Long-acting non-selective beta-blocker

Table 10.3. The main characteristics of β-blockers.

Due to the extensive experience in the use of propranolol, this drug is a kind of standard with which other beta-blockers are compared (Table 10.3).

The affinity of propranolol for β1 and β2-adrenergic receptors is the same; it does not have internal sympathomimetic activity and does not react with a-adrenergic receptors.

Pharmacokinetics With its high fat solubility, propranolol is almost completely absorbed from the digestive tract. However, a significant part of it undergoes metabolism during the first passage through the liver, and therefore, on average, only 25% of the dose taken orally enters the systemic circulation. In addition, the intensity of this metabolism is subject to significant individual fluctuations, as a result of which the difference in the serum concentration of propranolol after ingestion of the same dose in different patients can vary by 20 times;

accordingly, the doses required for the clinical effect also differ. Thus, sometimes when choosing a dose of propranolol it is necessary to increase it repeatedly, which, of course, creates inconvenience. As the dose of the drug increases, the degree of its elimination by the liver decreases. The bioavailability of propranolol increases when taken with food and with prolonged use.

Propranolol has a large distribution volume (4 l/kg) and easily penetrates the blood-brain barrier. In the blood, it is approximately 90% bound to plasma proteins. Propranolol undergoes intensive hepatic metabolism, and most of the metabolites are removed by the kidneys (one of them, 4-hydroxypropranolol, has some β-adrenergic blocking effect).

Studies of the distribution, hepatic elimination, and activity of propranolol are hampered by the fact that all these processes are stereospecific (Walle et al., 1988). The active isomers of propranolol (as well as other β-blockers) are the/-isomers. Elimination of β-propranolol appears to be slower than d-npo-pranolol.

786045307860 - Long-acting non-selective beta-blocker

In addition, the rate of elimination of propranolol depends on hepatic blood flow, changes with liver diseases and with the use of a number of drugs that affect liver metabolism. Rarely resort to measuring the serum concentration of propranolol – it is much easier to monitor clinical indicators such as blood pressure and heart rate.

In addition, the relationship between the serum concentration of propranolol and its action is quite complex: so, despite a short T 1/2 (about 4 hours), propranolol has a rather long hypotensive effect, which allows it to be taken 2 times a day. A certain amount of/-propranolol (and other/-isomers of β-blockers) is captured by the sympathetic endings and released upon irritation of the sympathetic nerves (Walle et al., 1988).

There is a long-acting propranolol preparation that allows maintaining a therapeutic serum concentration of this drug for 24 hours (Nace and Wood, 1984). At the same time, tachycardia caused by physical exertion is suppressed throughout the interval between doses. Obviously, this form of propranolol is more convenient for patients.

Application. The usual initial dose of propranolol for arterial hypertension and ischemic heart disease is 40–80 mg/day orally. Further, it is sometimes gradually increased until the desired result is achieved, but usually no more than 320 mg/day. In case of BS, the intervals between successive dose increases can be (if indicated) less than 1 week. With arterial hypertension, it sometimes takes weeks to achieve the full effect of propranolol.

If propranolol is taken 2 times a day as an antihypertensive, then before each dose you should measure your blood pressure to make sure that the effect of the drug persists. A sign of sufficient beta-adrenergic blockade is the suppression of tachycardia caused by physical exertion. With life-threatening cardiac arrhythmias and under conditions of general anesthesia, propranolol is sometimes prescribed iv.

At the same time, 1 — Zmg of the drug is administered first at a rate of less than 1 mg/min under conditions of constant monitoring of blood pressure, ECG and other indicators of cardiac activity. If the result is not achieved, after a few minutes the dose is repeated. With excessive bradycardia, atropine is prescribed. At the first opportunity, they switch to taking propranolol inside.

The drug has approximately the same affinity for β1 and β2 adrenergic receptors. He has no quinidine-like action and internal sympathomimetic activity. The main feature of nadolol is a long-term effect.

pharmacokinetics. Nadolol has a high water solubility and is not completely absorbed from the digestive tract: its bioavailability is about 35% (Frishman, 1981). Individual differences in pharmacokinetics in nadolol are less than in propranolol. Since the fat solubility of nadolol is low, its concentration in the central nervous system should be lower than most other β-blockers.

In this regard, it is often claimed that when using water-soluble β-blockers, the likelihood of central side effects is less, although there are few controlled studies on this subject. Nadolol is mainly excreted unchanged in urine. Its T1/2 is about 20 hours, and therefore it is usually taken 1 time per day. With renal failure, nadolol can accumulate; in such patients, its dose is reduced.

It is a powerful non-selective beta-blocker. He has no quinidine-like action and internal sympathomimetic activity.

Pharmacokinetics Timolol is well absorbed from the gastrointestinal tract and is moderately metabolized during the first passage through the liver. Elimination occurs mainly through hepatic metabolism, unchanged in the urine, only a small amount of the drug is excreted. T1/2 – about 4 hours. It is important to note that eye drops with timolol (used for glaucoma; Ch. 66) can have a pronounced systemic effect – up to attacks of bronchial asthma and worsening heart failure.

It is an indiscriminate beta-blocker with internal sympathomimetic activity, weak quinidine-like action and moderate fat solubility.

beta blockers - Long-acting non-selective beta-blocker

It is possible that beta-blockers with internal sympathomimetic activity reduce blood pressure and heart rate to a lesser extent, although there is little data on this. In this regard, such drugs may be preferable as antihypertensive drugs for patients with a tendency to bradycardia or decreased pumping function of the heart. In controlled trials of this kind, the advantages of beta-blockers with internal sympathomimetic activity were not identified, but for individual patients they can be significant (Fitzerald, 1993). Pindolol and similar drugs suppress tachycardia and increased cardiac output caused by physical exertion.

Pharmacokinetics Pindolol is almost completely absorbed from the digestive tract, and its bioavailability is quite high. Due to this, individual differences in the serum concentration of this drug when taken orally are insignificant. Elimination of 50% occurs through hepatic metabolism. The main metabolites are hydroxylated derivatives, which, after conjugation with glucuronic acid or sulfate, are excreted by the kidneys. The rest of the drug excreted in the urine unchanged. T1/2 for about 4 hours. With renal failure, elimination of pindolol slows down.

This is a typical representative of competitive β1 blockers and a-adrenergic receptors. The labetalol molecule has 2 chiral centers, and therefore there are 4 of its optical isomers; a commercially available preparation is a mixture of all four in approximately equal amounts (Gold et al., 1982). Since the activities of these isomers differ, the pharmacological properties of labetalol are complex.

It selectively blocks a1-adrenergic receptors (compared with a2-adrenergic receptors), blocks β1 and β2-adrenergic receptors, is a partial agonist of the latter and suppresses reverse neuronal uptake of norepinephrine (the so-called cocaine-like action; Ch. 6). Beta-adrenergic blocking activity of labetalol is 5-10 times higher than a-adrenergic blocking.

The pharmacological properties of labetalol became somewhat clearer after all four of its isomers were isolated and studied. The beta-adrenergic blocking activity of the d, d-isomer is about 4 times higher than the racemic labetalol, and it is it that largely determines the β-adrenergic blocking effect of the latter (in the United States, this isomer was tested as a separate drug – dilavalol – but at present they have stopped).

The alpha1-adrenergic blocking activity of the d, d-isomer is more than 5 times lower than that of racemic labetalol (Sybertz et al., 1981; Gold et al., 1982). d,/- the isomer practically does not possess either a1 or β-adrenergic blocking activity. The latter is also almost absent in the /.d-isomer, but the a1-adrenergic blocking activity is approximately 5 times higher than in racemic labetalol. Y /.

42 1 - Long-acting non-selective beta-blocker

There is no β-isomer of β-adrenergic blocking activity, and the a1-blocking activity is the same as that of racemic labetalol (Gold et al., 1982). The d, d-isomer has some internal sympathomimetic activity against β2-adrenergic receptors, which may make a certain contribution to vasodilation caused by labetalol (Baum et al., 1981). Labetalol also has a direct vasodilating effect.

The hypotensive effect of labetalol is associated with its effect on both a1- and β-adrenergic receptors. Blockade of a1-adrenergic receptors is accompanied by relaxation of the smooth muscles of the vessels and expansion of the latter (especially in the standing position). Blockade of β1-adrenergic receptors suppresses reflex sympathetic stimulation of the heart.

Labetalol is available in tablets (for the treatment of arterial hypertension) and in the form of solutions for iv administration (for stopping hypertensive crises). Rare cases of hepatotoxic effects have been described (Clark et al., 1990).

Pharmacokinetics Although labetalol is almost completely absorbed from the gastrointestinal tract, it is significantly metabolized the first time it passes through the liver. Therefore, its bioavailability is only 20–40% and is subject to significant individual fluctuations (McNeil and Louis, 1984). It rises when taking labetalol with food.

Labetalol is rapidly metabolized by the liver by oxidation and conjugation with glucuronic acid; unchanged with urine, only a small part of it is excreted. The metabolic rate of labetalol depends on hepatic blood flow. T1/2 is about 8 hours (d, d-isomer is about 15 hours). Studying the effects of labetalol is a good example of applying pharmacokinetic and pharmacodynamic models to a drug that is a mixture of isomers with different pharmacokinetics and activity (Donnelly and Macphee, 1991).

List of beta-adrenergic blocking drugs

  • Selective beta-1-adrenergic blockers are drugs that block β1-adrenergic receptors in the kidneys and myocardium. They increase the resistance of the heart muscle to oxygen starvation, reduce its contractility. With the timely adrenergic blocking, the load on the cardiovascular system is reduced, as a result of which the likelihood of death from myocardial insufficiency is reduced. New generation drugs practically do not cause unwanted effects. They eliminate bronchospasm and prevent hypoglycemia. Therefore, they are prescribed to people suffering from chronic diseases of the bronchi, diabetes mellitus.
  • Non-selective beta-blockers are drugs that reduce the sensitivity of all types of β-adrenergic receptors in the bronchioles, myocardium, liver, and kidneys. They are used to prevent arrhythmias, reduce renin synthesis by the kidneys, and improve the rheological properties of blood. Beta-2 adrenergic blocking agents prevent fluid production in the sclera of the eye, therefore it is recommended for the symptomatic treatment of glaucoma.

The higher the selectivity of adrenergic blockers, the lower the risk of complications. Therefore, drugs of the latest generation are much less likely to provoke adverse reactions.

7860453087604560 - Long-acting non-selective beta-blockerSelective adrenoblockers inhibit exclusively β1 receptors. They hardly affect β2 receptors in the uterus, skeletal muscles, capillaries, bronchioles. Such drugs are safer, therefore, they are used in the treatment of heart diseases with serious concomitant problems.

Classification of drugs depending on solubility in lipids and water:

  • Lipophilic (Timolol, Oxprenolol) – soluble in fats, easily overcome tissue barriers. More than 70% of the components of the drug are absorbed in the intestine. Recommended for severe heart failure.
  • Hydrophilic (Sotalol, Atenolol) – slightly soluble in lipids, therefore, absorbed from the intestine only 30-50%. The breakdown products of adrenergic blockers are excreted mainly by the kidneys, so they are used with caution in case of renal failure.
  • Amphiphilic (Celiprolol, Acebutolol) – easily soluble in fats and water. When ingested, they are absorbed in the intestine by 55-60%. Drugs are allowed for compensated kidney or liver failure.

Some adrenergic blockers have a sympathomimetic effect – the ability to stimulate β-receptors. Other drugs have a moderate dilating effect on the capillaries.

Selective and non-selective beta-blockers

!  Brain angioma causes types symptoms diagnosis treatment consequences and prognosis
Adrenergic blocking groupWith sympathomimetic activityNo sympathomimetic activity
cardioselectiveCeliprolol
non-cardioselectiveDilevalal
with the properties of α-blockersBucindolol

78604530786045036 - Long-acting non-selective beta-blockerIf the drug belongs to beta-blockers, it is taken only on the recommendation of a doctor in the dosage prescribed by him. The abuse of this type of medicine is dangerous with a sharp drop in pressure, asthma attacks, and a slow heartbeat.

  • Nitrates. The vasodilating effect on capillaries is enhanced, bradycardia is leveled by tachycardia.
  • Alpha blockers. Medicines mutually reinforce each other’s action. This leads to a more powerful hypotensive effect, a decrease in peripheral vascular resistance.
  • Diuretics. Adrenergic blockers prevent the release of renin from the kidneys. Because of this, the period of action of diuretic drugs increases.

786045307860453076580 - Long-acting non-selective beta-blockerIt is strictly forbidden to combine adrenergic blockers with calcium antagonists. This is dangerous with cardiac complications – a decrease in heart rate and the strength of myocardial contractions.

Beta-blockers cannot be combined with these medicines without a doctor’s recommendation:

  • Cardiac glycosides. The risk of bradyarrhythmia, a decrease in myocardial contractions increases.
  • Antihistamines. The anti-allergic effect is weakened.
  • Sympatolytics. The sympathetic effect on the heart muscle is reduced, which is fraught with cardiological complications.
  • MAO inhibitors. The risk of an excessive increase in blood pressure and hypertensive crisis increases.
  • Antidiabetic agents. The hypoglycemic effect increases several times.
  • Indirect coagulants. Antithrombotic activity of drugs is reduced.
  • Salicylates. Adrenolytics reduce their anti-inflammatory activity.

Non-selective β-blockers [edit | edit code]

Pharmacokinetics Due to active metabolism, the first pass through the liver makes bioavailability of carvedilol only 25–35%. The main route of elimination is hepatic metabolism. Most of the drug is eliminated with T1/2 for about 2 hours, and the remaining amount with T1/2 is 7-10 hours.

Application. With arterial hypertension, 6,25 mg 2 times a day is usually prescribed first. If the effect is insufficient, the dose is gradually increased; the maximum dose is usually 25 mg 2 times a day. With heart failure, great caution is necessary in connection with the risk of a sudden deterioration in the pumping function of the heart. As a rule, they start with a dose of 3,125 mg 2 times a day and increase it under close supervision.

Non-selective β-blockers [edit | edit code]

Application. Doses and regimen of metoprolol for arterial hypertension and coronary heart disease are quite well established. With arterial hypertension, usually begin with 100 mg/day by mouth. Each week, the dose can be increased to achieve the required level of blood pressure. Typically, the dose is divided into 2 doses, although a single dose is sometimes effective (in the latter case, you need to make sure that the blood pressure is maintained at a satisfactory level during the day).

It is a selective β1-blocker without internal sympathomimetic activity (Wadworth et al., 1991). Atenolol has a high water solubility and therefore poorly penetrates the blood-brain barrier. Tatenolol is slightly higher than metoprolol.

Pharmacokinetics Atenolol is absorbed from the digestive tract only by 50%, but most of this amount goes into the systemic circulation. Individual fluctuations in its serum concentrations are relatively small – the maximum serum concentration in different patients varies only 4 times (Cruickshank, 1980).

Application. With arterial hypertension, usually start with 50 mg once a day by mouth. If after a few weeks a satisfactory result is not achieved, the dose can be increased to 1 mg/day. A further increase in the dose usually does not give an effect. Atenolol in combination with diuretics has been shown to be effective in the elderly with systolic hypertension.

It is a selective β1-blocker with a very short action. He has almost no internal sympathomimetic activity, he also does not have a quinidine-like effect. Esmolol is administered iv in cases where it is necessary to achieve a short-term blockade of β-adrenergic receptors, as well as in severe patients who, because of the high likelihood of bradycardia, heart failure or a sharp drop in blood pressure, longer-acting drugs are too dangerous.

Pharmacokinetics and use. T1/2 of esmolol is approximately 8 min, and the volume of distribution is about 2 l/kg. There is an ester bond in its molecule, and therefore it is rapidly hydrolyzed by red blood cell esterases. T1/2 of the hydrolysis product is much larger (4 hours), and with prolonged infusion of esmolol, this metabolite accumulates (Benfleld and Sorkin, 1987); however, its β-adrenergic blocking activity is 500 times less than that of esmolol (Reynolds et al., 1986). In the future, it is excreted in the urine.

Esmolol causes rapid and short-term blockade of β-adrenergic receptors. The maximum hemodynamic effect is achieved 10 minutes after the introduction of a saturating dose; 20 min after the cessation of infusion, the β-blocking effect is significantly reduced. In healthy individuals, esmolol can cause a sharp drop in blood pressure; the mechanism of this phenomenon is not known (Reilly et al., 1985).

Since esmolol is used in emergency situations when it is necessary to achieve the fastest possible blockade of β-adrenergic receptors, the method of its application is as follows. First, a part of the saturating dose is administered, then a continuous infusion is started; if the desired effect is not observed after 5 minutes, repeat the saturating dose and increase the rate of infusion. Then this cycle (with a gradual increase in the rate of infusion) is repeated until the desired result is achieved, for example, the required level of heart rate or blood pressure.

It is a selective β1-blocker with moderate internal sympathomimetic activity. Pharmacokinetics Acebutolol is well absorbed from the gastrointestinal tract and then quickly turns into an active metabolite (diacetolol), which mainly determines the β-adrenergic blocking activity of the drug (Singh et al., 1985). T1/2 acebutolol is approximately 3 hours, and diacetolol is 8-12 hours. Diacetolol is excreted unchanged in the urine.

Application. With arterial hypertension, usually start 400 mg/day by mouth. Acebutolol can be taken once, but usually to maintain a stable level of blood pressure, the dose should be divided into 2 doses. As a rule, a satisfactory result is achieved at a dose of 400-800 mg/day (daily dose range is 200-1200 mg). With ventricular arrhythmias, acebutolop is taken 2 times a day.

Currently, many other β-blockers have been developed and to a greater or lesser extent. Bopindolol (not applicable in the USA), karteolol, oxprenolol and penbutolol are non-selective β-blockers with internal sympathomimetic activity. Medroxapol and bucindolol are non-selective β-blockers, which also have A1-blocking activity (RosendorfT, 1993).

Levobunolol and metipranolol are also non-selective β-blockers used locally for glaucoma (Brooksand Gillies, 1992). Bisoprolol and nebivolol are selective β1-blockers without internal sympathomimetic activity (Jamin et al., 1994; Van de Water et al., 1988). Betaxolol is a selective β1-blocker used internally for hypertension and locally for glaucoma.

Apparently, it causes bronchospasm less often than ophthalmic preparations with indiscriminate β-blockers timolol and levobunolol. There is also evidence that eye drops with cartolol less likely to have systemic side effects than drops with timolol, possibly due to the fact that cartolol has an internal sympathomimetic activity.

However, caution is required when using cartolol locally (Chrisp and Sorkin, 1992). Celiprolol is a selective β1-blocker with moderate β2-adrenostimulating activity and with a weak additional vasodilating effect of an unknown nature (Milne and Buckely, 1991). Sotalol is a non-selective β-blocker without quinidine-like action.

Most of the side effects of β-blockers are due to their main effect. Side effects not associated with β-adrenoreceptor blockade are rare.

The cardiovascular system. In patients with myocardial damage, β-blockers can cause heart failure, since in such patients sympathetic tone is of primary importance for the pumping function of the heart. This includes primarily patients with compensated heart failure, myocardial infarction, cardiomegaly.

It is not known whether β-blockers with internal sympathomimetic activity or direct vasodilating action have advantages in such cases. At the same time, there is convincing evidence that in a certain contingent of patients with heart failure the constant use of beta-adrenergic blockers increases life expectancy (see below, as well as Ch. 34).

Heart rate reduction is a natural reaction to β-blockers. At the same time, with violations of AV conduction, these drugs can cause dangerous arrhythmias. Particular caution should be exercised if the patient simultaneously takes verapamil or other antiarrhythmic drugs that have a negative chronotropic or dromotropic effect.

Some patients complain that β-blockers cause cold extremities. Sometimes (though rarely), these drugs exacerbate peripheral vascular disease (Lepantalo, 1985); Raynaud’s syndrome may develop. The likelihood of developing intermittent claudication is apparently extremely small, and the advantages of β-adrenergic blockers with a combination of coronary heart disease and peripheral vascular diseases are unconditional.

Sudden withdrawal of beta-blockers after prolonged use can aggravate angina pectoris and increase the risk of sudden death. The mechanisms of this are not completely clear, although it is known that in patients who have been taking some of these drugs for a long time, after their withdrawal, sensitivity to β-adrenostimulants is increased. So, against the background of β-blockers, the chronotropic effect of isoprenaline is reduced, and the sudden cancellation of propranolol leads to an increase in the action of isoprenaline.

This increased sensitivity develops several days after the discontinuation of propranolol and can last up to a week (Nattel etal., 1979). It can be reduced if a few weeks before withdrawal begin to gradually reduce the dose of the drug (Rangnoetal., 1982). An increase in sensitivity to isoprenaline is also observed after discontinuation of metoprolol, but not pindolol (Rangno and Langlois, 1982).

In patients taking propranolol for a long time, the density of β-adrenergic receptors on lymphocytes increases, and in those taking pindolol, on the contrary (Hedberg et al., 1986). The optimal method for canceling β-blockers has not yet been established, but in any case, it is better to reduce their dose gradually and at this time limit physical activity.

Respiratory system. The most important side effect of β-adrenergic blockers is associated with blockade of β2-adrenergic receptors of the smooth muscles of the bronchi. These receptors play a large role in the expansion of the bronchi in patients with obstructive pulmonary lesions, and P-blockers can cause life-threatening bronchospasm in such patients. The likelihood of this complication is less if the patient takes selective β1-blockers or drugs with a β2-adrenostimulating effect.

List of beta-adrenergic blocking drugs

42 2 - Long-acting non-selective beta-blocker

Indications for the use of non-selective adrenergic blockers:

  • tremor;
  • hypertension;
  • painful heart palpitations;
  • mitral valve prolapse;
  • intense angina pectoris;
  • cholecystocardial syndrome;
  • high intraocular pressure;
  • cardiomyopathy;
  • prevention of ventricular arrhythmias;
  • warning of the risk of myocardial infarction.

Selective adrenergic blockers act on the myocardium, with almost no effect on the capillaries. Therefore, such means treat heart pathologies:

  • heart attack;
  • paroxysmal arrhythmia;
  • coronary heart disease;
  • neurocirculatory dystonia;
  • atrial tachycardia;
  • atrial fibrillation;
  • prolapse of the left valve.

Beta-blockers with the properties of α-adrenolytics are used in combination therapy:

  • glaucoma;
  • myocardial insufficiency;
  • hypertension and hypertensive crisis;
  • arrhythmias.

780876045307860 - Long-acting non-selective beta-blockerDrugs that affect the contractile activity of the myocardium cannot be used for self-medication. Irrational therapy is fraught with an increase in the load on the vascular system and cardiac arrest.

Metabolism. As already mentioned, β-blockers can smooth out the signs of impending hypoglycemia, and in addition, they can slow recovery after insulin-induced hypoglycemia. In this regard, in patients with diabetes mellitus-prone hypoglycemia, β-blockers should be used with extreme caution, preferring selective β1-blockers.

Other side effects The likelihood of impaired sexual function in men with arterial hypertension taking β-blockers has not been established. These agents are increasingly being used in pregnancy, but nevertheless, their safety in pregnant women is also not fully understood (Widerhom et al., 1987).

Poisoning. The signs of β-adrenergic blocking poisoning depend on the properties of a particular drug, in particular on selectivity for β1-adrenergic receptors, internal sympathomimetic activity, and a quinidine-like action (Frishman etal., 1984). The most common symptoms are arterial hypotension, bradycardia, slowing of AV-conduction, expansion of the QRS complex.

Epileptic seizures and depression are possible. Hypoglycemia is rare, bronchospasm – unless there are obstructive pulmonary lesions – too. With severe bradycardia, atropine is used, but sometimes you have to resort to pacing. With arterial hypotension, large doses of isoprenaline or a-adrenostimulants may be required. Glucagon is effective – the positive chronotropic and inotropic effects of this drug are not due to activation of β-adrenergic receptors.

Drug interactions. Described as pharmacokinetic. and pharmacodynamic interactions between β-blockers and other drugs. Absorption of β-blockers decreases with the intake of cholestyramine, colestipol and aluminum salts. Phenytoin, rifampicin, phenobarbital and related drugs, as well as tobacco smoke substances, induce liver enzymes, which can lead to a decrease in serum concentrations of β-blockers with predominantly hepatic elimination (e.g., propranolol).

Pharmacodynamic interactions include, for example. mutual enhancement of effects on the cardiac conduction system of β-blockers and calcium antagonists. Often seek to use this kind of synergism between β-blockers and other antihypertensive drugs to more effectively reduce AL. On the contrary, the hypotensive effect of β-blockers decreases against the background of indomethacin and other NSAIDs (chap. 27).

Beta-blockers are widely used for arterial hypertension (Ch. 33), angina pectoris and acute coronary circulation disorders (Ch. 32), heart failure (Ch. 34). In addition, they are often used for supraventricular and ventricular arrhythmias (Ch. 35).

Myocardial infarction. Of great interest is the use of β-blockers in the acute period of myocardial infarction and to prevent repeated heart attacks.

Many trials have shown that the use of these drugs in the early period of myocardial infarction, followed by their constant intake, reduces mortality by 25% (Freemantle et al., 1999). The mechanisms of such a beneficial effect of β-blockers are not fully understood. Possibly, a decrease in myocardial oxygen demand, redistribution of coronary blood flow, and antiarrhythmic action play a role.

Short-term administration of beta-blockers seems to be much less effective. In studies on the prevention of recurrent myocardial infarction, the most convincing data were obtained for propranolol, metoprolol and timolol. Despite this, many patients who have had myocardial infarction do not receive β-blockers.

Heart failure. It is well known that β-blockers can aggravate heart failure in patients with myocardial damage, for example, with ischemic or dilated cardiomyopathy. Therefore, the assumption that β-blockers can be effective in the long-term treatment of heart failure, initially caused distrust among doctors.

Teerlink and Massie, 1999; see also chap. 34). This is an interesting example of how the preparations of a whole group, which were initially considered almost absolutely contraindicated at a certain disease, later became one of the mainstays of its treatment.

In heart failure, myocardial sensitivity to catecholamines changes. It is known that sympathetic tone is increased in such ballrooms (Bristow, 1993). In many experimental animals, administration of β-adrenostimulants can lead to cardiomyopathy. Excessive expression of β-adrenergic receptors in mice is also accompanied by dilated cardiomyopathy (Engelhardt et al., 1999).

In the myocardium of patients in experimental animals with heart failure, many changes were found in the systems of intracellular signal transmission from β-adrenergic receptors (Post et al., 1999). Almost always, a decrease in density and a violation of the function of β1-adrenergic receptors are observed, leading to a decrease in the positive inotropic effect mediated by these receptors. Perhaps this phenomenon is partly due to increased expression of the GRK2 β-adrenergic receptor kinase (Lefkowitz et al., J 2000; see also Chapter 6).

Interestingly, in heart failure, the expression of β2-adrenergic receptors is relatively unchanged. Both β1 and β2-adrenergic receptors activate adenylate cyclase through protein G „however, there is evidence that stimulation of β2-adrenergic receptors also leads to activation of protein G ,. Perhaps this last effect not only reduces the positive inotropic effect of β2-adrenoreceptor activation, but also triggers other ways of intracellular signal transmission (Lefkowitz et al., 2000). With over-expression of β2-adrenergic receptors in the heart of mice, an increase in contractility without heart failure is observed (Liggett et al., 2000).

The mechanisms by which β-blockers reduce mortality in heart failure have not been established. There is little surprising in this – the mechanisms of the hypotensive effect of these agents have not been fully clarified, and a huge number of works have been devoted to them (Ch. 33). There are several hypotheses, and all of them require experimental confirmation.

The interest in this issue is far from only theoretical: understanding the action of β-blockers in heart failure may lead to a more focused choice of drugs and to the development of new drugs with the desired effect. The differences between the function of β1- and β2-adrenergic receptors in heart failure are an example of how complex the role of adrenergic effects is in this condition.

As already mentioned, there are several hypotheses regarding the beneficial effects of β-blockers in heart failure. Firstly, an excess of catecholamines has a cardiotoxic effect, especially through β1-adrenergic receptors, and the elimination of this action can positively affect myocardial function.

Secondly, the blockade of β-adrenergic receptors can prevent post-infarction reconstruction of the left ventricle, which usually disturbs the activity of the heart. Interestingly, the activation of β-adrenergic receptors can lead to apoptosis of cardiomyocytes (Singh et al., 2000). Finally, some β-blockers can have important effects that are not related to their main effect.

Tests, including a large number of ballroom tests, have shown that with mild to moderate heart failure, some β-blockers can improve myocardial function and increase life expectancy. Reliable data from controlled trials have been obtained for many of these drugs. It is important to emphasize that beneficial action

Despite the large number of drugs that affect adrenergic transmission, and their extensive use in various fields of medicine, the development of new such drugs, both for scientific and practical tasks, is of great interest. Molecular biological studies of the expression of different subtypes and subgroups of adrenergic receptors have significantly outstripped the study of the physiological role of all these receptors in different organs.

Since it was clearly shown that all of these receptors are products of individual genes, pharmacologists faced a unique opportunity to develop new drugs that can affect different receptors in different organs or departments of the central nervous system. This will provide more targeted therapy, expand its capabilities and reduce the risk of side effects.

There are more and more new drugs that stimulate and block adrenergic receptors, but at the same time, the clinical significance of the pharmacological features of existing drugs is not always clarified. Studying the differences between different adrenergic receptors at the molecular level makes it possible to purposefully develop agents that selectively act on one or another of these receptors.

Principles for the selection of β-blockers [edit | edit code]

Currently, there are many β-blockers. They differ in selectivity for β1-adrenergic receptors, fat solubility, duration of action, internal sympathomimetic activity (including the ability to more or less stimulate β1- and β2-adrenergic receptors), α1-adrenergic blocking activity and non-adrenergic vasodilator action.

individual differences in response to β-blockers are very large. Along with the development of new drugs with new mechanisms of action, intensive clinical trials are needed to identify the benefits of such drugs in various conditions – coronary heart disease (including myocardial infarction), arterial hypertension, heart failure, etc.

Thus, it was found, for example, that carvedilol (a β-blocker with vasodilator and antioxidant activity), used as an adjunct to conventional therapy for heart failure, reduces mortality from this condition. Elucidation of the mechanisms of such a positive effect of β-blockers in heart failure can lead to the development of drugs with appropriate properties, and therefore, more effective.

With prostate adenoma, α1-blockers are increasingly being used, although comparative tests of drugs in this group are still not enough. Studies of these drugs are complicated by the fact that many subjective symptoms in prostate adenoma are mediated by α1-adrenergic receptors not of this gland itself, but, apparently, of its innervating neurons.

Theoretically, α1-blockers should be especially useful for arterial hypertension, since they have a beneficial effect on the blood lipid profile and glucose tolerance; however, in practice their benefits still need to be proven using clear criteria such as, for example, the incidence of myocardial infarction or stroke.

This question is complicated by the fact that, as recently shown, monotherapy of arterial hypertension with doxazosin often leads to heart failure than monotherapy with a diuretic. The discovery of different subgroups of α1-adrenergic receptors allows us to hope for the development of new drugs that selectively act on adrenergic receptors, for example, the prostate gland or blood vessels.

Alpha-2 adrenostimulants (e.g., clonidine) are mainly used for arterial hypertension. At the same time, the study of the physiological function of different subgroups of α2-adrenergic receptors will probably allow the development of selective stimulators of these receptors (Linket al., 1996). Such drugs, such as dexmedetomidine, may be more effective and safe as drugs used to combat pain and with general anesthesia (chap. 14). Alpha-2 adrenostimulants have shown themselves to be promising experimental remedies for ischemia of the brain and myocardium.

Features and rules of admission

If a cardiologist prescribes adrenergic blockers, you should tell him about the systematic use of prescription and over-the-counter drugs. It is necessary to notify the specialist of serious concomitant pathologies – emphysema, sinus rhythm disturbance, bronchial asthma.

To avoid adverse reactions and complications, adrenergic blockers are used in accordance with the instructions:

  • tablets are taken after meals;
  • during therapy, monitor heart rate;
  • in case of deterioration of well-being, consult a doctor;
  • therapy does not stop without the recommendation of a specialist.

Dosage and duration of treatment depend on the type of disease and are determined by the doctor. You can not combine adrenergic blockers with other drugs or alcohol. Violation of the rules for the use of β-adrenolytics is fraught with aggravation of health status.

Unwanted consequences

Adrenolytic drugs have an irritating effect on the gastrointestinal mucosa. That is why they need to be taken during or after meals. An overdose and prolonged use of β-blockers adversely affects the work of the genitourinary, digestive, respiratory and endocrine systems. Therefore, it is extremely important to observe the dosage prescribed by the doctor.

Possible side effects:

  • hyperglycemia;
  • angina attack;
  • bronchospasm;
  • decreased libido;
  • decreased renal blood flow;
  • depressive state;
  • emotional lability;
  • violation of taste perception;
  • bradycardia;
  • abdominal pains;
  • decreased visual acuity;
  • asthma attacks;
  • stool disorders;
  • sleep disturbance.

7860786054078604530860 - Long-acting non-selective beta-blockerInsulin-dependent patients should be aware of the increased risk of hypoglycemic coma while taking antidiabetic drugs and adrenolytics.

contraindications

β1- and β2-adrenolytics have similar contraindications. Drugs are not prescribed for:

  • atrioventricular block;
  • bradycardia;
  • orthostatic hypotension;
  • sinoatrial blockade;
  • left ventricular failure;
  • terminal cirrhosis of the liver;
  • obstructive pulmonary disease;
  • decompensated renal failure;
  • chronic pathologies of the bronchi;
  • vasospastic angina pectoris;
  • acute myocardial failure.

Selective adrenergic blockers are not taken in case of impaired peripheral circulation, pregnancy and lactation.

Withdrawal Syndrome and How to Prevent It

A sharp rejection of therapy after prolonged adrenergic blocking leads to withdrawal syndrome, which manifests itself:

  • arrhythmia;
  • increased heart rate;
  • angina attacks;
  • heartbeat.

The group of beta-blockers reduces the sensitivity of receptors to adrenal hormones. The body is trying to compensate for this by increasing the number of target cells for adrenaline and norepinephrine. Additionally, drugs of this group inhibit the transformation of thyroxine into triiodothyronine. Therefore, the rejection of the pills leads to a sharp increase in the blood of thyroid hormones.

To prevent withdrawal, you must:

  • gradually reduce the dose of adrenergic blockers over 1.5-2 weeks;
  • temporarily limit the load;
  • include antianginal agents in therapy;
  • limit the use of drugs that lower blood pressure.

Beta-blockers are drugs whose overdose is fraught with cardiological complications and even heart failure. Therefore, before taking pills and increasing the dosage, they must consult a doctor. Proper treatment reduces the risk of adverse reactions and unwanted consequences.

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Svetlana Borszavich

General practitioner, cardiologist, with active work in therapy, gastroenterology, cardiology, rheumatology, immunology with allergology.
Fluent in general clinical methods for the diagnosis and treatment of heart disease, as well as electrocardiography, echocardiography, monitoring of cholera on an ECG and daily monitoring of blood pressure.
The treatment complex developed by the author significantly helps with cerebrovascular injuries and metabolic disorders in the brain and vascular diseases: hypertension and complications caused by diabetes.
The author is a member of the European Society of Therapists, a regular participant in scientific conferences and congresses in the field of cardiology and general medicine. She has repeatedly participated in a research program at a private university in Japan in the field of reconstructive medicine.

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