Without intrinsic sympathomimetic activity. Adrenergic blockers: action, application features

How do beta blockers work?
Modern beta blockers: list

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

Beta blockers: purpose

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

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

Return to contents

Beta blockers: types

The list of drugs in this group is very extensive.

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

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

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

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

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

Return to contents

Lipo- and hydrophilic preparations

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

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

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

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

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

Taking beta blockers can cause hypotension, an excessive decrease in blood pressure, and bradycardia, a decrease in heart rate. The patient should quickly seek medical help if the systolic pressure is less than 100 mmHg and the pulse is less than 50 beats per minute. Beta blockers should not be taken during pregnancy as they may cause fetal growth retardation.

Beta blockers have numerous side effects. Here are the most serious of them.

Increased fatigue: This may result from decreased blood flow to the brain as blood pressure drops.
Slow heart rate: a sign of general weakness.
Heart blocks: If there is a problem with the conduction system of the heart, taking beta blockers may be harmful.
Exercise intolerance: Not the best choice of drug for an active athlete.
Exacerbation of asthma: drugs in this group can worsen the condition of patients with bronchial asthma.
Reducing levels of LDL cholesterol, or low-density lipids in the blood: Some beta blockers reduce levels of “good” cholesterol.
Toxicity: If you have liver disease or kidney failure, beta blockers can accumulate in the body as they are cleared from the body through the liver, kidneys, or both.
Possibility of increased blood pressure if you stop taking the drug: If you suddenly stop taking the drug, your blood pressure may rise even higher than before you started treatment. These medications should be stopped gradually over several weeks.
Lower blood sugar levels: Diabetics taking this class of drugs may have a reduced response to low sugar levels because the hormones that raise blood sugar levels are dependent on nerves blocked by beta blockers.
The most dangerous side effect of stopping beta blockers: heart attacks. Beta blockers should be stopped gradually to avoid heart pain and heart attacks.

Conditions requiring special caution when using beta blockers:

Diabetes mellitus (especially patients receiving insulin);
Chronic obstructive pulmonary disease without bronchial obstruction;
Peripheral arterial disease with mild to moderate intermittent claudication;
Depression;
Dyslipidemia (problems with cholesterol and triglyceride levels in the blood);
Asymptomatic sinus node dysfunction, 1st degree atrioventricular block.

In these conditions you should:

choose cardioselective beta blockers;
start with a very low dose;
increase it more gradually than usual;
for patients with diabetes - carefully monitor blood glucose levels.

Absolute contraindications to the use of beta blockers:

Individual hypersensitivity;
Bronchial asthma and chronic obstructive pulmonary diseases with bronchial obstruction (or requiring the use of bronchodilators);
Atrioventricular block of 2-3 degrees, in the absence of an artificial pacemaker;
Bradycardia with clinical manifestations;
Sick sinus syndrome;
Cardiogenic shock;
Severe damage to peripheral arteries;
Low blood pressure with clinical manifestations.

Approaches to stopping beta blockers

Regardless of the pharmacological characteristics of beta-blockers (the presence or absence of cardioselectivity, internal sympathomimetic activity, etc.), their abrupt withdrawal after long-term use (or a significant reduction in dosage) increases the risk of developing acute cardiovascular complications, which are called “withdrawal syndrome” or “ rebound syndrome."

This beta-blocker withdrawal syndrome in people with hypertension can manifest itself as an increase in blood pressure until the development of a hypertensive crisis. In patients with angina pectoris - an increase in frequency and/or increase in the intensity of anginal episodes and, less commonly, the development of acute coronary syndrome. In persons suffering from heart failure - the appearance or increase in signs of decompensation.

Reducing the dose or completely stopping beta blockers, if necessary, should be done gradually (over several days or even weeks), carefully monitoring the patient's well-being and blood tests. If rapid discontinuation of a beta blocker is still necessary, then it is necessary to organize and implement the following set of measures in advance to reduce the risk of crisis situations:

the patient must be provided with medical supervision;
the patient should reduce physical and emotional stress as much as possible;
start taking additional medications from other groups (or increase their dosages) to prevent possible deterioration.

For hypertension, other classes of blood pressure-lowering medications must be used. For coronary heart disease - nitrates alone or together with calcium antagonists. For heart failure, patients are prescribed diuretics and ACE inhibitors instead of beta blockers.

General information about beta blockers and their properties: " ".

Side effects for all beta blockers are generally similar, but they differ in severity for different drugs in this group. For more information, see articles about specific beta blocker medications.

Raisa
I have suffered from hypertension for about 6 years. I take deltiazem 2 times a day, concor in the evening and nifedipine as needed. I would like to switch to a 24-hour drug. Tell me which drug will suit me.
Olga
Is it necessary to take blockers for neurosis?
ANNA
Hello! My son is 36 years old, overweight, elevated and diastolic 140/100, the doctor prescribed medications: Lozap, Concor, Enap, Diraton. The drugs did not give the expected result. The kidneys are normal. Tell me why high diastolic pressure occurs and what tests should be taken? Are there drugs that reduce diastolic pressure? THANK YOU
Alina
I have heart neurosis, due to a sick child with cerebral palsy. I am 54 years old. I am very afraid of getting sick, although I have always been healthy. This summer I had panic attacks with severe surges in blood pressure. Ultrasound of the heart is good, only diastole function is impaired. And so everything is normal, there is still a complete blockade in front of her of the branch of the left leg of the PG and RBBB. I took a course in the neurological department. I drank Coronal at 1.25 for 2 months. Mexidol and magneB6. I want to switch to supplements. Your opinion
Boris
Thanks for your hard work! May God bless you.
Please tell me about my problem...
I am 45 years old. Thin, fast, resilient, never had any health problems, although he had not been involved in sports for a long time. In the summer I moved to the fifth floor - I moved a lot of furniture up and down. Suddenly an arrhythmia appeared. I lay down and calmed down. And in the fall, one day she appeared from morning until lunch - she got worried. Doctors sent me to the hospital - tachycardia. The pressure jumped a little, although it had always been normal. They gave me potassium-magnesium droppers and started giving me carvediol. Ultrasound of the heart showed mitral valve insufficiency and an elongated cusp.
I somehow didn’t like Carvediol - it seemed like sometimes I didn’t have enough air before going to bed. The cardiologist prescribed calcium (a blocker?) for 10 days, and nothing more.
I went to see a private cardiologist. I examined it on a computer, found a bunch of other sores, and from my heart I said: apparently it’s a congenital problem with the valve, but if you don’t overload, you can live until old age.
I prescribed dietary supplements. A whole complex of sequential treatment. And if there is arrhythmia, she prescribed to take: Coenzyme Q10 + colloidal solution of minerals. So I had a question.
Somehow my heart “twitches” in response to the weather, especially at night, then I don’t sleep well and worry.
Can I take magnesium B6 along with dietary supplements? I understand that magnesium should greatly help with arrhythmia and valve problems?
Do they interfere with each other?
Now I’ve been drinking chlorophyll and colloidal silver for cleansing for 20 days. Then other dietary supplements for a month. The Q10 will be there for a long time. Omega3 will also be there - for a long time. But before I get to them, the doctor said: the body is contaminated, and they will not have a full effect, you need to first cleanse yourself with others.
And I think while I cleanse myself, my heart will suffer? So I’m thinking about drinking magnesium. Is that right? Is it possible at the same time? Kidneys are fine.
1. admin Post author
  > I examined it on a computer,
  > the doctor said: the body is contaminated
  > I drink chlorophyll and colloidal silver for 20 days
  >you need to cleanse yourself first
  
  I believe that you have ended up with a charlatan
  
  > Can I take magnesium-B6 along with dietary supplements?
  
  Yes, and start quickly. You can even use colloidal silver INSTEAD.
  Keep in mind that silver is poisonous to the human body, read on Wikipedia. True, most likely, there is no trace of silver in the supplements they sold you :).
  
  > Ultrasound of the heart showed
  >mitral valve insufficiency
  
  It is vital for you to visit this page - - and do what is written there.
  
  But! If you decide to start running or other physical activity, only after a face-to-face consultation with a competent (!) doctor. Hypertensive people without heart problems can be bolder, but you shouldn’t, otherwise you’ll collapse from a heart attack while jogging.
  
  Carefully study all our articles in the block “Cure from hypertension in 3 weeks - it’s real.” It tells you what tests you need to take and undergo examinations in an independent laboratory, as well as what supplements, other than magnesium, are useful to take to support your heart. If you are thin, then a low-carb diet is not important for you.
Tatiana
I am 30 years old, 164 cm, 65 kg now. In June 2013 (weight was 86 kg) I had a very strong, long-term stressful situation, after which I fell ill. Tachycardia up to 150 beats per minute during exercise, frequent increases in blood pressure up to 180/105, severe dizziness and general weakness. The blood test is normal, only blood density is 118% and cholesterol is 5.2. Cardiologists came to the conclusion that this is not cardiology but psychosomatics. I was prescribed Noofen and bisoprorol. I have already completed the entire course and lead a completely healthy lifestyle. Exercise, sports, regular walks, proper nutrition. I felt better, I lost 20 kg, blood clotting is already 87% and cholesterol is 4. Blood pressure is stable 112/70, pulse 60-75 after exercise. Now is the time to discontinue bisoprolol. Tell me - how to stop taking it correctly so that there is no withdrawal syndrome? I took it for 4 months at 2.5 and another 2 weeks at 1.25, and then what is the dose and how much more should I take it? Thank you very much for your help :).
Hermann
I am 73 years old. Due to the increasing incidence of arrhythmia and cardiac ultrasound readings, stress echocardiography is recommended. Do I need to stop Verospiron, Norvan, Preductal, Cardiomagnyl, Crestor on the eve of the study?
Igor
Good afternoon Thank you for helping people. I have a question. Height 177 cm, weight 109 kg, age 40 years. Periodically, three times a month, the pressure rises to 165/98/105 with tachycardia. My general practitioner 4 months ago prescribed me to take Bisoprolol once a day and said that it would last me for life. I drank regularly, there were no problems, my blood pressure returned to 117/70/75. I decided to get off Bisoprolol - I began to reduce the dose, but after 3 days tachycardia appeared and the pressure was 140/90/98. I went to the ambulance - they gave me pills - after 20 minutes my hands felt warm, everything calmed down. The next day I took the same dose of Bisoprolol - everything was fine. After 4 days I started drinking half again. 2 days passed - my blood pressure and tachycardia increased again. What should I do? Previously, during a crisis, I took Anaprilin and Valocordin. Now I don’t know how to put everything in order. I understand that my therapist doesn't care, but I want to live! What should I do? Thank you!
Lydia
Hello! Can beta blockers have side effects such as burning of the tongue, a feeling of plaque in the throat and palate. Previously, this occurred occasionally, then more often, but now it does not go away at all within a month. I contacted a gastroenterologist - the prescribed treatment did not help. I noticed that these symptoms intensified half an hour after taking beta blockers, as well as other blood pressure medications.

I am 67 years old, height 161 cm, weight 86 kg. I have been taking beta blockers for many years. I started with the drug Atenolol, then Coronal, now Binelol once a day in the morning. An hour later I take two Valz tablets. Before that I took Enap. Diagnosis: stage 2 hypertension. No diabetes. There were problems with the intestines.

Is it possible to stop taking beta blockers? Are there any pills for hypertension without such side effects?
Karina
Hello! My height is 155 cm, weight 52 kg, age 29 years. After a series of stressful situations (childbirth 2.5 years ago, and then the father’s funeral 11 months after the birth of the child), heart problems began. Panic attacks started. The resting pulse rose too high. I had a cardiogram - except for tachycardia, no abnormalities were detected. Daily ECG monitoring also did not reveal any serious problems. An ultrasound of the heart revealed a very small prolapse - the doctor said that half the country lives with such a pathology and lives to a ripe old age. Everything would be fine, but the rapid heartbeat began to bother me. Also tingling pain in the heart area. I don’t dare to say that it’s the heart, but colic appears regardless of the load and sometimes even in a supine position. The doctor prescribed nebivolol and adaptol. Later, adaptol was replaced with lemon balm and valerian in tablets. I gradually stopped taking the beta blocker a couple of times - thank God, without consequences. Now I drink them again, but there is a problem. Tachycardia does not go away. Of course, the pulse is no longer 120-150, but sometimes it reaches 100 in a calm physical state. My child is very active, thank God, but this leads to constant stress and lack of sleep. What can be added to nebivolol to calm the rhythm and nerves? Maybe Valocordin drops? Thank you in advance for your answer and I apologize for spelling and punctuation errors. I’m very worried about my increased heart rate and difficulty typing on my phone. And my therapist also diagnosed me with VSD.

Hello! I am 41 years old. 80kg, went in for sports. 12 years ago, a cardiologist prescribed Coronal 5 mg (half the table for life) (because 12 years ago, suddenly, out of the blue, sitting at the PC, it became stuffy and scary, I ran to the window, it seemed to let me go, I immediately went to the clinic to see a therapist, they tried it on blood pressure (although maybe it was a reaction to stress), they said that it was hypertension (it seemed to be 150/100), they injected me with something lowering (I felt sick for two days later) and then the cardiologist prescribed this blocker (I also took thromboass).
In general, I drank in a disciplined manner for 12 years, everything was normal, pressure was normal, BUT for the last six months I began to have a headache and there was apathy towards physical activity and some kind of reluctance to do anything at all! I tried lowering and increasing the dose (gradually, naturally), and as a result, in the morning the pressure was 140/85, and my head was in such a wobbly state. (coffee doesn’t really help) In general, I’m confused, please help. Maybe I should stop taking BB altogether (the dose was minimal)? Or, on the contrary, increase the dose (but the pressure also INCREASES with the increasing dose of BB!!!) I tried to change the Coronal to Concor (it didn’t work, I started getting dizzy, I went back to the Coronal)….
I have consulted doctors several times over 12 years about stopping BB. BUT everyone spoke negatively. (but when they were prescribed at the time, no real research was carried out!!! And as I understand it, everyone is now afraid of the responsibility for canceling them:((Please explain and help!

Didn't find the information you were looking for?
Ask your question here.

How to cure hypertension on your own
in 3 weeks, without expensive harmful drugs,
"starvation" diet and heavy physical training:
free step-by-step instructions.

Ask questions, thank you for useful articles
or, conversely, criticize the quality of site materials

Content

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

What are beta blockers

A large group of pharmaceutical drugs that protect the heart's beta receptors from the effects of adrenaline are called beta blockers (BBs). The names of medicines that contain these active substances end in “lol”. They can easily be chosen among medications for the treatment of cardiovascular diseases. The active ingredients used are atenolol, bisoprolol, propranolol, timolol and others.

Mechanism of action

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

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

the heart rhythm changes towards a decrease in contraction frequency;
the strength of heart contractions decreases;
vascular tone decreases.

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

Blood pressure medications - a list of the latest generation medications with minimal side effects
Medicines for hypertension without side effects - main groups according to mechanism of action, composition and treatment regimen
Popular medications for high blood pressure and how to prescribe them

Indications for use

Beta blockers are prescribed for hypertension and heart disease. This is a general characteristic of their therapeutic action. The most common diseases for which they are used are:

Hypertension. Beta blockers for hypertension reduce the load on the heart, its need for oxygen decreases and blood pressure normalizes.
Tachycardia. When the pulse is 90 beats per minute or more, beta blockers are most effective.
Myocardial infarction. The action of the substances is aimed at reducing the affected area of the heart, preventing relapse, and protecting the cardiac muscle tissue. In addition, the drugs reduce the risk of sudden death, increase physical endurance, reduce the development of arrhythmia, and promote oxygen saturation of the myocardium.
Diabetes mellitus with cardiac pathologies. Highly selective beta blockers improve metabolic processes and increase tissue sensitivity to insulin.
Heart failure. The 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, various types of arrhythmia, mitral valve prolapse, tremor, cardiomyopathy, acute aortic dissection, hyperhidrosis, complications of hypertension. The drugs are prescribed for the prevention of migraines, variceal bleeding, for the treatment of arterial pathologies, and depression. Therapy of the listed diseases involves the use of only some BBs, since their pharmacological properties are different.

Classification of drugs

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

Adrenaline receptor blockers can 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.
Solubility in certain substances distinguishes groups: lipophilic (soluble in fat) and hydrophilic (soluble in water).
BBs that are capable of partially stimulating adrenergic receptors are combined into a group of drugs with intrinsic sympathomimetic activity.
Adrenaline receptor blockers are divided into short-acting and long-acting drugs.
Pharmacologists have developed three generations of beta blockers. All of them are still used in medical practice. The latest (third) generation drugs have the fewest 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 being therapeutic, they have strong side effects (for example, bronchospasm). The second generation of BBs are cardioselective drugs; they have a targeted effect only on type 1 cardiac receptors and have no contraindications for people with diseases of the respiratory system.

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

Intrinsic sympathomimetic activity

Alprenolol, Carteolol, Labetalol are the 1st generation of beta blockers with internal sympathomimetic activity, Epanolol, Acebutanol, Celiprolol are the 2nd generation of medications with this 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 and is a prevention of angina attacks, but the drug has been found to interact with many medications.

Lipophilic drugs

Lipophilic adrenaline receptor blockers include Propranolol, Metoprolol, Retard. These drugs are actively processed by the liver. In case of liver pathologies or in elderly patients, an overdose may occur. Lipophilicity determines side effects that manifest themselves through the nervous system, such as depression. Propranolol is effective for thyrotoxicosis, cardiomyalgia, and myocardial dystrophy. Metoprolol inhibits the effect of catecholamines in the heart during physical and emotional stress and 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 failure, they accumulate in the body. They have a prolonged effect. It is better to take medications before meals and drink plenty of water. Atenolol belongs to this group. Effective in the treatment of hypertension, the hypotensive effect lasts for about a day, while peripheral vessels remain in good shape. The use of beta blockers is dangerous in the following conditions and pathologies:

diabetes mellitus;
depression;
lung diseases;
increased levels of lipids in the blood;
peripheral circulatory disorders;
asymptomatic sinus node dysfunction.

Side effects

Numerous side effects of beta blockers do not always occur, including:

chronic fatigue;
decrease in heart rate;
exacerbation of bronchial asthma;
heart block;
reducing the concentration of “good” cholesterol and sugar;
after discontinuation of medications, there is a risk of increased blood pressure;
heart attacks;
increased fatigue during physical activity;
effect on potency in patients with vascular pathologies;
toxic effect.

Video

Attention! The information presented in the article is for informational purposes only. The materials in the article do not encourage self-treatment. Only a qualified doctor can make a diagnosis and give treatment recommendations based on the individual characteristics of a particular patient.

Found an error in the text? Select it, press Ctrl + Enter and we will fix everything!

28733 0

β-adrenergic receptor blockers, or β-blockers, are a group of drugs that can reversibly block β-adrenergic receptors. They have been used in clinical practice since the early 60s of the 20th century for the treatment of coronary artery disease and cardiac arrhythmias; later they began to be used for the treatment of hypertension, and subsequently for the treatment of heart failure. The importance of β-blockers for the secondary prevention of diseases of the cardiovascular system turned out to be so high that in 1988 the scientists who took part in the creation of this group of drugs were awarded the Nobel Prize. In recent years, after obtaining the results of several large controlled clinical trials and meta-analyses, the range of use of β-blockers has narrowed somewhat, primarily due to their less active use as drugs for primary prevention in patients with hypertension.

Mechanism of action

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

Pharmacokinetics

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

Table 1

Main properties of β-blockers used in the clinic

Preparation	Presence of β1-selectivity	Presence of intrinsic sympathomimetic activity	Presence of vasodilating properties	T1/2
Atenolol Betaxolol Bisoprolol Carvedilol Metoprolol Nadolol Nebivolol Pindolol Proxodolol Propranolol Sotalol Talinolol Timolol Esmolol	Yes Yes Yes No Yes No Yes No No data No No Yes No Yes	No No No No No No No Yes No No Yes Yes No No	No No No Yes No No Yes No Yes No No No No No	6-9 hours 16-22 h 7-15 h 6 hours 3-7 hours 10-24 h 10 o'clock 2-4 hours No data 2-5 hours 7-15 h 6 hours 2-4 hours 9 min

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

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

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

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

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

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

β-Adrenergic blockers with α1-adrenergic blocking activity. Due to this new effect, the drugs have an additional vasodilator effect (carvedilol).
β-blockers capable of producing nitric oxide (nebivolol).

Groups of β-blockers depending on fat solubility

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

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

Groups of β-blockers depending on metabolism in the liver

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

These properties of the drugs have virtually no clinically significant effect.

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

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

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

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

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

β-blockers of medium duration of action. The effect of regular metoprolol tartrate tablets lasts from 8 to 10 hours, so they must be prescribed 2 or even 3 times a day.
Short-acting β-blockers. The shortest-acting drugs include esmolol. Its antianginal and antihypertensive effect lasts only 10-20 minutes after stopping the infusion.

Martsevich S.Yu., Tolpygina S.N.

Beta blockers

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

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

In the 90s, it was established that beta-adrenergic receptors are divided into three subtypes:

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

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

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

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

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

Beta blockers simultaneously improve myocardial perfusion by reducing left ventricular (LV) end-diastolic pressure and increasing the pressure gradient that determines coronary perfusion during diastole, the duration of which increases as a result of a slower cardiac rhythm.

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

Decrease in heart rate (negative chronotropic effect);

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

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

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

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

Hypotensive effect beta blockers are due to:

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

Decreased secretion and decreased concentration of renin in plasma;

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

Central depression of sympathetic tone;

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

Competitive antagonism with catecholamines for receptor binding;

Increased levels of prostaglandins in the blood.

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

The effect on beta2-adrenergic receptors determines a significant part of the side effects and contraindications to their use (bronchospasm, constriction of peripheral vessels). A feature of cardioselective beta-blockers compared to non-selective ones is their greater affinity for beta1-receptors of the heart than for beta2-adrenergic receptors. Therefore, when used in small and medium doses, these drugs have a less pronounced effect on the smooth muscles of the bronchi and peripheral arteries. It should be taken into account that the degree of cardioselectivity varies among different drugs. The index ci/beta1 to ci/beta2, characterizing the degree of cardioselectivity, is 1.8:1 for non-selective propranolol, 1:35 for atenolol and betaxolol, 1:20 for metoprolol, 1:75 for bisoprolol (Bisogamma). However, it should be remembered that selectivity is dose-dependent; it decreases with increasing dose of the drug (Fig. 1).

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

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

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

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

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

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

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

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

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

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

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

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

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

Due to these unique pharmacological properties, carvedilol may be superior to traditional beta1-selective blockers in improving myocardial perfusion and helping to preserve systolic function in patients with coronary artery disease. As shown by Das Gupta et al., in patients with LV dysfunction and heart failure due to coronary artery disease, carvedilol monotherapy reduced filling pressure and also increased LV ejection fraction (EF) and improved hemodynamic parameters, without being accompanied by the development of bradycardia.

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

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

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

The good tolerability and antiremodeling effect of carvedilol indicate that this drug can reduce the risk of death in patients who have had a MI. The large-scale CAPRICORN (CArvedilol Post InfaRct Survival ContRol in Left Ventricular DysfunctionN) trial was designed to study the effect of carvedilol on survival in LV dysfunction after myocardial infarction. The CAPRICORN trial is the first to demonstrate that carvedilol in combination with ACE inhibitors is able to reduce all-cause and cardiovascular mortality, as well as the incidence of recurrent non-fatal myocardial infarction in this group of patients. New evidence that carvedilol is at least as effective, if not more effective, in reversing remodeling in patients with heart failure and coronary artery disease supports the need for earlier administration of carvedilol for myocardial ischemia. In addition, the effect of the drug on the “sleeping” (hibernating) myocardium deserves special attention.

Carvedilol in the treatment of hypertension

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

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

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

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

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

As is known, dyslipidemia is one of the four main risk factors for the development of CVD. Its combination with hypertension is especially unfavorable. However, some beta blockers may also cause unwanted changes in blood lipid levels. As mentioned, carvedilol does not have a negative effect on serum lipid levels. A multicenter, blinded, randomized study examined the effect of carvedilol on lipid profiles in patients with mild to moderate hypertension and dyslipoproteinemia. The study included 250 patients who were randomized to treatment groups with carvedilol at a dose of 25-50 mg/day or the ACE inhibitor captopril at a dose of 25-50 mg/day. The choice of captopril for comparison was determined by the fact that it either has no effect or has a positive effect on lipid metabolism. The duration of treatment was 6 months. In both compared groups, positive dynamics were noted: both drugs comparablely improved the lipid profile. The beneficial effect of carvedilol on lipid metabolism is most likely related to its alpha-adrenergic blocking activity, since beta1-adrenergic receptor blockade has been shown to cause vasodilation, thereby improving hemodynamics and also reducing the severity of dyslipidemia.

In addition to blocking beta1, beta2 and alpha1 receptors, carvedilol also has additional antioxidant and antiproliferative properties, which is important to consider in terms of influencing CVD risk factors and providing target organ protection in patients with hypertension.

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

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

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

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

Beta-blockers in the treatment of CHF

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

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

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

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

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

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

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

Literature

Devereaux P.?J., Scott Beattie W., Choi P.?T. L., Badner N.?H., Guyatt G.?H., Villar J.?C. et al. How strong is the evidence for the use of perioperative b-blockers in non-cardiac surgery? Systematic review and meta-analysis of randomized controlled trials // BMJ. 2005; 331: 313-321.

Feuerstein R., Yue T.?L. A potent antioxidant, SB209995, inhibits oxy gene-radical-mediated lipid peroxidation and cytotoxicity // Pharmacology. 1994; 48: 385-91.

Das Gupta P., Broadhurst P., Raftery E.?B. et al. Value of carvedilol in congestive heart failure secondary to coronary artery disease // Am J Cardiol. 1990; 66: 1118-1123.

Hauf-Zachariou U., Blackwood R.?A., Gunawardena K.?A. et al. Carvedilol versus verapamil in chronic stable angina: a multicentre trial // Eur J Clin Pharmacol. 1997; 52:95-100.

Van der Does R., Hauf-Zachariou U., Pfarr E. et al. Comparison of safety and efficacy of carvedilol and metoprolol in stable angina pectoris // Am J Cardiol 1999; 83: 643-649.

Maggioni A. Review of the new ESC quidelines for the pharmacological management of chronic heart failure // Eur. Heart J. 2005; 7: J15-J21.

Dargie H.?J. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomized trial // Lancet. 2001; 357: 1385-1390.

Khattar R.?S., Senior R., Soman P. et al. Regression of left ventricular remodeling in chronic heart failure: Comparative and combined effects of captopril and carvedilol // Am Heart J. 2001; 142: 704-713.

Dahlof B., Lindholm L., Hansson L. et al. Morbility and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-hypertension) // The Lancet, 1991; 338: 1281-1285.

Rangno R.?E., Langlois S., Lutterodt A. Metoprolol withdrawal phenomena: mechanism and prevention // Clin. Pharmacol. Ther. 1982; 31: 8-15.

Lindholm L., Carlsberg B., Samuelsson O. Shouted b-blockers remain first choice in the treatment of primary hypertension? A meta-analysis // Lancet. 2005; 366:1545-1553.

Steinen U. The once-daily dose regimen of carvedilol: a meta-analysis approach //J Cardiovasc Pharmacol. 1992; 19(Suppl. 1):S128-S133.

Jacob S. et al. Antihypertensive therapy and insulin sensitivity: do we have to redefine the role of beta-blocking agents? // Am J Hypertens. 1998.

Giugliano D. et al. Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin-dependent diabetes mellitus and hypertention. A randomized, controlled trial // Ann Intern Med. 1997; 126:955-959.

Kannel W.?B. et al. Initial drug therapy for hypertensive patients with dyslipidaemia // Am Heart J. 188: 1012-1021.

Hauf-Zahariou U. et al. A double-blind comparison of the effects of carvedilol and captopril on serum lipid concentration in patients with mild to moderate essential hypertention and dislipidaemia // Eur J Clin Pharmacol. 1993; 45: 95-100.

Fajaro N. et al. Long-term alfa 1-adrenergic blockade attenuates diet-induced dyslipidaemia and hyperinsulinemia in the rat // J Cardiovasc Pharmacol. 1998; 32: 913-919.

Yue T.?L. et al. SB 211475, a metabolite of carvedilol, a novel antihypertensive agent, is a potent antioxidant // Eur J Pharmacol. 1994; 251: 237-243.

Ohlsten E.?H. et al. Carvedilol, a cardiovascular drug, prevents vascular smooth muscle cell proliferation, migration and neointimal formation following vascular injury // Proc Natl Acad Sci USA. 1993; 90: 6189-6193.

Poole-Wilson P.?A. et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the carvedilol or metoprolol European trial (COMET): randomized controlled trial // Lancet. 2003; 362(9377): 7-13.

Ner G. Vasodilatory action of carvedilol //J Cardiovasc Pharmacol. 1992; 19(Suppl. 1):S5-S11.

Agrawal B. et al. Effect of antihypertensive treatment on qualitative assessments of microalbuminuria // J Hum Hypertens. 1996; 10: 551-555.

Marchi F. et al. Efficacy of carvedilol in mild to moderate essential hypertention and effects on microalbuminuria: multicenter, randomized.

Tendera M. Epidemiology, treatment and quidelines for the treatment of heart failure in Europe // Eur. Heart J., 2005; 7: J5-J10.

Waagstein F., Caidahl K., Wallentin I. et al. Long-term beta-blockade in dilated cardiomyopathy: effects of short-term and long-term metoprolol followed by withdrawal and readministration of metoprolol // Circulation 1989; 80: 551-563.

The International Steering Commitee on behalf of the MERIT-HF Studi Group // Am. J. Cardiol., 1997; 80 (suppl. 9 B): 54J-548J.

Packer M., Bristow M.?R., Cohn J.?N. et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. US Carvedilol Heart Failure Study Group // N Engl J Med. 1996; 334:1349.

COPERNICUS investigators resource. F.?Hoffman-La Roche Ltd, Basel, Switzerland, 2000.

Does R., Hauf-Zachariou U., Praff E. et al. Comparison of safety and efficacy of carvedilol and metoprolol in stable angina pectoris // Am. J.?Cardiol. 1999; 83: 643-649.

Randomized, pacebo-controlled trial of carvedilol in patients with congestive heart failure due to ischemic heart disease. Australia/New Zealand Heart Failure Research CollaborativeGroup // Lancet, 1997; 349: 375-380.

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

*MMA im. I. M. Sechenova, Moscow
**Clinic of the Moscow Institute of Cybernetic Medicine, Moscow