Treatment of an arterial hypertonia: blockers b-adrenoreceptors

In 1948 Ahlquist has described existence a - and b - adrenoreceptors. In 1958 there was a first report on possibility by means of pharmacological agents to quench b - adrenoreceptors. It is possible to consider as the beginning of clinical application of b-blockers 1964 when article B has been published. Prichard and P. Gillam about treatment of an arterial hypertonia by propranolol. In many countries b - adrenoblockers are preparations of the first row for treatment of an arterial hypertonia, and for the first time it has been noted in methodical references a WHO. Now at the disposal of clinicians there is a wide choice of preparations of this bunch which differ on the pharmacological and pharmacokinetic properties.

Pharmacological properties

Till now there is no standard classification b - adrenoblockers. Usually them part on bunches depending on their selectivity, presence intrinsic sympathomimetic, a membrane of stabilising and vasodilate activity.

Selectivity

It is accepted to part b - adrenoblockers depending on ability to quench only b1 - or b1 - both b2-receptors on selective and not selective, thus expression of selectivity at preparations considerably varies. So if to accept an ability interrelation to quench b1 b2-receptors at propranolol for 1 for metoprolol this interrelation will compound 6, for atenolol - 9, a bisoprolol (Concor) - 12. However it is necessary to consider, that such selectivity is relative, as in tissues receptors of both types usually contain, but one of kinds prevails only, besides, b-adrenoblokatory react on both types of receptors, but on one of them is stronger. Therefore at application of the big doses selectivity implication can decrease. The cardioselective provides therapeutic effect not so much, how many can reduce expression undesirable and by-effects.

Particulate agonistic effect (intrinsic sympathomimetic activity)

Some b-adrenoblockers, quenching action of connatural agonists, possess ability to suscitate b1 - and-or b2-receptors. It causes features of action of such preparations on heart and pots. They do not reduce warm outlier, frequency of warm reductions (FWR), renin level in blood. At their application the bronchospasm, metabolic disturbances and deterioration of peripheric blood supply are to a lesser degree expressed. Besides, at their application there is an appreciable depression of density of b-adrenoreceptors, therefore at the subitaneous termination of therapy the withdrawal can be less expressed, than at use of the preparations which do not have intrinsic sympathomimetic activity. At the same time do not recommend to use preparations with intrinsic sympathomimetic activity at treatment of the patients having a combination of a hypertonia and an ischemic heart disease (IHD) as they have no cardioprotective properties, are not capable to prevent subitaneous mors from arrhythmias.

So, in particular, in research IPPPSH (International Prospective Primary Prevention Study of Hypertension) it is not taped any advantages of Oxprenololum in comparison with other kinds of therapy concerning primary preventive maintenance of cardiovascular complications at 6357 patients at the age of 40-64 years.

Vasodilate effect

Some preparations, besides b-adrenoblokirujushchih properties, possess ability to quench and a-adrenoretseptory. The last not only provides more expressed depression of arterial pressure (AP) at the expense of depression of a tonus of a smooth musculation of pots, but also reduces expression of by-effects.

Membranestabilizing effect

The membranestabilizing effect causes antiarrhytmic properties of b-adrenoblockers. Expression of this effect does not correlate with antihypertensive action. Moreover, the sotalol which is the most effective antiarrhytmic preparation, does not render significant influence on AP. The account membrane stabilising effect is necessary for a choice of this or that preparation in certain clinical situations.

Bioavailability

Bioavailability (quantity of active material which is soaked up from a place of introduction from the medicinal form, reaching a system blood flow, whence it will arrive to a scene of action and will give the effect) at preparations of a type of propranolol low (10-30 %), and at preparations of a type of a betaxolol, a bisoprolol, a penbutolol, Pindololum high (reaches 80-100 %).

Differences in bioavailability depend on many causes. One of them is a presence of effect of primary transit through a liver (ability of preparations to be metabolized by a liver in the course of an absorption with formation of active or inactive metabolites), characteristic basically for lipophilic preparations. If metabolites are inactive and nontoxic, it has no clinical value if metabolites are active, as, for example, at propranolol, acebutolol their activity should be considered at an assessment of total action of a preparation.

Deducing pathes

Lipophilic preparations (propranolol) are deduced mainly by a metabolism in a liver, and hydrophilic (atenolol) - nephroses. According to these data doses should be corrected at a lesion of a liver for lipophilic preparations and at a lesion of nephroses for the hydrophilic. It is necessary to consider, that the clearance of materials through nephroses with the years can variate and arise necessity of reduction of doses of hydrophilic preparations. At the same time some preparations (a bisoprolol, acebutolol, Pindololum) are capable to be deduced both through a liver, and through nephroses. Thus, depression of functional capacity of one of systems influences their deducing less, and their application can be in some cases more preferable.

Lipophily

Ability to solve in Adeps defines preparation possibility to inpour through a blood-brain barrier. It can render double effect. On the one hand, it causes appearance of such undesirable effect as depression, with another - congenial an effect can have on the vagus nerve centres in a brain and reduce frequency of lethal outcomes at patients IHD which has tolerated a myocardial infarction, caused by arrhythmias.

Some of preparations are highly lipophilic (propranolol, a penbutolol), moderately lipophilic (metoprolol, Timololum, Oxprenololum, a bisoprolol), some - highly hydrophilic (atenolol, a sotalol), some - moderately hydrophilic (a betaxolol, acebutolol, Pindololum).

So, not selective lipophilic preparation propranolol really worsens quality of life of men with an arterial hypertonia, and hydrophilic selective atenolol enriches it. Recently believe, that the lipophily is faster not, and absence of selectivity can define these undesirable effects from party CNS. New slowly liberated forms of preparations render is essential smaller side effect, do not cause the expressed fluctuations of concentration in a blood plasma, and effects from party CNS are more caused by value of the maximum concentration, than its average level. It is not taped differences in overall health and subjective symptoms at patients with an arterial hypertonia, treated two selective preparations - hydrophilic atenolol and lipophilic metoprolol in the medicinal form with controllable liberation.

Such factors can influence kinetics of highly lipophilic preparations, as smoking, reception of other preparations causing an induction (rifampicin, phenobarbital, Phenytoinum) or inhibition (Cimetidinum) of metabolizing enzymes of system of cytochrome Р-450, accelerating or slowing down accordingly their deducing. These factors do not render or have insignificant influence on kinetics of hydrophilic, moderately hydrophilic and moderately lipophilic preparations that does not demand updating of their doses.

The mechanism of antihypertensive action of b-blockers is combined and ambiguous at different preparations. However all of them lead more or to less expressed depression of warm outlier at the expense of negative inotropic (contractility depression) and negative chronotropic (depression FWR) effects. It is important, that arising thus, especially in the therapy beginning, peripheral resistance rising (PR) is always expressed essential less, than should be for the given size of warm outlier, as provides depression AP. At long therapy expression of rising PR becomes still smaller or in general disappears.

These hemodynamic effects are caused by ability of preparations to quench renin liberation and in this connection to reduce angiotensin and Aldosteronum secretion, to raise sensitivity of baroreceptors of a carotid sine and an aortic arch, to reduce liberation of Noradrenalinum from the terminals of postganglionic sympathetic nerve fibrils, to reduce activity of vasomotor centres of a brain (lipophilic preparations).

The important difference from other antihypertensive preparations is ability of b-adrenoblockers to reduce expression of gain AP and FWR in reply to an exercise stress and other stressful influences. It allows to enlarge a chronotropic and inotropic reserve of heart, considerably to lower requirement of a myocardium for oxygen that leads to augmentation of physical effeciency of patients and reduction of expression of the ischemic changes caused by an exercise stress. This property of b-adrenoblockers gives advantage before other preparations in respect of their use for sick of a stenocardia.

Results of clinical application

Despite differences of the pharmacological properties described above, practically all b-adrenoblockers effectively reduce AP. It is theoretically possible to believe, that not selective preparations reduce AP is less expressed at the expense of available blockage of b2-adrenoreceptors and larger growth PR, and the preparations possessing besides b-blocking also a-blocking activity, have more expressed hypotensive an effect.

Expression of effect of preparations usually depends on their dose. So, for example, in 2-3 months of treatment at patients with an easy and moderate arterial hypertonia a bisoprolol (Concor) in a daily dose of 5 mg AP decreased on 10-12 %, in a dose of 10 mg - on 14 %, and in a dose of 20 mg - on 18-20 %, it was enlarged as well number of patients with a positive effect (depression diastolic AP less than 90 mm hg).

Similarly and for Carvedilol effect intensifying is observed at rising of a dose of a preparation, but noticed, that effect increase is is essential more expressed at augmentation of a dose with 12,5 to 25 mg, than with 25 to 100 mg a day.

Believe, that the modern hypotensive preparation should have long enough an effect and give effect at 1-2-кратном reception. It is caused by that necessity of more frequent receptions reduces adherence of the patient to treatment and conducts to therapy discontinuing. For b-adrenoblokatorov it has also the special value because rests in treatment can lead to a withdrawal - to an exacerbation of attacks of a stenocardia, up to development of an acute myocardial infarction, a hypertensive crisis, rhythm disturbance.

The majority of preparations of this bunch is given by enough long-term effect and possibility to supervise AP at 1-2-кратном reception (tab. 2 see). Duration of action of a bisoprolol, a betaxolol and metoprolol exceeds atenolol action, and Carvedilol - metoprolol. b-adrenoblokatory do not break circadian rhythm AP at sick of an arterial hypertonia.

For augmentation of hypotensive effect of b-adrenoblockers they can be combined with preparations of other bunches. The rational combination of various bunches of preparations can enhance their cardioprotective properties and reduce expression of undesirable effects. b-adrenoblokatory it is preferable to combine with diuretics, antagonists of calcium (nifedipine, an amlodipine, a felodipine), a-adrenoblokatorami, and also with agonists I1-imidazolinovyh of receptors.

Less expedient combination to inhibitors of angiotensin-converting enzyme (ACE) or antagonists of receptors of angiotensin II. Do not use a combination of b-adrenoblockers to verapamil or diltiazem because of possible intensifying of a negative inotropic effect and retardation of atrioventricular conductivity. It is necessary to remember, what even at the conventional congenial combination of b-adrenoblockers to diuretics they can potentiate undesirable effects on a lipide, carbohydrate and purine exchange, and also cause sex disorders.

At a choice of a medicinal preparation for treatment of an arterial hypertonia it is important not only to reduce its ability AP, but also possibility to reduce risk factors of flow, advance and disease failures.

The left ventricle hypertrophy is one of the factors promoting risk of development of disturbances of a rhythm of development IHD, arrhythmias and mors sick of an arterial hypertonia. Unfortunately, the big prospective researches concerning ability of b-adrenoblockers to reduce a left ventricle hypertrophy are not present till now. Metaanalysis of 109 publications in which the effect of treatment of 336 patients is estimated, has shown, that at long therapy by b-adrenoblockers the left ventricle mass decreases approximately for 9 %, i.e. 0,9 gramme on depression of 1 mm hg average AP that is close to effect of antagonists of calcium and twice less, than action of inhibitors ACE. At application highly selective it is long a reacting preparation of a bisoprolol specify, that the left ventricle mass decreases is more expressed (on 14,5 %) mainly at the expense of depression of a thickness of sides without essential change of size of an enddiastolic volume.

Some b-adrenoblockers can worsen function of nephroses owing to depression of warm outlier and a renal vasoconstriction. But in most cases b-adrenoblokatory are neutral concerning function of nephroses even at its depression. However, in comparison with inhibitors ACE enalapril metoprolol has considerably more expressed an effect on depression of size of a glomerular filtration at patients with a diabetic nephropathy. At the same time Carvedilol does not cause change of a renal hemodynamic, a glomerular filtration that can be caused simultaneous depression PR and vascular resistances of nephroses. The preparation is capable to reduce number of patients with a microalbuminuria by 60 % while at treatment by atenolol the number of such patients is enlarged. Believe, that antiproliferative properties (reduction of a proliferation of smooth muscle cells of pots and mesangial cells of glomuluses of nephroses), described for Carvedilol, play the important role in its rhinoprotect action.

Clinical advantages and use in the special bunches of patients

In references the WHO on conducting sick of an arterial hypertonia is underlined, that b-adrenoblockers are preparations of a choice for sick of the arterial hypertonia combined with a stenocardia, after the tolerated myocardial infarction and at tachyarrhythmias.

Advanced age

Application of b-adrenoblockers at elderly is not pathogenetically proved as with the years there is a hypokinetic type of a circulation is more often. Besides, the frequent combination at this contingent sick of an arterial hypertonia with other diseases (chronic obstructive diseases of lungs, an atherosclerosis of the inferior extremities) confines application of b-adrenoblockers.

However at least 3 large researches in which b-adrenoblockers in a combination or without diuretics have been used, have shown, that at older persons this kind of therapy leads to depression of frequency of strokes and infarcts and is well enough tolerated by them.

At comparison of expression of hypotensive effect, for example a bisoprolol (Concor), at young (60 years are younger, middle age of 50,5 years) and older persons (is more senior 60 years, middle age 72 years) significant differences are not received, and percent of the patients who had a positive effect, was a little big among elderly, than at young, - 83,8 both 76,1 accordingly, and larger number of patients answer low doses of a preparation: 60 and 53,7 % accordingly. At the same time frequency of by-effects essential does not differ.

By us also it is shown, that the betaxolol has expressed enough hypotensive an effect at elderly, is frequent for achievement of effect it smaller doses, than young are necessary. The preparation does not render an essential side effect, in particular does not cause obstruction of respiratory tracts.

Similarly and for Carvedilol frequency of hypotensive effect at elderly and young men is identical - 84 %, and doses are necessary for achievement of hypotensive effect a little smaller - 25 mg.

Heart failure

Earlier was considered, that application of b-adrenoblockers at a heart failure is contraindicative because of depression of contractile ability of a myocardium. However the researches carried out in last years have shown, that some of these preparations at skilful use not only do not worsen pump function of heart, but can result and in its enriching. At long therapy note augmentation of fraction of outlier even at patients with initially expressed symptoms of a heart failure. Now only 3 preparations are recommended to use at patients with a heart failure - selective blockers metoprolol and a bisoprolol, not selective preparation with a-blocking and antioxidatic effect Carvedilol. The success of application at a heart failure is provided with very slow gradual titration of preparations from very small doses. The initial dose карведилола compounds 6,25 mg 2 times a day, a bisoprolol - 1,25 mg a day. The titration season should compound not less than 4-6 weeks or to be is essential big before achievement of as much as possible transferable or recommended dosages. Appointment the big doses can lead at once to appreciable disorder of a hemodynamic and an aggravation of symptoms of patients. It is necessary to begin therapy by b-adrenoblockers already against stabilisation of a condition of patients by means of inhibitors ACE and diuretics. In case of good shipping at patients with a heart failure it is possible to receive appreciable effect concerning depression of the general mortality, frequency of subitaneous morses and hospitalisation.

By-effects

B-adrenoblockers reduce contractile ability of a myocardium up to development of clinically expressed circulatory unefficiency. At an overdosage of b-adrenoblockers and sharp deterioration of contractility of heart introduce Isoproterenolum or a glucagon.

At a bradycardia it is necessary to apply black cherry preparations, atropine Zinci sulfas, an orciprenaline. b-adrenoblokatory slow down atrioventricular conductivity, cause a chilliness of extremities, intensifying of the Raynaud's syndrome, alternating lameness.

The bronchospasm noted at reception of b-adrenoblockers, is taken out by inhalations bronchial spasmolytic and intravenous introduction of Theophyllinum.

In case of drowsiness, weariness, depressions if necessary it is possible to continue treatment, however it is necessary to avoid appointment of lipophilic preparations and to use preparations with controllable liberation.

Influence on an exchange of lipids

Not selective b-adrenoblokatory raise the maintenance in blood of triglycerides (30-40 %), in some cases cholesterol, its atherogenous fractions - low-density lipoproteins (LDL), reduce the maintenance of antiatherogenous fractions of cholesterol - high density lipoproteins (HDL) (approximately on 5-20 %). These effects are considerably less expressed at the preparations possessing cardioselectivity (a bisoprolol, metoprolol), and practically are absent at preparations with intrinsic sympathomimetic activity (acebutolol) or with vasodilate properties (Carvedilol).

Influence on carbohydrate metabolism

Use of not selective b-adrenoblockers at patients with achrestic diabetes is undesirable. In connection with that that the exit of a glucagon and a glycogenolysis is mediated through b2-adrenoreceptors, their blockage can enlarge risk of occurrence of a hypoglycaemia, difficulty of an exit from it and development of a hyperosmolar coma. b-adrenoblokatory can mask clinical implications of a hypoglycaemia - a tremor and a tachycardia (blockage of b1-adrenoreceptors, action on CNS), that detains and complicates diagnostics. Besides, at application of not selective preparations (elimination of counteraction to effect of a-receptors) during a hypoglycaemia can educe a hypertensive crisis and a sharp vasospasm.

Selective preparations do not possess these adverse effects and can be used for treatment of an arterial hypertonia at sick of diabetes. However at predilection to hypoglycemic conditions it is necessary to avoid their appointment. At a part sick of diabetes the metabolism of b-adrenoblockers can be lowered and the season of their action that demands depression of doses is extended.

Insulinresistance it is often taped at an arterial hypertonia and can render variety of adverse effects in disease advance. So, the hyperinsulinemia causes augmentation of a reabsorbtion of sodium, activation of sympathoadrenal system, disturbance of transmembrane transport of cations with augmentation of concentration of the intracellular calcium causing the raised tonus of pots, stimulation of the growth factors leading to a thickening of an inside layer of pots with narrowing of their lumen.

Unfortunately, the majority of b-adrenoblockers worsen or do not influence on insulinresistance at sick of an arterial hypertonia. The Carvedilol as a preparation possessing a-adrenoblokirujushchej activity, can enrich some sensitivity of tissues to insulin. b-adrenoblokatory can raise level of urinary acid in blood.

Contraindications and precautions at use of b-adrenoblockers

Contraindications to appointment of b-adrenoblockers are chronic obstructive diseases of lungs, a bronchial asthma and atrioventricular block II-III of degree. It is necessary to be careful at presence at patients of a lesion of peripheric pots, a bradycardia and a heart failure. It is not recommended to prescribe b-adrenoblockers to persons at serious physical work and to sportsmen.

In summary it is necessary to notice, that it is necessary to carry long experience of their use, validity to clinical advantages of b-adrenoblockers in respect of depression of frequency of cardiovascular complications and a mortality at an arterial hypertonia, good shipping of representatives of new generations of this class. A number of new preparations (a bisoprolol (a Concor), a betaxolol, nebivolol) possesses high selectivity or additional vasodilate and antioxidatic (Carvedilol) properties in a combination to a congenial pharmacokinetic profile, especially at medicinal forms with the slowed down controllable liberation, and can be reliable, safely and is predictedly used for treatment sick of an arterial hypertonia.