Beta-blockers and diuretics

Without BB, which have been used in clinical practice since the 60s, it is impossible to provide treatment for a wide range of cardiac diseases, such as hypertension, coronary heart disease, heart failure, tachyarrhythmias. However, in recent years, the issue of negative side effects of BB has been widely discussed. This enabled some researchers to raise the question of restricting their use.

Back in the early 90s, based on an analysis of large-scale studies, it was suggested that the positive side effects of antihypertensive drugs may affect the effectiveness of therapy in the long term [4]. The basis of this assumption is a meta-analysis of placebo-controlled studies on the efficacy of long-term treatment of BB and diuretics from the point of view of preventing SSO [5].

As it is known, BB and diuretics were the first of antihypertensive drugs, which proved to be effective not only in terms of adequate blood pressure control, but also in reducing the risk of MTR. On the other hand, this meta-analysis showed that the existing decrease in the risk of SSO was significantly lower than expected (calculated on the basis of a decrease in blood pressure). This was especially true for CHD. AT the risk of developing coronary artery disease was only 14–16% lower than in the placebo group. Considering that coronary artery disease is the main complication of hypertension, the efficacy of treatment of BB and diuretics was considered insufficient. Among the main causes of this phenomenon were considered and the negative side effects of these classes of drugs that could level the positive effect of reducing blood pressure. The negative effects of BB and diuretics include the worsening of insulin resistance, deterioration of the lipid profile and a decrease in glucose tolerance. Thus, if the positive effect of a decrease in blood pressure competes with the proatherogenic and prodiabetogenic effect of anti-hypertensive therapy, then the risk of developing diabetes increases, and in the long run, the SSO. Further studies have shownthat other classes of drugs – calcium antagonists, ACE inhibitors, ARA are, at least, metabolically neutral. Recently completed large-scale international multicenter studies have convincingly confirmed the validity of the metabolic theory. The frequency of development of type 2 diabetes with the use of calcium antagonist – verapamil SR in an INVEST (International Verapamil SR / Trandolapril Study) study [6], and an ACE inhibitor – lisinopril in a study of ALLHAT [ 7] and ARA-losartan in the LIFE (Losartan Intervention for Endpoint reduction) study [8] was significantly lower than in the group of patients who received BB and diuretics. Moreover, a meta-analysis of 22 studies published in 2007 that included more than 160,000 patients showedthat the use of BB and diuretics is associated with a higher risk of developing diabetes than placebo. In the same meta-analysis, it was revealed that the lowest risk of developing diabetes is observed when using ACE inhibitors and ARA [9].

The subject of negative side effects of some BB (mainly atenolol) and diuretics is currently being used by some scientists to limit their use in clinical practice. For example, a number of authors propose to completely remove BB from the arsenal of drugs used to treat patients with uncomplicated hypertension, leaving this class of drugs only for the purposes of secondary prevention of diseases [10]. Experts of the British recommendations for the treatment of hypertension, issued in 2006, went further than that in this regard. In them, they recommend using BB as a fourth-line treatment for treating hypertension [11]. How to be a practical doctor in this situation?

The recent criticism of the BB by individual researchers should not be misleading as a practical doctor. He should always ask himself what kind of BB are we talking about. Indeed, a number of BB, especially non-selective, have negative metabolic effects and in a number of clinical situations (metabolic disorders, COPD, peripheral atherosclerosis) cannot be used. At the same time, modern superselective BBs do not have these negative effects and can be widely used in clinical practice, including those with uncomplicated AH.

Thus, regarding the use of BB in clinical practice, it is necessary to take a flexible position. This is the opinion of experts from the European and Russian recommendations for the treatment of diagnosis and treatment of hypertension. These documents noted that modern BB have a less pronounced negative effect on metabolism. This number of BB includes, as is known, metoprolol, nebivolol, bisoprolol, carvedilol.

For example, bisoprolol has a solid evidence base regarding its metabolic neutrality: lack of influence on the lipid and carbohydrate profile. Moreover, in a recent randomized study in 92 patients with hypertension and compensated type 2 diabetes, bioprolol, like captopril, did not adversely affect glycated hemoglobin, fasting sugar and 2 hours after the glucose tolerance test.

Of particular interest is nebivolol with additional vasodilating effect by increasing the synthesis of NO. First of all, it should be noted good antihypertensive efficacy and tolerance of nebivolol. It has a prolonged effect and at the same time provides uniform control of blood pressure throughout the day, which is the most important requirement of modern antihypertensive therapy. This is evidenced by the 90% value of the ratio of the residual hypotensive effect to the maximum (T / P). The data of foreign and domestic studies convincingly demonstrate the improvement of endothelial function in the treatment of people with hypertension with nebivolol [95-97].

Moreover, in our own open-label study, in 25 patients with mild and moderate hypertension, positive microcirculatory effects of Nebivolol (Nebilet, Berlin-Chemie, Germany) were revealed. The study of microcirculation was carried out using laser Doppler flowmetry on a LAKK-01 apparatus by Lazma, Russia. Laser Doppler flowmetry (LDF) is a simple and safe method for studying microcirculation and indirect assessment of endothelial function. The method allows to investigate changes in blood flow in the microvasculature using laser radiation, using the Doppler effect. The LDF method is objective, accurate and gives reproducible results.

The most important parameters for assessing the state of microcirculation are the microcirculation index (PM) and the capillary blood flow reserve (RCM). PM is formed as a result of the reflection of a laser signal from erythrocytes moving at different speeds in the arterio- lar, capillary and venu- lar parts of the microvasculature. The decrease in PM occurs with spasm bringing reduction of the number of functioning capillaries and desolation of the arteriolar microcirculation link (MC), or with a decrease in the speed of red blood cells, i.e., with symptoms of stasis. An increase in PM occurs when the arterioles tone decreases and the blood supply in the microcirculation system increases. PM is calculated in perfusion units (perf. Units). RSC, expressed as a percentage, is calculated by the ratio of the maximum PM to the initial PM. RCC reflects the microvascular reactivity. A decrease in RSC is observed both with an increase in the inflow into arterioles and an increase in the number of functioning capillaries, as well as with stasis and stagnation. An increase in RSC is noted in spastic phenomena, when initially the majority of microvessels are in a non-functioning state,but retains the ability to expand in response to stress (in this case, clamping the cuff). The parameters of PM and RSC are determined by the hemodynamic type of microcirculation, which is an integral indicator for assessing the functional state of microcirculation. Normocirculatory, spastic, hyperemic, and congestive-stasis hemodynamic types of microcirculation are distinguished.

After Nebilet therapy in the group of patients with spastic type of MC (14 people), there was a marked increase in the microcirculation index. PM before treatment was 3.4 ± 0.3; after treatment – 7.2 ± 0.8 perf.ed, p <0.05. This indicates an improvement in blood flow in the microcirculation system. This is also evidenced by the dynamics of the RSC. As a result of treatment, the initially elevated RCC decreased by 30.6% (p <0.001). These changes indicate a decrease in spastic phenomena, an increase in the number of functioning capillaries and an improvement in tissue perfusion.

In patients with hyperemic type of MC (8 people) while receiving Nebivolol there was a decrease in PM from 7.2 ± 1.1 perf. units up to 4.0 ± 0.6 perf. units (p <0.05). In this case, a decrease in PM can be regarded as a positive moment since this indicates a decrease in the phenomena of hyperemia. In addition, in this group of patients, there was an increase in the initially reduced RCC by 36.8% (p <0.001). This may be due to a decrease in excess blood filling in the arteriolar circuit of the ICR. Thus, the use of Nebivolol led in general to an improvement in the microcirculation system in patients with AH. Of course, the positive microcirculatory effects of Nebilet are a consequence of the vasodilating properties of this drug.

Thus, the emergence of super-selective beta-blockers significantly expanded the boundaries of their use, and the practitioner should be more boldly prescribed in various clinical situations, including in the case of the metabolic syndrome and diabetes.

The same ambiguous approach is necessary when prescribing diuretics in clinical practice. Appointment of diuretics, of course, requires consideration of their negative metabolic effects, especially characteristic of high doses [17]. However, in some situations it is necessary to be guided by clinical expediency. Diuretics have been and remain indispensable means of treating hypertension complicated by CHF. In hypertension and concomitant renal failure, the appointment of loop diuretics is indicated. In these situations, diuretics can be given in high doses, since the clinical relevance outweighs the risk of exacerbating metabolic disorders. However, with uncomplicated hypertension, especially in the presence of concomitant metabolic disorders, it is better to avoid prescribing high doses of thiazide diuretics because of the increased risk of diabetes, as was shown in large-scale studies. The same applies to patients with hypertension and diabetes,since the use of high doses of diuretics may increase the risk of developing vascular complications. In these situations, it is better to use a metabolically neutral indapamide. In addition, thiazide diuretics in low doses do not adversely affect metabolism, but they enhance the effects of almost all classes of antihypertensive drugs.

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