimination. 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 a little more than 10-40% (Table 5.4).

The state of hepatic blood flow affects the rate of metabolism, the size of single doses and the frequency of taking drugs. This must be taken into account in the treatment of elderly patients, patients with heart failure, with cirrhosis of the liver. In severe liver failure, the elimination rate decreases by

Table 5.4

Pharmacokinetic parameters of lipophilic β-blockers

in proportion to the decrease in liver function. Lipophilic drugs with prolonged 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 (malicious 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, reduce the rate of microsomal oxidation in hepatocytes (cimetidine, chlorpromazine).

Among lipophilic β-blockers, the use of betaxolol does not require dose adjustment for liver failure, however, when using betaxolol, dose adjustment of the drug is required for severe renal failure and dialysis. Metoprolol dose adjustment is carried out at severe violations liver function.

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

Hydrophilic drugs are excreted mainly 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).

Reduced glomerular filtration rate (in elderly patients, with chronic kidney 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 concentration of creatinine, the level of which increases with a decrease in the glomerular filtration rate below 50 ml / min. In this case, the frequency of administration of a 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 in case of impaired renal function. Nadolol does not reduce renal blood flow and glomerular filtration rate, exerting 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 infusions. β-blockers, which are destroyed by blood esterases, have a very short half-life, their action stops 30 minutes after the infusion is stopped. Such drugs are used to treat acute ischemia, control the ventricular rhythm in paroxysmal supraventricular tachycardia during surgery or in the postoperative period. The short duration of action makes it safer to use them in patients with hypotension, with heart failure, and the βl-selectivity of the drug (esmolol) - with symptoms of bronchial obstruction.

Amphophylic β-blockers dissolve in fats and water (acebutolol, bisoprolol, pindolol, celiprolol), 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, low probability of interaction with other medicines. The elimination rate of drugs decreases only in severe renal and hepatic insufficiency. In this case, the daily doses of β-blockers with balanced clearance should be reduced by 1.5-2 times.

The amphophylic 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, levels of heart rate, blood pressure. The initial dose of β-blocker should be 1/8-1/4 of the average therapeutic single dose, with insufficient effect, the dose is increased every 3-7 days to the average therapeutic single dose. Heart rate at rest in a vertical position should be within 55-60 per minute, systolic blood pressure - not less than 100 mm Hg. The maximum severity of the β-adrenergic blocking effect is observed after 4-6 weeks of regular intake of the β-blocker; lipophilic β-blockers require special control during these periods,

ability to slow down your own metabolism. The frequency of taking the drug depends on the frequency of anginal attacks and the duration of action of the β-blocker.

It should be borne in mind that the duration of the bradycardic and hypotensive action of β-blockers significantly exceeds their elimination half-life, and the duration of the antianginal action is less than the duration of the negative chronotropic effect.

MECHANISMS OF ANTI-ANGINAL AND ANTISCHEMIC ACTION OF β-ADRENOBLOCKERS IN THE TREATMENT OF ANGINA

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, reducing heart rate, increase the duration of diastole. Delivery of oxygen to the myocardium of the left ventricle is carried out mainly in diastole, since in systole 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 a prolongation of the time of distolic relaxation with a decrease in heart rate, contributes to a prolongation of the period of diastolic myocardial perfusion. 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), which provides 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 influences (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 blood return to the left ventricle (nirovazodilators).

Lipophilic β-adrenergic blockers that do not have intrinsic sympathomimetic activity, regardless of selectivity, have a greater cardioprotective effect in patients who have had 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 efficacy. The cardioprotective effects of carvedilol and bisoprolol are comparable to those of the retarded form of metoprolol. Hydrophilic β-blockers - atenolol, sotalol did not affect overall mortality and sudden death in patients with coronary heart disease. Data from a meta-analysis of 25 controlled trials 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 appointment of drugs of this class, especially in patients over 50 years of age with anterior left ventricular wall infarction, early postinfarction angina pectoris, high heart rate, ventricular arrhythmias, symptoms of stable heart failure.

Table 5.7

β-blockers in the treatment of angina pectoris

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

* - single dose.

Table 5.8

Cardioprotective efficacy of β-blockers in patients after 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 dilated ventricular ischemia even in the absence of CAD, and suppression of apoptosis of myocardiocytes activated under conditions of βl-adrenergic stimulation.

With 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 the basal level of plasma norepinephrine 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 improves perfusion of vital organs. In the future, an increase in the activity of sympathetic-adrenal-

howling system leads to an increase in the oxygen demand of the myocardium, increased ischemia, heart rhythm disturbance, a direct effect on cardiomyocytes - remodeling, hypertrophy, apoptosis and necrosis.

With a long elevated level catecholamines, β-adrenergic receptors of the myocardium go into a state of reduced sensitivity to neurotransmitters (a state of desensitization) due to a decrease in the number of receptors on the plasma membrane, impaired coupling of receptors with adenylate cyclase. The density of myocardial β-adrenergic receptors decreases by half, the degree of reduction of receptors is proportional to the severity of CHF, myocardial contractility and ejection fraction. The ratio changes and β 2 -adrenergic receptors in the direction of increasing β 2 -adrenergic receptors. Violation of the conjugation of β-adrenergic receptors with adenylate cyclase leads to direct cardiotoxic effects of catecholamines, overload of mitochondria of cardiomyocytes with calcium ions, disruption of ADP rephosphorylation, depletion of creatine phosphate and ATP. 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 the depletion of local stores of norepinephrine, a violation of an adequate load of adrenergic support of the myocardium, and the 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 data from USCP - American Carvedilol Program, CIBIS II with bisoprolol and MERIT HF with sustained release metoprolol succinate, COPERNICUS, CAPRICORN on a significant reduction in total, cardiovascular, sudden death, a decrease in the frequency of hospitalizations, a decrease 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 of 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 (level of evidence A). β-blockers should be used in all patients with CHF who do not have contraindications common to this group of drugs. The severity of decompensation, gender, age, baseline pressure (SBP not less than 85 mm Hg) and baseline heart rate do not play an independent role in determining contraindications to the appointment of β-blockers. Appointment of β-blockers begins with 1 /8 therapeutic dose for patients with achieved stabilization of CHF. β-adrenergic blockers in the treatment of CHF do not belong to the first aid drugs and cannot remove patients from the state of decompensation and hyperhydration. Perhaps the appointment of β l-selective β-blocker bisoprolol as an initial therapy drug in patients over 65 years of age with CHF II - III FC NYHA, left ventricular ejection fraction<35% с последующим присоединением ингибитора АПФ (степень доказанности В). Начальная терапия βl-selective β-adrenoblocker can be justified in clinical situations with a predominance of severe tachycardia with low blood pressure, followed by the addition of an ACE inhibitor.

The tactics of prescribing β-blockers in patients with CHF is 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, a decrease in systolic myocardial function, which requires titration of the dose of β-blocker prescribed to a CHF patient, 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 (low doses of cardiac glycosides or calcium sensitizers - levosimendan), slower titration of the dose of β-blocker.

Contraindications to the appointment of β-blockers in heart failure are:

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

Symptomatic bradycadia (<50 уд/мин);

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

Table 5.9

Starting, target doses and dosing regimen for β-blockers in heart failure based on the results of large-scale placebo-controlled

research

A-V block II degree and above;

Severe obliterating endarteritis.

Absolutely indicated is the appointment of β-blockers in patients with CHF and type 2 diabetes. All the positive properties of drugs of this class are fully preserved in the presence of diabetes mellitus. The use of a non-cardioselective and adrenoblocker with additional properties 0 4 The β-blocker carvedilol may be the treatment of choice in these patients by improving insulin sensitivity in peripheral tissues (Evidence A).

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

Doses of β-arenoblockers for the treatment of patients with CHF, enshrined in the National Recommendations of the VNOK and OSSN, 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 hospitalization rates due to CHF; there was a deterioration in prognosis and an increase in the risk of death by 17% in the group of patients of the black race.

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

MAIN MECHANISMS OF THE HYPOTENSIVE ACTION OF β-ADRENOB LOCATIONS

β-blockers are drugs of initial therapy 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 pectoris, heart failure, in persons intolerant to ACE inhibitors and / or ATII receptor blockers, in women of childbearing age planning pregnancy.

As a result of the 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 renin secretion, a decrease in the formation of angiotensin, and a decrease in OPSS. A decrease in aldosterone production helps to reduce fluid retention. The sensitivity of baroreceptors of the aortic arch and carotid sinus changes, the release of norepinephrine from the endings of postganglionic sympathetic nerve fibers is inhibited. Inhibition of central adrenergic influences occurs (for β-blockers that penetrate the blood-brain barrier).

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

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

β-blockers, as a result of a decrease in the activity of the sympathetic and renin-angiothesin systems, are the optimal class of drugs for the prevention and regression of left ventricular hypertrophy. The mediated decrease in aldosterone levels limits the simulation of myocardial fibrosis, improving left ventricular diastolic function.

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

β-blockers in combination with vasodilators or labetolol are the drugs of choice when there is a risk 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 introduction of a β-blocker should precede the appointment of a vasodilator to prevent an increase in cardiac output, which can 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 in the management of patients with traumatic brain injury complicated by hypertensive crises.

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

In table. 5.11 shows the main doses and frequency of taking β-blockers for the treatment of hypertension.

Table 5.11

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

CONTROL OF THE EFFICACY OF THERAPY WITH β-ADRENOBLOCKERS

The effective heart rate at the maximum expected action of the next dose of β-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 insufficiency require attention, such patients need a longer titration of the dose of β-blocker due to the threat of developing decompensation phenomena (fatigue, weight gain, shortness of breath, wheezing in the lungs).

Age-related features of the pharmacodynamics of β-blockers are due to changes in the interaction between β-adrenergic receptors and stimulation of the production of alanine aminotransferase, binding of the receptor to adenylate cyclase. The sensitivity of β-adrenergic receptors to β-blockers is changed and perverted. This determines the multidirectional and difficult to predict the 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 decreases, the volume of adipose tissue increases, and tissue perfusion changes. The volume and speed of hepatic blood flow is reduced by 35-45%. The number of hepatocytes decreases, the level of their enzymatic activity - the mass of the liver decreases by 18-25%. The number of functioning glomeruli of the kidneys, the rate of glomerular filtration (by 35-50%) and tubular secretion decrease.

INDIVIDUAL β-ADRENOBLOCKER DRUGS

Non-selectiveβ - adrenoblockers

propranolol- a non-selective beta-blocker without its own sympathomimetic activity with a short duration of action. 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 concentration in blood plasma after taking the same dose can vary in different people by 7-20 times. With urine in the form of metabolites, 90% of the dose taken is eliminated. The distribution of propranolol and, apparently, other β-blockers in the body is influenced by a number of drugs. At the same time, β-blockers themselves can change the metabolism and pharmacokinetics of other drugs. Propranolol is prescribed orally, starting with small doses - 10-20 mg, gradually (especially in the elderly and with suspected heart failure) over 2-3 weeks, bringing the daily dose to an effective one (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 may be lengthy. It should be remembered that high

doses of propranolol may lead to an increase in side effects. To select the optimal dose, regular measurement of heart rate and blood pressure is necessary. It is recommended to cancel the drug gradually, especially after prolonged use or after using large doses (reduce the dose by 50% within one week), since a sharp cessation of its administration can cause a withdrawal syndrome: an increase in angina attacks, the development of gastric tachycardia or myocardial infarction, and when AG - a sharp rise in blood pressure.

Nadolol- non-selective β-blocker without internal sympathomimetic and membrane stabilizing activity. It differs from other drugs in this group by its long-term effect and the ability to improve kidney function. Nadolol has antianginal activity. It has a lesser 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. The peak concentration in the blood after oral administration is reached after 3-4 hours, T 1/2

From 14 to 24 hours, which allows you to prescribe the drug once a day in the treatment of patients with both angina pectoris and hypertension. Nadolol is not metabolized in the body, it is excreted by the kidneys and intestines unchanged. Complete excretion 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 blocker of β-adrenergic receptors with sympathomimetic activity. It is well absorbed when taken orally. Differs in high bioavailability, T 1/2

3-6 hours, the beta-blocking effect persists for 8 hours. About 57% of the dose taken is bound to the 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 elimination of the drug is reduced only in severe renal and hepatic insufficiency. The drug crosses the blood-brain barrier and the placenta. Compatible with diuretics, antiadrenergic drugs, methyldopa, reserpine, barbiturates, digitalis. According to β-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 drops 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 is weaker than other non-selective β-blockers, affects β 2 -adrenergic receptors and therefore, in normal doses, it is safer for bronchospasm and diabetes mellitus. With 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 - adrenoblockers

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

The level of the hypothetical effect and the number of patients responding to therapy increases in proportion to 2.5-5 mg of the daily dose of the drug, so the average effective dose of nebivolol is taken as 5 mg per day; in case of renal insufficiency, 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, with long-term treatment up to 12 months, the effect is stably maintained. Blood pressure after discontinuation of nebivolol slowly returns to the initial level within 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 on the background of arterial hypertension.

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

Carvedilol has β- and a 1 -blocking, as well as antioxidant properties. It reduces the effects of stress on the heart due to 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 by 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 plasma, carvedilol is 95% protein bound. The drug is excreted through the liver. Applied with hypertension - 25-20 mg once a day; with angina pectoris and with chronic heart failure - 25-50 mg twice a day.

bisoprolol- a highly selective long-acting β-blocker without internal sympathomimetic activity, does not have a membrane stabilizing effect. Possesses amphiphilic properties. Due to the prolonged action, it can be administered once a day. The peak action 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. Eating does not affect the bioavailability of bisoprolol. A small association with 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 in 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%. Possible accumulation of bisoprolol in the blood in violation of the liver and kidneys. Equally excreted by the liver and kidneys. The rate of elimination of the drug decreases only in severe renal and hepatic insufficiency, and therefore the accumulation of bisoprolol in the blood is possible in case of impaired liver and kidney function.

Penetrates through the blood-brain barrier. It is 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, with insufficient 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 mellitus and the level of thyroid hormones, it practically does not affect the potency in men.

Betaxolol- a cardioselective β-blocker without its own sympathomimetic activity and with weakly expressed membrane-stabilizing properties. The strength of the blockade of β-adrenergic receptors is 4 times greater than the effects of propranolol. It has a high lipophilicity. Well (more than 95%) absorbed in the gastrointestinal tract. After a single dose, it reaches maximum plasma concentrations after 2-4 hours. Food intake does not affect the degree and rate of absorption. Unlike other lipophilic drugs, the oral bioavailability of betaxolol is 80-89%, which is explained by the absence of the "first pass" effect through the liver. The individuality of the metabolism does not affect the variability of drug concentrations in blood serum, which allows us to expect a more stable response to the effect of the drug when it is 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 by 3-4 hours after administration and then for 24 hours, the effect is dose-dependent. With regular intake of betaxolol, the antihypertensive effect reaches its maximum value 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 T 1/2. T 1/2 is 14-22 hours, which allows you to take the drug 1 time per day. In older people, T 1/2 increases to 27 hours.

It binds to plasma proteins by 50-55%, of which 42% to albumin. Disease of the liver and kidneys does not affect the degree of protein binding, it does not change while taking digoxin, aspirin, diuretics. Betaxolol and its metabolites are excreted in the urine. The rate of elimination of the drug is reduced only in severe renal and hepatic insufficiency. Features of the pharmacokinetics of betaxolol do not require a change in the dosing regimen in severe hepatic and moderate renal insufficiency. Dose adjustment of the drug is necessary only in case of severe renal insufficiency and in patients on dialysis. In patients with significant renal insufficiency 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, o 1 -blockers. The advantage over other selective β 1 -adrenergic receptors is the absence of a decrease in the concentration of HDL. Betaxolol does not affect the process of glucose metabolism and compensatory mechanisms in hypoglycemia. According to the degree of reduction in heart rate, blood pressure, increased 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 a regular release dosage form. About 12% of the drug binds to blood proteins. Metoprolol rapidly collapses in tissues, crosses the blood-brain barrier, and is found in breast milk at higher concentrations than in plasma. The drug undergoes intensive hepatic metabolism in the cytochrome P4502D6 system, has two active metabolites - α-hydroxymetoprolol and o-dimethylmetoprolol. Age does not affect the concentration of metoprolol, cirrhosis increases bioavailability to 84% and T 1/2 to 7.2 hours. In chronic renal failure, the drug does not accumulate in the body. In patients with hyperthyroidism, the level of the achieved maximum concentration and the area under the kinetic curve decreases. The drug exists in the form of metoprolol tartrate (regular and sustained release forms).

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

Table 5.12

Pharmacokinetics of dosage forms of metoprolol

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

With 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 intake. Sustained release forms are the drugs of choice in the treatment of circulatory failure. The clinical efficacy of ACE inhibitors in heart failure is significantly increased when a β-blocker is added to them (studies ATLAS, MERIT HF, PRECISE, MOCHA).

Atenolol- selective β l- adrenoblocker, which 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

appointment. After oral administration, a decrease in cardiac output occurs within an hour, the maximum effect is between 2 and 4 hours and the duration is at least 24 hours. The hypotensive effect, as with all β-blockers, does not correlate with plasma levels and increases after continuous administration for several weeks. With 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 the elderly in the presence of 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 side of 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 blockade, manifestation of latent congestive heart failure, exacerbation of bronchial asthma or other obstructive pulmonary diseases, hypoglycemia, violation of the

Table 5.14

Characteristics of side effects of β-blockers

howling function in men, various manifestations of angiospasm, general weakness, drowsiness, depression, dizziness, decreased reaction speed, the possibility of developing a 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, high 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 vasodilatory effect).

PLACE OF β-ADRENOBLOCKERS

IN COMBINATION THERAPY

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

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

The indisputable advantages of rational combinations are the potentiation of the hypotensive effect by influencing various links in the pathogenesis of arterial hypertension, improving drug tolerance, reducing the number of side effects, limiting counterregulatory 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 vasodilatory effect of the diuretic limits sodium retention and increased peripheral vascular tone, which is characteristic of β-blockers. β-blockers, in turn, suppress the activity of the sympathoadrenal and renin-angiotensin systems, which are characteristic of a diuretic. It is possible to restrain 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 of atenolol and 25 mg of chlorthalidone), lopressor HGT (50-100 mg of metoprolol and 25-50 mg of hydrochlorothiazide), corzoid (40-80 mg of nadolol and 5 mg of bendroflumetazide), viskaldix (10 mg of pindolol and 5 mg of clopamide), ziak (2.5-5-10 mg of bisoprolol and 6.25 mg of gyrochlorothiazide).

When combined with dihydropyridine slow calcium channel antagonists, β-blockers have an additive effect, counteract the development of tachycardia and activation of the sympathetic nervous system, characteristic of initial therapy with dihydropyridines. Such combination therapy is indicated in patients with hypertension with coronary artery disease, patients with severe refractory arterial hypertension. Logimax is a fixed combination with a long-term release system of the 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 part of the preparation tenochek.

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

A combination of β-blockers and blockers of a 1 -adrenergic receptors is favorable. β-blockers inhibit the development of tachycardia, characteristic of the appointment of α-blockers. Blockers of a 1 -adrenergic receptors reduce such effects of β-blockers as an increase in peripheral vascular resistance, the effect on lipid and carbohydrate metabolism.

Medicinal preparations of β-blockers and ACE inhibitors, reducing the activity of the renin-angiotensin system, can have a synergistic hypotensive effect. The appointment of an ACE inhibitor does not completely suppress the formation of angiotensin II, since there are alternative ways of its formation. Hyperreninemia resulting from ACE inhibition can be reduced by the direct inhibitory 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 vasodilatory properties of ACE inhibitors may reduce the vasoconstrictor effects of β-blockers. The organoprotective effect of this combination in patients with congestive heart failure has been proven.

The combination of a β-blocker and an imidazoline receptor agonist (a drug of central action) may be rational in the combination therapy of arterial hypertension in order to achieve target blood pressure figures 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, dyslipidemia, characteristic of the class of β-blockers.

Table 5.15

Combined antihypertensive therapy with β-blockers

Beta-blockers, or beta-adrenergic receptor blockers, are a group of drugs that bind to beta-adrenergic receptors and block the action of catecholamines (adrenaline and norepinephrine) on them. Beta-blockers belong to the basic drugs in the treatment of essential arterial hypertension and high blood pressure syndrome. This group of drugs has been used to treat hypertension since the 1960s, when they first entered clinical practice.

In 1948, R. P. Ahlquist described two functionally distinct types of adrenergic receptors, alpha and beta. Over the next 10 years, only alpha-adrenergic antagonists were known. In 1958, dichloisoprenaline was discovered, combining the properties of an agonist and an antagonist of beta receptors. He and a number of other subsequent drugs have not yet been suitable for clinical use. And only in 1962 propranolol (Inderal) was synthesized, which opened a new and bright page in the treatment of cardiovascular diseases.

The Nobel Prize in Medicine in 1988 was awarded to J. Black, G. Elion, G. Hutchings for the development of new principles of drug therapy, in particular for the rationale for the use of beta-blockers. It should be noted that beta-blockers were developed as an antiarrhythmic group of drugs, and their hypotensive effect turned out to be an unexpected clinical finding. Initially, it was regarded as a side, not always desirable action. Only later, beginning in 1964, after the publication of Prichard and Giiliam, was it appreciated.

Mechanism of action of beta-blockers

The mechanism of action of this group of drugs is due to their ability to block beta-adrenergic receptors of the heart muscle and other tissues, causing a number of effects that are components of the mechanism of the hypotensive action of these drugs.

• Decrease in cardiac output, frequency and strength of heart contractions, resulting in a decrease in myocardial oxygen demand, an increase in the number of collaterals and a redistribution of myocardial blood flow.
• Decreased heart rate. In this regard, diastole optimizes the total coronary blood flow and supports the metabolism of the damaged myocardium. Beta-blockers, "protecting" the myocardium, are able to reduce the zone of infarction and the frequency of complications of myocardial infarction.
• Reducing the total peripheral resistance by reducing the production of renin by the cells of the juxtaglomerular apparatus.
• Decreased release of norepinephrine from postganglionic sympathetic nerve fibers.
• Increased production of vasodilating factors (prostacyclin, prostaglandin e2, nitric oxide (II)).
• Reducing the reabsorption of sodium ions in the kidneys and the sensitivity of the baroreceptors of the aortic arch and carotid (carotid) sinus.
• Membrane stabilizing effect - a decrease in the permeability of membranes for sodium and potassium ions.

Along with antihypertensive beta-blockers have the following actions.

• Antiarrhythmic activity, which is due to their inhibition of the action of catecholamines, slowing down the sinus rhythm and reducing the speed of impulses in the atrioventricular septum.
• Antianginal activity is a competitive blocking of beta-1 adrenergic receptors in the myocardium and blood vessels, which leads to a decrease in heart rate, myocardial contractility, blood pressure, as well as to an increase in the duration of diastole, and an improvement in coronary blood flow. In general, to reduce the need for oxygen in the heart muscle, as a result, exercise tolerance increases, periods of ischemia are reduced, and the frequency of anginal attacks in patients with exertional angina and post-infarction angina pectoris decreases.
• Antiplatelet ability - slow down platelet aggregation and stimulate the synthesis of prostacyclin in the endothelium of the vascular wall, reduce blood viscosity.
• Antioxidant activity, which is manifested by the inhibition of free fatty acids from adipose tissue, caused by catecholamines. The need for oxygen for further metabolism decreases.
• Decrease in venous blood flow to the heart and the volume of circulating plasma.
• Reduce insulin secretion by inhibiting glycogenolysis in the liver.
• They have a sedative effect and increase the contractility of the uterus during pregnancy.

From the table it becomes clear that beta-1 adrenergic receptors are located mainly in the heart, liver and skeletal muscles. Catecholamines, affecting beta-1 adrenoreceptors, have a stimulating effect, resulting in an increase in the frequency and strength of heart contractions.

Classification of beta-blockers

Depending on the predominant action on beta-1 and beta-2, adrenoreceptors are divided into:

• cardioselective (Metaprolol, Atenolol, Betaxolol, Nebivolol);
• cardiononselective (Propranolol, Nadolol, Timolol, Metoprolol).

Depending on the ability to dissolve in lipids or water, beta-blockers are pharmacokinetically divided into three groups.

1. Lipophilic beta-blockers (Oxprenolol, Propranolol, Alprenolol, Carvedilol, Metaprolol, Timolol). When administered orally, it is rapidly and almost completely (70-90%) absorbed in the stomach and intestines. The drugs of this group penetrate well into various tissues and organs, as well as through the placenta and the blood-brain barrier. As a rule, lipophilic beta-blockers are prescribed in low doses for severe hepatic and congestive heart failure.
2. Hydrophilic beta-blockers (Atenolol, Nadolol, Talinolol, Sotalol). Unlike lipophilic beta-blockers, when administered orally, they are absorbed only by 30-50%, are metabolized to a lesser extent in the liver, and have a long half-life. They are excreted mainly through the kidneys, and therefore hydrophilic beta-blockers are used in low doses with insufficient kidney function.
3. Lipo- and hydrophilic beta-blockers, or amphiphilic blockers (Acebutolol, Bisoprolol, Betaxolol, Pindolol, Celiprolol), are soluble in both lipids and water, 40-60% of the drug is absorbed after oral administration. They occupy an intermediate position between lipo- and hydrophilic beta-blockers and are equally excreted by the kidneys and liver. The drugs are prescribed to patients with moderately severe renal and hepatic insufficiency.

Classification of beta-blockers by generation

1. Cardiononselective (Propranolol, Nadolol, Timolol, Oxprenolol, Pindolol, Alprenolol, Penbutolol, Karteolol, Bopindolol).
2. Cardioselective (Atenolol, Metoprolol, Bisoprolol, Betaxolol, Nebivolol, Bevantolol, Esmolol, Acebutolol, Talinolol).
3. Beta-blockers with the properties of alpha-adrenergic receptor blockers (Carvedilol, Labetalol, Celiprolol) are drugs that share the mechanisms of hypotensive action of both groups of blockers.

Cardioselective and non-cardioselective beta-blockers, in turn, are divided into drugs with and without internal sympathomimetic activity.

1. Cardioselective beta-blockers without internal sympathomimetic activity (Atenolol, Metoprolol, Betaxolol, Bisoprolol, Nebivolol), along with an antihypertensive effect, slow down the heart rate, give an antiarrhythmic effect, and do not cause bronchospasm.
2. Cardioselective beta-blockers with internal sympathomimetic activity (Acebutolol, Talinolol, Celiprolol) slow down the heart rate to a lesser extent, inhibit the automatism of the sinus node and atrioventricular conduction, give a significant antianginal and antiarrhythmic effect in sinus tachycardia, supraventricular and ventricular arrhythmias, have little effect on beta -2 adrenoreceptors of the bronchi of the pulmonary vessels.
3. Non-cardioselective beta-blockers without internal sympathomimetic activity (Propranolol, Nadolol, Timolol) have the greatest antianginal effect, so they are more often prescribed to patients with concomitant angina pectoris.
4. Non-cardioselective beta-blockers with internal sympathomimetic activity (Oxprenolol, Trazikor, Pindolol, Visken) not only block, but also partially stimulate beta-adrenergic receptors. The drugs of this group to a lesser extent slow down the heart rate, slow down the atrioventricular conduction and reduce myocardial contractility. They can be prescribed to patients with arterial hypertension with a mild degree of conduction disturbance, heart failure, and a rarer pulse.

Cardioselectivity of beta-blockers

Cardioselective beta-blockers block beta-1 adrenergic receptors located in the cells of the heart muscle, the juxtaglomerular apparatus of the kidneys, adipose tissue, the conduction system of the heart and intestines. However, the selectivity of beta-blockers depends on the dose and disappears with the use of large doses of beta-1 selective beta-blockers.

Non-selective beta-blockers act on both types of receptors, on beta-1 and beta-2 adrenoreceptors. Beta-2 adrenergic receptors are located on the smooth muscles of blood vessels, bronchi, uterus, pancreas, liver and adipose tissue. These drugs increase the contractile activity of the pregnant uterus, which can lead to premature birth. At the same time, the blockade of beta-2 adrenergic receptors is associated with negative effects (bronchospasm, spasm of peripheral vessels, impaired glucose and lipid metabolism) of non-selective beta-blockers.

Cardioselective beta-blockers have an advantage over non-cardioselective in the treatment of patients with arterial hypertension, bronchial asthma and other diseases of the bronchopulmonary system, accompanied by bronchospasm, diabetes mellitus, intermittent claudication.

Indication for appointment:

• essential arterial hypertension;
• secondary arterial hypertension;
• signs of hypersympathicotonia (tachycardia, high pulse pressure, hyperkinetic type of hemodynamics);
• concomitant coronary artery disease - angina pectoris (selective beta-blockers for smokers, non-selective for non-smokers);
• previous heart attack, regardless of the presence of angina pectoris;
• heart rhythm disturbance (atrial and ventricular extrasystole, tachycardia);
• subcompensated heart failure;
• hypertrophic cardiomyopathy, subaortic stenosis;
• mitral valve prolapse;
• risk of ventricular fibrillation and sudden death;
• arterial hypertension in the preoperative and postoperative period;
• beta-blockers are also prescribed for migraine, hyperthyroidism, alcohol and drug withdrawal.

Beta blockers: contraindications

• bradycardia;
• atrioventricular blockade of 2-3 degrees;
• arterial hypotension;
• acute heart failure;
• cardiogenic shock;
• vasospastic angina.

• bronchial asthma;
• chronic obstructive pulmonary disease;
• stenosing peripheral vascular disease with limb ischemia at rest.

Beta Blockers: Side Effects

From the side of the cardiovascular system:

• decrease in heart rate;
• slowing atrioventricular conduction;
• a significant decrease in blood pressure;
• ejection fraction reduction.

From other organs and systems:

• disorders of the respiratory system (bronchospasm, impaired bronchial patency, exacerbation of chronic lung diseases);
• peripheral vasoconstriction (Raynaud's syndrome, cold extremities, intermittent claudication);
• psycho-emotional disorders (weakness, drowsiness, memory impairment, emotional lability, depression, acute psychosis, sleep disturbance, hallucinations);
• gastrointestinal disorders (nausea, diarrhea, abdominal pain, constipation, exacerbation of peptic ulcer, colitis);
• withdrawal syndrome;
• violation of carbohydrate and lipid metabolism;
• muscle weakness, exercise intolerance;
• impotence and decreased libido;
• decreased renal function due to reduced perfusion;
• decreased production of tear fluid, conjunctivitis;
• skin disorders (dermatitis, exanthema, exacerbation of psoriasis);
• fetal hypotrophy.

Beta blockers and diabetes

In type 2 diabetes, preference is given to selective beta-blockers, since their dysmetabolic properties (hyperglycemia, reduced tissue sensitivity to insulin) are less pronounced than in non-selective ones.

Beta blockers and pregnancy

During pregnancy, the use of beta-blockers (non-selective) is undesirable, since they cause bradycardia and hypoxemia, followed by fetal hypotrophy.

What drugs from the group of beta-blockers are better to use?

Speaking about beta-blockers as a class of antihypertensive drugs, they mean drugs that have beta-1 selectivity (have fewer side effects), without internal sympathomimetic activity (more effective) and vasodilating properties.

What is the best beta blocker?

Relatively recently, a beta-blocker appeared in our country, which has the most optimal combination of all the qualities necessary for the treatment of chronic diseases (arterial hypertension and coronary heart disease) - Lokren.

Lokren is an original and at the same time inexpensive beta-blocker with high beta-1 selectivity and the longest half-life (15-20 hours), which allows it to be used once a day. However, it does not have internal sympathomimetic activity. The drug normalizes the variability of the daily rhythm of blood pressure, helps to reduce the degree of morning increase in blood pressure. In the treatment of Lokren in patients with coronary heart disease, the frequency of angina attacks decreased, and the ability to tolerate physical activity increased. The drug does not cause a feeling of weakness, fatigue, does not affect carbohydrate and lipid metabolism.

The second drug that can be isolated is Nebilet (Nebivolol). It occupies a special place in the class of beta-blockers due to its unusual properties. Nebilet consists of two isomers: the first of them is a beta-blocker, and the second is a vasodilator. The drug has a direct effect on the stimulation of the synthesis of nitric oxide (NO) by the vascular endothelium.

Due to the dual mechanism of action, Nebilet can be prescribed to a patient with arterial hypertension and concomitant chronic obstructive pulmonary diseases, peripheral arterial atherosclerosis, congestive heart failure, severe dyslipidemia and diabetes mellitus.

As for the last two pathological processes, today there is a significant amount of scientific evidence that Nebilet not only does not have a negative effect on lipid and carbohydrate metabolism, but also normalizes the effect on cholesterol, triglycerides, blood glucose and glycated hemoglobin. Researchers attribute these properties, unique to the class of beta-blockers, to the NO-modulating activity of the drug.

Beta-blocker withdrawal syndrome

Sudden withdrawal of beta-blockers after their prolonged use, especially at high doses, can cause phenomena characteristic of the clinical picture of unstable angina, ventricular tachycardia, myocardial infarction, and sometimes lead to sudden death. The withdrawal syndrome begins to manifest itself after a few days (less often - after 2 weeks) after stopping the use of beta-adrenergic blockers.

To prevent the serious consequences of discontinuing these drugs, the following recommendations should be followed:

• stop the use of beta-adrenergic blockers gradually, within 2 weeks, according to the following scheme: on the 1st day, the daily dose of propranolol is reduced by no more than 80 mg, on the 5th - by 40 mg, on the 9th - by 20 mg and on the 13th - by 10 mg;
• patients with coronary artery disease during and after discontinuation of beta-adrenergic blockers should limit physical activity and, if necessary, increase the dose of nitrates;
• for persons with coronary artery disease who are planned for coronary artery bypass grafting, beta-adrenergic blockers are not canceled before surgery, 1/2 daily dose is prescribed 2 hours before surgery, beta-blockers are not administered during surgery, but within 2 days. after it is prescribed intravenously.

Oddly enough, humanity has only started talking about beta blockers in the last few years, and this is not at all related to the moment these drugs were invented. Beta blockers have been known to medicine for a long time, but now every conscious patient suffering from pathology of the heart and blood vessels considers it necessary to have at least minimal knowledge about what drugs can be used to defeat the disease.

The history of the appearance of drugs

The pharmaceutical industry has never stood still - it was pushed to success by all the updated facts about the mechanisms of a particular disease. In the 30s of the last century, doctors noticed that the heart muscle begins to work much better if it is influenced by certain means. A little later, the substances were called beta-agonists. Scientists have found that these stimulants in the body find a "pair" for interaction, and in research twenty years later, the theory of the existence of beta-adrenergic receptors was first proposed.

A little later, it was found that the heart muscle is most susceptible to adrenaline, which causes cardiomyocytes to contract at a breakneck pace. This is how heart attacks happen. To protect the beta receptors, scientists intended to create special tools that prevent the harmful effects of the aggressive hormone on the heart. Success was achieved in the early 60s, when protenalol was invented - a pioneer beta blocker, protector of beta receptors. Due to the high carcinogenicity, protenalol was modified and propranolol was released for mass production. The developers of the theory of beta receptors and blockers, as well as the drug itself, received the highest mark in science - the Nobel Prize.

Operating principle

Since the release of the first drug, pharmaceutical laboratories have developed more than a hundred of their varieties, but in practice no more than a third of the funds are used. The latest generation drug - Nebivolol - was synthesized and certified for treatment in 2001.

Beta blockers are medicines for stopping heart attacks by blocking adrenoreceptors that are sensitive to the release of adrenaline.

Their mechanism of action is as follows. The human body under the influence of certain factors produces hormones and catecholamines. They are able to irritate beta 1 and beta 2 receptors located in different places. As a result of such exposure, the body undergoes significant negative effects, and especially the heart muscle suffers.

For example, it is worth remembering what feelings a person feels when, in a state of stress, the adrenal glands make an excessive release of adrenaline and the heart begins to beat ten times faster. In order to somehow protect the heart muscle from such irritants, blockers have been created. These drugs block the adrenoreceptors themselves, susceptible to the effects of adrenaline on them. By breaking this ligament, it was possible to significantly facilitate the work of the heart muscle, make it contract more calmly and throw blood into the bloodstream with less pressure.

Consequences of taking drugs

Thus, the work of beta blockers can reduce the frequency of angina attacks (increased heart rate), which are the direct cause of sudden death in humans. Under the influence of beta blockers, the following changes occur:

• blood pressure normalizes
• decreased cardiac output,
• the level of renin in the blood decreases,
• CNS activity is inhibited.

As established by doctors, the largest number of beta-adrenergic receptors is localized in the cardiovascular system. And this is not surprising, because the work of the heart ensures the vital activity of every cell of the body, and the heart becomes the main target of adrenaline, a stimulating hormone. When recommending beta blockers, doctors also note their detrimental effect, so they have such contraindications: COPD, diabetes mellitus (for some), dyslipidemia, and the patient's depressive state.

What is drug selectivity

The key role of beta blockers is to protect the heart from atherosclerotic lesions, the cardioprotective effect that this group of drugs has is to provide an antiarrhythmic effect by reducing ventricular regression. Despite all the bright prospects for the use of drugs, they have one significant drawback - they affect both the necessary beta-1-adrenergic receptors and beta-2-adrenergic receptors, which do not need to be inhibited at all. This is the main disadvantage - the impossibility of selecting some receptors from others.

The selectivity of drugs is considered to be the ability to selectively act on beta-adrenergic receptors, blocking only beta-1-adrenergic receptors, and not affecting beta-2-adrenergic receptors. Selective action can significantly reduce the risk of side effects of beta blockers, sometimes observed in patients. That is why doctors are currently trying to prescribe selective beta blockers, i.e. "smart" drugs that can distinguish beta-1 from beta-2 adrenoreceptors.

Classification of drugs

In the process of creating drugs, many drugs were produced, which can be classified as follows:

• selective or non-selective beta blockers (based on selective action for beta-1 and beta-2 blockers),
• lipophilic agents or hydrophilic (based on solubility in fats or water),
• drugs with and without intrinsic sympathomimetic activity.

Today, three generations of medicines have already been released, so there is an opportunity to be treated with the most modern means, contraindications and side effects of which are minimized. Medicines are becoming more affordable for patients with various complications of cardiopathology.

Classification refers to non-selective agents for first-generation drugs. The “pen test” at the time of the invention of even such drugs was successful, since patients were able to stop heart attacks even with beta blockers, which are imperfect today. Nevertheless, at that time this was a breakthrough in medicine. So, Propranolol, Timolol, Sotalol, Oxprenolol and other drugs can be classified as non-selective drugs.

The second generation is already more “smart” drugs that distinguish beta-1 from beta-2. Cardioselective beta-blockers are Atenolol, Concor (read more in this article), Metoprolol succinate, Lokren.

The third generation is recognized as the most successful due to its unique properties. They are able not only to protect the heart from an increased release of adrenaline, but also have a relaxing effect on blood vessels. List of drugs - Labetalol, Nebivolol, Carvedilol and others. The mechanism of their effect on the heart is different, but the means are able to achieve a common result - to normalize cardiac activity.

Features of drugs with ICA

As it turned out in the process of testing drugs and using them in patients, not all beta blockers are able to completely inhibit the activity of beta-adrenergic receptors. There are a number of drugs that initially block their activity, but at the same time stimulate it. This phenomenon is called internal sympathomimetic activity - ICA. It is impossible to evaluate these funds negatively and call them useless. As the results of studies show, when taking such drugs, the work of the heart also slowed down, however, with their help, the pumping function of the organ did not significantly decrease, peripheral vascular resistance increased, and atherosclerosis was provoked least of all.

If such drugs are taken for a long time, then beta-adrenergic receptors are stimulated chronically, which leads to a decrease in their density in tissues. Therefore, if beta-blockers were suddenly stopped being taken, this did not provoke a withdrawal syndrome - the patients did not at all suffer from hypertensive crises, tachycardia and angina attacks. In critical cases, the cancellation could provoke a fatal outcome. Therefore, doctors note that the therapeutic effect of drugs with internal sympathomimetic activity is no worse than classic beta blockers, but the absence of negative effects on the body is significantly lower. This fact distinguishes the group of funds among all beta blockers.

Feature of lipophilic and hydrophilic drugs

The main difference between these funds is where they dissolve better. Lipophilic representatives are able to dissolve in fats, and hydrophilic - only in water. In view of this, in order to remove lipophilic substances, the body needs to pass them through the liver in order to decompose them into components. Water-soluble beta blockers are more readily accepted by the body because they are not passed through the liver, but are evacuated from the body unchanged in the urine. The action of these drugs is much longer than that of lipophilic representatives.

But fat-soluble beta blockers have an undeniable advantage over hydrophilic drugs - they can penetrate the blood-brain barrier that separates the blood system from the central nervous system. So, as a result of taking such drugs, it was possible to significantly reduce the mortality rate among those patients who suffered from coronary heart disease. However, while having a positive effect on the heart, fat-soluble beta blockers contribute to sleep disturbance, provoke severe headaches, and can cause depression in patients. Bisoprolol is a universal representative - it is able to dissolve perfectly both in fats and in water. Therefore, the body itself decides how to remove the residues - in case of liver pathology, for example, the drug is perfectly excreted by the kidneys, which take on this responsibility.