Clinical use of fixed combinations of antihypertensive drugs

Clinical use of fixed combinations of antihypertensive drugs

Currently, the issues of rational pharmacotherapy and the optimal choice of drugs for various diseases are of particular relevance, including cardiovascular diseases (CVD), which remain the leading cause of mortality throughout the world. The number of people with diseases of the cardiovascular system (CVD), according to modern foreign sources, exceeds 100 million. Every year, 16.7 million people worldwide die from CVD, and in almost 50% of cases the cause of death is coronary heart disease (CHD) and almost in 30% of cases - cerebral stroke (MI) [1]. Among CVDs, the most common is arterial hypertension (AH). It is this problem that practitioners most often have to deal with, and it is this that is a serious prognostic risk factor (RF) for the development of myocardial infarction (MI), MI, chronic heart failure (CHF), general and cardiovascular mortality [2].

In this regard, the issues of rational pharmacotherapy and optimal choice of drugs for CVD are of particular relevance. Based on evidence-based medicine, treatment algorithms for various CVDs are being actively developed. They are reflected in international and national clinical guidelines. The use of clinical recommendations in the practical work of a doctor undoubtedly helps to improve treatment results and prognosis for CVD [3, 4].

However, often prescribing optimal therapy is a difficult task, especially in the context of the expansion of the pharmaceutical market and the emergence of a large number of more and more new drugs (drugs), as well as due to the increasing prevalence of comorbid conditions, which in many ways complicate the implementation of drug therapy and require special close attention to monitoring the effectiveness and safety of drugs. As practice shows, the degree of compliance of the pharmacotherapy with accepted recommendations in real clinical practice remains quite low both in our country and abroad [5, 6].

In 2013, new recommendations of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) for the treatment of hypertension were issued [7], as well as Russian recommendations “Diagnostics and treatment of arterial hypertension” [8 ], which are the basis for the selection of rational pharmacotherapy for hypertension by doctors of all specialties. The main goal of treatment of patients with hypertension is to minimize the risk of developing cardiovascular complications (CVD) and death from them. To achieve this goal you need:

• reducing blood pressure (BP) to the target level;
• correction of all modifiable risk factors (smoking, dyslipidemia, hyperglycemia, obesity);
• prevention, slowing the rate of progression and/or reducing target organ damage;
• treatment of associated and concomitant diseases (coronary artery disease, diabetes mellitus, etc.).

Choice of pharmacotherapy

Currently, five classes of antihypertensive drugs with a proven effect on the degree of cardiovascular risk and no significant differences in the severity of the antihypertensive effect are recommended for the treatment of patients with hypertension:

• angiotensin-converting enzyme inhibitors (ACEIs);
• angiotensin II receptor blockers (ARBs);
• beta-blockers (BAB);
• calcium antagonists (CA);
• thiazide diuretics.

Each class has its own application features, advantages and limitations associated with the possibility of developing undesirable reactions.

The large arsenal of available drugs makes it extremely important and at the same time difficult to select specific drugs, and the differentiated choice of drugs remains a pressing problem for practicing physicians at the present time. This is especially true for patients who have additional risk factors and concomitant diseases, which, on the one hand, worsen the prognosis for hypertension, and on the other hand, limit the use of a number of antihypertensive drugs. Pharmacotherapeutic approaches to the treatment of patients with hypertension with concomitant risk factors and associated diseases require an integrated approach that makes it possible to influence not each disease separately, but the patient as a whole.

Of course, each patient requires serious thought and analysis of the characteristics of his clinical situation, and taking this into account, one or another class of drugs should be chosen. Recommendations summarizing the evidence base for all classes of antihypertensive drugs can be of great help to the practitioner at this stage. It is reasonable to consider certain drugs to be preferred for specific situations because they have been used in those situations in clinical trials or have demonstrated superior efficacy for specific types of target organ damage.

Adherence to treatment

When discussing the problem of rational pharmacotherapy of hypertension, one cannot help but dwell on its very important aspect - the low effectiveness of treatment of hypertension and failure to achieve target blood pressure (BP) values. This is explained by various factors, not the least of which is the low adherence of patients with hypertension to treatment. This is evidenced by the results of clinical and epidemiological studies conducted both abroad and in our country. Thus, according to various researchers, up to 50% of patients with hypertension independently stop treatment prescribed by a doctor [9, 10]. Low adherence to treatment is also evidenced by the results of the Russian multicenter study RELIF (Regular Treatment and Prevention), conducted in the Central and Northwestern Federal Districts, which showed that 58.2% of patients with hypertension take medications only when their blood pressure increases. Of these, 63.6% do not take drugs every day, 39.7% stop treatment after normalization of blood pressure, 32.9% skip doses due to forgetfulness, and only 3.3% do not skip medications [11].

Basic concepts of adherence to treatment

Adherence to treatment refers to the compliance of the patient's behavior with the doctor's recommendations, including taking medications, diet and/or lifestyle changes. Adherence to treatment involves concepts such as retention in therapy (persistence) and compliance.

Retention on therapy is determined by the length of time a patient receives drug therapy and is measured by the number of days a patient receives therapy or the percentage of patients who remain on treatment over a given period.

Compliance is an indicator of adherence to drug therapy (compliance with the dose, frequency and regimen). Compliance is assessed by the drug use index, which is the quotient of the number of days of taking the full dose of the drug (or its amount given to the patient) by the duration (in days) of the entire study (observation) period. Achieving 100% adherence seems to be the ideal goal, but this is difficult to achieve with any chronic disease. If the drug utilization index reaches 80% or more, compliance is considered acceptable.

In order to increase the information content of patient surveys regarding adherence to treatment, specialized questionnaires and scales for assessing adherence are being created. They, as a rule, include not only questions directly related to compliance with recommendations for taking medications and non-drug treatment methods, but also questions of a general psychological nature regarding the patient’s readiness to interact, responsibility, follow advice, etc. Some of these scales have now been validated and recommended for widespread use.

The simplest test for assessing compliance is the Morisky-Green test, consisting of four questions:

1. Have you ever forgotten to take your medications?
2. Are you sometimes inattentive to the hours of taking medications?
3. Do you skip taking medications if you feel well?
4. If you feel unwell after taking medication, do you skip the next dose?

Patients who score 4 points are considered compliant, and those who score less than 3 are considered non-compliant [12]. Using this simple and accessible method will help the practitioner pay attention to those patients who need additional attention in order to increase their compliance.

What are the ways to increase patients' adherence to treatment?

Today there is no single effective strategy for increasing compliance, however, when talking about the impact on treatment adherence, two main aspects should be kept in mind.

The first, concerning the patient’s actual adherence to the doctor’s recommendations, primarily depends on the motivation for treatment. In this aspect, the main efforts should be aimed at creating this motivation, which, first of all, requires establishing contact with the patient and training him. A number of authors and groups of experts, based on large analytical reviews of the literature, emphasize a fundamental change in the very approach to patient participation in the treatment process and more active involvement in medical decision-making. In their opinion, without the active participation and desire of the patient to be treated, it is difficult to achieve solutions to short- and medium-term, and even more so long-term problems.

It has also been proven that patients do not tend to follow doctor’s recommendations if they are not informed about their disease and its complications. Therefore, in this aspect, the main efforts should be aimed at creating a stable and high-quality doctor-patient relationship, at providing the patient with complete information about the disease and its complications in order to create motivation for strict and regular implementation of preventive measures and taking medications.

One of the ways to form a “doctor-patient” partnership is to educate patients, in particular in health schools for patients with hypertension, which essentially represent a medical preventive technology based on a combination of individual and group influence on patients and aimed at increasing the level of their knowledge, awareness and practical skills for the rational treatment of hypertension, increasing patient adherence to treatment and preventing complications of the disease, improving the prognosis and improving the quality of life.

The second aspect of adherence to therapy is the actual daily intake of drugs without significant deviations from the dose and regimen. This aspect can be significantly improved by simplifying the treatment regimen itself and introducing special techniques to help the patient not miss the next dose.

The need to use combination therapy for hypertension

The key point of modern antihypertensive therapy is combination therapy using rational combinations of drugs, which allows not only to achieve the target blood pressure level without reducing the quality of life of patients with hypertension, but also to reduce the risk of developing cardiovascular complications.

The results of a meta-analysis of large-scale clinical trials in recent years strongly suggest that to achieve target blood pressure and reduce cardiovascular risk (CVR), most patients need to be prescribed multiple antihypertensive drugs [13]. Combination therapy, in fact, is currently a priority in the treatment of patients with hypertension, which is reflected in the new European and Russian guidelines on hypertension [7, 8]. Combinations of two or more antihypertensive drugs are recommended to be prescribed to patients already at the stage of initial therapy, primarily to patients with high cardiovascular risk, i.e. patients with three or more risk factors, with subclinical target organ damage, as well as those with there are already associated clinical conditions.

Carrying out combination therapy for patients with hypertension seems justified and justified also due to the fact that, according to the mechanisms of development and formation, hypertension is a multifactorial disease, and the combination of drugs with different mechanisms of action, complementary to each other, makes it possible to optimally influence the various pathogenetic mechanisms of hypertension. A rational combination of drugs involves the use of drugs from different classes with different mechanisms of action in order to obtain an additional hypotensive effect and reduce the risk of adverse events. The combination of drugs with different mechanisms of action can also reduce changes in tissues, differently affecting the mechanisms of damage to target organs: the heart, blood vessels and kidneys.

Fixed drug combinations - a path to improving patient adherence

Increasing adherence to antihypertensive therapy is one of the most realistic ways to increase its effectiveness. Obviously, compliance with recommendations can only be achieved through cooperation between the doctor and the patient, which is largely achieved through detailed and at the same time accessible informing the latter about the purpose of treatment for hypertension.

The use of fixed combinations of antihypertensive drugs, which have become increasingly widespread in recent years, can also help improve adherence [14]. Clinical studies have shown that fixed combinations of small doses of antihypertensive drugs belonging to different classes are more effective than the use of the same drugs alone. Fixed combination drugs, for the creation of which improved dosage forms are used, are of great importance for rational pharmacotherapy. The advantages of fixed drug combinations are ease of prescription and dose titration, increased treatment efficiency and more frequent achievement of target blood pressure, convenience for the patient, improved patient adherence to treatment, as well as pharmacoeconomic advantages - improved cost/effectiveness ratio. The widespread use of fixed combinations of drugs already at the initial stage of treatment is a priority trend in the rational pharmacotherapy of hypertension today.

The advantages of fixed combinations are that they allow you to simultaneously influence different parts of the pathogenesis of hypertension. As a result, this approach to treatment makes it possible to achieve a more pronounced hypotensive effect compared to the use of monotherapy with drugs included in the combination drug, especially in cases where one of them sufficiently completely blocks the activation of counter-regulatory mechanisms caused by the action of the other component. This often eliminates the need to use high doses of individual drugs.

An important advantage of the use of fixed-dose combination antihypertensive drugs is improved patient compliance with the prescribed treatment regimen.

Most patients do not take medications regularly and often stop treatment for several days. Even in cases where patients take prescribed antihypertensive drugs, they do not always do so at the prescribed time. In a special study using electronic devices, it was shown that in 25% of patients, the time of taking the drug was 6 hours different from the one prescribed by the doctor. The greatest deviations from the prescribed therapy regimen are observed in cases where the drug dosage regimen is too complex or significant adverse drug reactions occur. Reducing the number of tablets taken daily to lower blood pressure is considered an important advantage of fixed-dose combinations. Moreover, if a combination drug has to be taken 2 times a day, the degree of compliance with the prescribed therapy regimen decreases, so preference is given to drugs that are effective when taken once a day.

To date, a large evidence base has been accumulated in the world to study the effectiveness, tolerability, benefits in terms of the effect on the state of target organs and cardiovascular indicators of various two-component combinations of antihypertensive drugs.

One of the relatively new combination drugs is the drug Concor AM, which is a fixed combination of a beta blocker (bisoprolol) and a dihydropyridine AK (amlodipine). Each of these drugs has been used in clinical practice for a long time and has a large evidence base.

Over the past 50 years, beta blockers have taken a strong position in the pharmacotherapy of the most common CVDs, and it is no longer possible to imagine modern cardiology without them. A large evidence base has made it possible to include this class of drugs in almost all modern recommendations - for the treatment of hypertension, coronary artery disease, and heart failure. They reduce the risk and frequency of CVD, have a positive effect on the clinical manifestations of the disease and improve the quality of life of patients with various CVD, as well as with concomitant pathology [7, 8].

The basis for the widespread use of beta blockers was the identification of the role of chronic hyperactivation of the sympathoadrenal system (SAS) in the development of endothelial dysfunction, left ventricular hypertrophy, malignant heart rhythm disorders and the progression of chronic heart failure. BBs are a very heterogeneous group of drugs in their pharmacological effects, within which there are significant differences in pharmacokinetics and pharmacodynamics regarding two main indicators - cardioselectivity and lipophilicity. A common property of all beta blockers is competitive antagonism of β1-adrenergic receptors. Along with blocking β1-adrenergic receptors, beta-blockers can also block β2-adrenergic receptors.

Experience in the clinical use of beta blockers in the treatment of hypertension indicates that they, especially β1-selective drugs, have fairly high antihypertensive efficacy and good tolerability when used long-term in average therapeutic doses in a wide variety of categories of patients [15–21].

Bisoprolol, which has high cardioselectivity, is widely used in clinical practice. If we take the ability to block β1 receptors in carvedilol as one, then for metoprolol this figure will be 6, for bisoprolol - 21 [22]. Also, being amphophilic, that is, soluble in both fats and water, bisoprolol has two elimination routes - renal excretion and hepatic metabolism. This ensures greater safety of use in patients with concomitant liver and kidney damage, elderly patients, as well as a low likelihood of drug interactions.

In terms of antihypertensive effect, bisoprolol is not only not inferior to other beta blockers, but is superior to them in a number of indicators. Thus, in the BISOMET study, it was shown that bisoprolol is comparable to metoprolol in terms of the degree of reduction in blood pressure at rest, but significantly exceeds it in its effect on the level of systolic blood pressure and heart rate during physical activity [23]. The effectiveness of bisoprolol in reducing cardiovascular risk in combination with the absence of a negative effect on carbohydrate metabolism has been proven in large randomized clinical studies, including such well-known ones as CIBIS-II (Cardiac Insufficiency Bisoprolol Study II) [24], TIBBS (Total Ischemic Burden Bisoprolol Study) [25], etc.

Amlodipine, which is part of Concor AM, is a third-generation AK, with a half-life of more than 35 hours, and has greater selectivity for coronary and cerebral vessels. The drug is practically devoid of inotropic effect and influence on the function of the sinus node, atrioventricular conduction, which determines its advantage over other AKs (the verapamil and diltiazem groups).

From the point of view of clinical pharmacology, the combination of a highly selective beta blocker and dihydropyridine AK is reasonable and justified. The effects of bisoprolol and amlodipine are complementary in reducing blood pressure, since they affect different parts of the pathogenesis, allowing for increased antihypertensive effectiveness: the vasoselective effect of amlodipine (reduction of total peripheral vascular resistance (TPVR)) and the cardioprotective effect of bisoprolol (reduction of cardiac output, reduction of heart rate) ), which in turn helps reduce the risk of developing pathological conditions in hypertension, such as angina pectoris, myocardial infarction, myocardial remodeling, and myocardial infarction [27].

In accordance with Russian recommendations for the treatment of hypertension, the primary indications for prescribing Concor AM are a combination of hypertension with coronary artery disease, atherosclerotic lesions of the carotid and coronary arteries, tachyarrhythmias, as well as isolated systolic hypertension, hypertension in elderly patients, and hypertension in pregnant women.

Clinical experience with the use of Concor AM indicates good antihypertensive efficacy of the drug with a high frequency of achieving target blood pressure values ​​[26, 28, 29].

It is important to note that the studies conducted have demonstrated a good tolerability profile of the drug. Adverse events were mild and did not require discontinuation of the drug. Also, none of the ongoing clinical studies noted negative effects on carbohydrate and lipid metabolism [28, 29].

Important from a practical point of view is the fact that the drug is available in a wide range of doses of bisoprolol and amlodipine: 5 mg + 5 mg, 5 mg + 10 mg, 10 mg + 5 mg, 10 mg + 10 mg. This allows you to choose the optimal dosage regimen for each patient, taking into account individual hemodynamic characteristics.

Conclusion

Currently, the issues of rational pharmacotherapy and the optimal choice of drugs for various diseases are of particular relevance.

The quality of pharmacotherapy directly depends on the degree of patient adherence to treatment. Adherence is a key position linking the process and outcome of medical intervention. The use of fixed combinations of antihypertensive drugs in clinical practice simplifies the treatment regimen for patients with hypertension and helps improve adherence to treatment.

The drug Concor AM is a fixed combination of different doses of bisoprolol and amlodipine, has proven antihypertensive effectiveness in combination with a good safety profile. The components of the drug are complementary in relation to lowering blood pressure, since they affect different parts of the pathogenesis, allowing for increased antihypertensive effectiveness: the vasoselective effect of amlodipine (reduction of vascular resistance) and the cardioprotective effect of bisoprolol (reduction of cardiac output, decrease in heart rate), which in turn helps reduce the risk of developing pathological conditions in hypertension, such as angina pectoris, myocardial infarction, myocardial remodeling, cerebral stroke.

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I. Yu. Yudina T. E. Morozova1, Doctor of Medical Sciences, Professor

GBOU VPO First Moscow State Medical University named after. I. M. Sechenova Ministry of Health of the Russian Federation, Moscow

1 Contact information

Modern rational combination therapy in the treatment of patients with arterial hypertension

According to epidemiological studies, the prevalence of arterial hypertension (AH) among adults in developed countries ranges from 20 to 40% and increases with age [1]. Elevated blood pressure is found in more than 50% of men and women over 60 years of age [2]. The relevance of the problem is supported by the increasing processes of urbanization of society, which create the preconditions for the emergence of risk factors (RFs), such as stress, physical inactivity, obesity, bad habits and disturbed ecology. Elevated blood pressure is one of the main risk factors for the development of cerebral stroke, coronary heart disease (CHD) and other cardiovascular diseases of atherosclerotic origin, which are associated with more than 50% of all deaths [3].

Clinical practice and the results of many multicenter studies have shown [4–6] that the use of monotherapy in the treatment of hypertension rarely leads to target blood pressure levels, increases the risk of adverse events and reduces patient adherence to treatment. The use of drugs in a rational combination regimen requires compliance with a number of mandatory conditions: safety and effectiveness of the components; the contribution of each component to the expected result; different but complementary mechanism of action of the components; the best result compared to each of the components; balance of components in terms of bioavailability and duration of action; strengthening organoprotective properties; impact on the universal (most common) mechanisms of blood pressure increase; reduction in adverse events and improved tolerability [7–9].

According to modern national recommendations [10], recommendations of the European Society of Arterial Hypertension (EOH) and the European Society of Cardiology (ESC) [11], the treatment tactics for essential hypertension depend on the level of blood pressure and the degree of risk of cardiovascular complications. The main goal of treatment is to minimize the risk of developing cardiovascular complications (CVD) and death from them. The main objectives are normalization of blood pressure levels in order to prevent complications, in the absence or minimal level of adverse drug reactions (ADRs), correction of all modifiable risk factors (smoking, dyslipidemia, hyperglycemia, obesity), prevention, slowing down the rate of progression and/or reducing organ damage - targets, as well as treatment of associated and concomitant diseases - coronary artery disease, diabetes mellitus (DM), etc. [10, 11].

When treating patients with hypertension, blood pressure should be less than 140/90 mm Hg. Art., which is its target level. If the prescribed therapy is well tolerated, it is advisable to reduce blood pressure to lower values. In patients with a high and very high risk of cardiovascular disease, it is necessary to reduce blood pressure to 140/90 mm Hg. Art. or less within 4 weeks. In the future, subject to good tolerance, it is recommended to reduce blood pressure to 130/80 mmHg. Art. and less. In patients with coronary artery disease, blood pressure should be reduced to the target value of 130/85 mm Hg. Art. In patients with diabetes and/or kidney disease, the target blood pressure level should be less than 130/85 mmHg. Art. [10].

Of course, treatment for hypertension should begin with lifestyle changes: reducing excess body weight, limiting the consumption of table salt and alcoholic beverages, increasing physical activity, etc. Limiting the consumption of table salt is a fairly effective way to reduce blood pressure. It was noted that limiting the consumption of table salt enhances the antihypertensive effect of many antihypertensive drugs, including AT1-angiotensin receptor blockers and β-blockers.

One of the most important conditions for ensuring adequate blood pressure control and increasing patient adherence to treatment is the optimal choice of antihypertensive drug as part of mono- or combination pharmacotherapy.

Currently, five main classes of antihypertensive drugs are recommended for the treatment of hypertension [10]:

1. angiotensin-converting enzyme inhibitors (ACE inhibitors) (captopril, enalapril, perindopril, lisinopril, fosinopril, quinapril, trandolapril, etc.);

2. AT1 receptor blockers (ARBs) (valsartan, losartan, telmisartan, candesartan, irbesartan, etc.);

3. slow calcium channel blockers (SCBC) (nifedipine, amlodipine, etc.);

4. beta-blockers (BAB) (carvedilol, bisoprolol, nebivolol, metoprolol tartrate, metoprolol succinate, atenolol, etc.);

5. thiazide and thiazide-like diuretics (hydrochlorothiazide (HCTZ), indapamide).

As additional classes of antihypertensive drugs for combination therapy, α-blockers (prazosin, doxazosin), imidazoline receptor agonists (moxonidine), and a direct renin inhibitor (aliskiren) can be used.

According to these national recommendations [10], the choice of an antihypertensive drug should be related to the characteristics of its action, belonging to a certain class, since at present, the results of clinical studies conducted according to the rules of evidence-based medicine have made it possible to establish situations of preferential class choice of drugs. When choosing an antihypertensive drug, it is necessary first of all to evaluate the effectiveness, the likelihood of side effects and the benefits of the drug in a specific clinical situation (Table 1).

The choice of drug is influenced by many factors, the most important of which are:

• the patient has a risk factor;
• target organ damage;
• concomitant clinical conditions, kidney damage, MS, diabetes;
• concomitant diseases for which it is necessary to prescribe or limit the use of antihypertensive drugs of various classes;
• the patient’s previous individual reactions to drugs of various classes;
• the likelihood of interaction with medications prescribed to the patient for other reasons;
• socioeconomic factors, including the cost of treatment.

It is necessary to begin treatment with the use of one drug in the minimum daily dose (this recommendation does not apply to patients with severe hypertension or those in whom previous therapy was ineffective). The use of new drugs should begin with the use of low doses, the goal of each successive stage of treatment should be to reduce blood pressure levels by 10–15% [10]. If blood pressure does not decrease to the desired level, further treatment is carried out by gradually - step by step - increasing doses or adding new drugs. Ineffective drugs (not causing a decrease in blood pressure by 10–15 mm Hg) and drugs that cause ADRs should be replaced [12].

There are no uniform recommendations regarding which drugs should be used to start treating a patient. The choice of drugs depends on age, gender and the presence of concomitant diseases.

Currently, the treatment of most patients with hypertension uses drugs that alter the activity of the RAAS. These are ACE inhibitors, beta blockers and angiotensin II receptor blockers (ARBs). ARBs are one of the modern and most dynamically developing classes of antihypertensive drugs. ARBs suppress the effect of angiotensin II through AT1 receptors. It has been established that hypersecretion of angiotensin II leads not only to the development of hypertension, but also to damage to target organs, being one of the main factors in the progression of hypertension and its complications, remodeling of the heart and blood vessels. It is no coincidence that AT1-angiotensin receptor blockers are classified as the main antihypertensive drugs. Numerous controlled studies, such as LIFE, VALUE, MARVAL, PRIME, IDNT, DETAIL [13], have shown that AT1 blockers are effective and safe antihypertensive drugs. AT1-angiotensin receptor blockers have proven to be particularly effective in preventing the development of cerebral stroke. To prevent stroke in patients with hypertension, AT1 blockers can be used both instead of diuretics or calcium antagonists, and together with them. ARBs, like ACEIs, can also prevent the development of type 2 diabetes, reducing the risk of its occurrence by 20–25% [14]. Therefore, it can be assumed that AT1-angiotensin receptor blockers should be used for the treatment of hypertension primarily in patients with a high risk of developing stroke or diabetes. Excellent tolerability is an undoubted advantage of AT1 blockers during long-term antihypertensive therapy. The use of AT1-angiotensin receptor blockers can improve patient adherence to long-term therapy, since ARBs are much less likely than other antihypertensive drugs to be discontinued due to the development of side effects. Unlike thiazide diuretics, beta blockers and ACE inhibitors, the antihypertensive effectiveness of AT1-angiotensin receptor blockers does not depend on the age, gender or race of patients [15].

The renin-angiotensin-aldosterone system (RAAS) plays a central role both in the occurrence of hypertension and in the implementation of pathophysiological processes that ultimately lead to serious cardiovascular complications such as cerebral stroke, myocardial infarction, vascular remodeling, nephropathy, congestive heart failure and the development of atherosclerotic processes. ACE inhibitors were the first group of drugs acting directly on the RAAS, which were widely introduced into clinical practice. The long period of their use, numerous clinical studies, and extensive experience of practical doctors in their use have led to the fact that these drugs are currently used in Russia more often than other antihypertensive drugs. ACE inhibitors in moderate doses reduce SBP to a slightly lesser extent than diuretics and calcium antagonists. The choice of a specific ACEI for long-term therapy in patients with hypertension has important clinical implications, since these drugs are prescribed essentially for life. Of the ACE inhibitors with proven effectiveness, perindopril and ramipril seem to be the most promising [16, 17].

Clinical practice and the results of many multicenter studies have shown that the use of monotherapy in the treatment of hypertension rarely leads to target blood pressure levels, increases the risk of adverse events and reduces patient adherence to treatment. The most important conditions for increasing patients’ adherence to treatment are their understanding of the goals, objectives, modern methods and principles of treatment, as well as the correct choice of antihypertensive treatment by the doctor. The tactics of using combination therapy with the selection of drugs with different mechanisms of action already at the beginning of treatment gives a much greater chance of successful blood pressure control. Low-dose combination rational antihypertensive therapy may be the first choice measure, especially in patients with a high risk of developing cardiovascular complications, the advantages of which include: a simple and convenient dosage regimen for the patient; facilitating titration; ease of prescribing the drug; increasing patient adherence; reduction of adverse events by reducing doses of components used; reducing the risk of using irrational combinations; confidence in the optimal and safe dosage regimen; reduction in price [17–21].

It should be noted that the latest both American and European recommendations emphasize the need to avoid, if possible, the tactics of frequent changes in medications and their dosages in patients. It is now becoming obvious that the effectiveness of monotherapy with drugs of all main groups is low and comparable: after a year of treatment, even with almost perfect adherence to treatment, the effect of monotherapy does not exceed 50% versus almost 30% with placebo. The tactics of “sequential monotherapy” in reality may require 4–5 changes in therapy, each of which may be complicated by the development of side effects. This tactic takes a lot of time, deprives the doctor and the patient of confidence in success, which ultimately has a negative psychological impact on the patient and leads to low adherence to treatment for hypertension. It is the underestimation of the role of combination therapy that is one of the common reasons for unsatisfactory blood pressure control [17–21].

Combination antihypertensive therapy has many advantages:

• enhancing the antihypertensive effect due to the multidirectional effects of drugs on the pathogenetic mechanisms of hypertension development, which increases the number of patients with a stable decrease in blood pressure;
• reducing the incidence of side effects both due to lower doses of combined antihypertensive drugs and due to the mutual neutralization of these effects;
• ensuring the most effective organ protection and reducing the risk of development and number of cardiovascular complications.

Numerous randomized clinical trials and real clinical practice experience have shown all the advantages of combination therapy, which can be summarized as follows [22, 23]:

• simultaneous use of drugs from two different pharmacological groups more actively reduces blood pressure due to the fact that there is an effect on various pathogenetic mechanisms of hypertension;
• the combined use of lower doses of two drugs acting on different regulatory systems will allow for better control of blood pressure, given the heterogeneity of the response of hypertensive patients to antihypertensive drugs;
• prescribing a second drug may weaken or balance the triggering of mechanisms to counteract the decrease in blood pressure that occurs when prescribing one drug;
• a sustained decrease in blood pressure can be achieved with smaller doses of two drugs (than with monotherapy);
• smaller doses allow you to avoid dose-dependent side effects, the likelihood of which is higher with a larger dose of a particular drug (during monotherapy);
• the use of two drugs can to a greater extent prevent damage to target organs (heart, kidneys) caused by hypertension;
• prescribing a second drug can to a certain extent reduce (and even completely eliminate) the undesirable effects caused by the first (even if quite effective) drug;
• Prescribing a second drug (in particular, a diuretic) allows you to obtain a rapid antihypertensive effect of a combination of drugs, since most antihypertensive drugs (ACE inhibitors, CCBs, ARBs, and partly beta blockers) exhibit their full effect only in the 2-3rd week . reception (and even later).

Combinations of two antihypertensive drugs are divided into rational (effective), possible and irrational. All the advantages of combination therapy are inherent only in rational combinations of antihypertensive drugs [24].

These include [10]:

• ACE inhibitor + diuretic;
• ARB + ​​diuretic;
• ACEi + dihydropyridine BMCC;
• ARB + ​​dihydropyridine BMCA;
• dihydropyridine BMCC + BAB;
• dihydropyridine BMCC + diuretic;
• beta blocker + diuretic;
• BAB + α-adrenergic blocker.

The issue of combining three or more drugs has not yet been sufficiently studied, since there are no results from randomized controlled clinical trials studying the triple combination of antihypertensive drugs. Thus, the antihypertensive drugs in these combinations are grouped together on a theoretical basis. However, in many patients, including patients with refractory hypertension, only with the help of three or more component antihypertensive therapy can the target blood pressure level be achieved [25]. Recommended combinations of three antihypertensive drugs include:

• ACE inhibitor + dihydropyridine BMCC + beta blocker;
• ARB + ​​dihydropyridine BMCA + BAB;
• ACE inhibitor + BMCC + diuretic;
• ARB + ​​BMCC + diuretic;
• ACE inhibitor + diuretic + beta blocker;
• ARB + ​​diuretic + beta blocker;
• dihydropyridine BMCC + diuretic + beta-blocker.

Since combination therapy has become one of the main directions in the treatment of patients with hypertension, fixed combinations of antihypertensive drugs containing two drugs in one tablet have become widespread, which improves the patient’s psychological attitude towards treatment and makes it possible to reduce the risk of complications and side effects. The optimal combination of components implies the absence of unwanted hypotension, which can lead, especially in elderly patients, to increased cardiovascular risk. Rational selection of components according to their pharmacokinetic profile creates the prerequisites for single use of drugs that require two or three times in monotherapy.

The advantages of fixed (official) combinations include:

• potentiation of the antihypertensive effect of drugs;
• ease of administration and dose titration process;
• reduction in the frequency of side effects (low dose, mutual neutralization of NDR);
• increasing patient adherence to treatment;
• reducing the cost of treatment.

Currently, there are quite a lot of official combination drugs: Capozide (captopril + HCTZ), Co-Renitek (enalapril + HCTZ), Noliprel (perindopril + indapamide), Accusid (quinapril + HCTZ), Co-diovan (valsartan + HCTZ), Gizaar (losartan + HCTZ), Exforge (valsartan + amlodipine), Equator (lisinopril + amlodipine), Logimax (metoprolol + felodipine), Tarka (verapamil + trandolapril), etc. The most frequently prescribed of all non-fixed and fixed drug combinations is the combination of an ACE inhibitor with a thiazide diuretic or an ARB with a thiazide diuretic. The high effectiveness and safety of this combination in the treatment of hypertension is noted in the recommendations of the WHO, VNOK, EOG - EOC and JNS 7. The action of type 1 AT receptor blockers is specific, since they, unlike ACE inhibitors, do not affect the activity of other neurohumoral systems, in particular bradykinin, which are associated with characteristic side effects (dry cough and angioedema). The effect of “escape” of pharmacological blockade of the RAAS from the action of ACE inhibitors is explained by the synthesis of angiotensin II in some organs and tissues with the help of other enzymes without the participation of ACE.

It is currently believed that chronic stimulation of the RAAS leads to the activation of growth factors and fibrosis at the tissue level, which determines the development of pathological processes in target organs, therefore the possibility of blocking the tissue link of the RAAS seems promising for achieving the organoprotective effect of antihypertensive therapy. A number of studies have not revealed a direct dependence of the reno- and cardioprotective effect of antihypertensive therapy on the degree of blood pressure reduction, which indicates the importance of non-hemodynamic effects of RAAS blockade. When used together, thiazide diuretics not only enhance but also prolong the antihypertensive effect of ARBs. The combined use of ARBs and diuretics has been shown to significantly reduce blood pressure in patients with both high and low renin activity, and the response to this combination therapy is about 80% or higher.

Another example of a favorable combination is the combination of BMCC with an ACE inhibitor, which leads to a decrease in the severity of edema associated with the use of dihydropyridines. In addition, the combination of a non-dihydropyridine BMCC with an ACE inhibitor may potentially enhance the positive effect of the latter on vascular elastic properties.

Irrational combinations, in which there is no potentiation of the antihypertensive effect of drugs and/or side effects are enhanced when used together, include combinations of beta blockers and centrally acting drugs, beta blockers and non-dihydropyridine BMCCs, and beta blockers with ACE inhibitors, ARBs, and imidazoline receptor agonists. The combination of ACEIs and ARBs is currently considered prohibited.

Conclusion

The most important conditions for increasing patients’ adherence to treatment are their understanding of the goals, objectives, modern methods and principles of treatment, as well as the correct choice of antihypertensive treatment by the doctor. The tactics of using combination therapy with the selection of drugs with different mechanisms of action already at the beginning of treatment provides a significantly greater chance of successfully controlling blood pressure and the risk of developing cardiovascular complications. The advantages of combination therapy consist in potentiating the antihypertensive effect and reducing the number of side effects and are inherent only in so-called rational combinations of antihypertensive drugs. For adequate treatment of hypertension, it is advisable to use combination therapy, starting with low doses of drugs.

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Choosing an antihypertensive drug for the treatment of arterial hypertension

O.D. OSTROUMOVA

, Doctor of Medical Sciences
professor, I.I.
KOPCHENOV , Candidate of Medical Sciences,
Department of Faculty Therapy and Occupational Diseases of Moscow State Medical University named after. A.I. Evdokimova The article presents modern approaches to the differentiated selection of antihypertensive drugs.
The advantages and limitations of the main 5 classes of antihypertensive medications are described. Data are provided on the choice of drug within a class, taking into account specific clinical situations. The main goal of treatment for patients with arterial hypertension (AH) is to minimize the risk of developing cardiovascular complications (CVC) and death from them [1]. To achieve this goal, it is necessary not only to reduce blood pressure (BP) to the target level, but also to correct all modifiable risk factors (smoking, dyslipidemia, hyperglycemia, obesity), prevention, slow the rate of progression and/or reduce target organ damage (TOD) , as well as treatment of associated and concomitant diseases (coronary artery disease, diabetes mellitus, etc.).

The target blood pressure level is considered to be not exceeding 140/90 mmHg. Art. If the prescribed therapy is well tolerated, it is recommended to reduce blood pressure to lower values. In patients with a high and very high risk of cardiovascular disease, it is necessary to maintain blood pressure at 140/90 mmHg. Art. and below for 4 weeks [1]. In the future, subject to good tolerance, it is recommended to reduce blood pressure to 130–139/80–89 mmHg. Art.

Currently, 5 main classes of antihypertensive drugs (AGDs) are used for the treatment of hypertension: angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II AT1 receptor blockers (ARBs), calcium antagonists (CAs), beta-blockers (BABs) and diuretics [1 ]. Alpha-adrenergic blockers (AABs), imidazoline receptor agonists, and direct renin inhibitors can be used as additional drugs in combination therapy [1].

The choice of drug is influenced by a number of factors, the most important of which are [1]:

• the patient has other risk factors; • POM; • associated clinical conditions (ACS), kidney damage, metabolic syndrome (MS), diabetes mellitus; • concomitant diseases for which it is necessary to prescribe or limit the use of antihypertensive drugs of various classes; • history of individual drug intolerance; • the likelihood of drug interactions with drugs prescribed to the patient for other diseases; • socio-economic factors, including the cost of treatment.

When choosing an antihypertensive, it is necessary first of all to evaluate its effectiveness, the likelihood of side effects and the benefits of the drug in a certain clinical situation (Fig. 1 and 2). According to the results of multicenter randomized trials, none of the main classes of antihypertensive drugs has a significant advantage either in lowering blood pressure or in reducing the risk of cardiovascular events and death from them. A more significant factor in reducing the risk of cardiovascular events during antihypertensive therapy is the amount by which blood pressure decreases, so it is impossible to accurately predict which antihypertensive agent will be most effective in a given patient. Each of the representatives of the main classes of AGP has its own pros and cons (Fig. 1 and 2), so a universal ranking of AGP does not seem necessary. In each specific clinical situation, it is necessary to take into account the peculiarities of the action of antihypertensive drugs of various classes, identified in randomized trials [1]. Thus, the choice of a particular antihypertensive, especially at the start of treatment, should be based on the results of large clinical studies that have proven the high effectiveness and safety of using this particular drug in patients in a similar clinical situation [1].

ACE inhibitors

According to Russian pharmacoepidemiological studies, ACEIs are the most prescribed class of drugs for the treatment of cardiovascular diseases, including hypertension, due to the important role of activation of the renin-angiotensin-aldosterone system (RAAS) in the pathogenesis of these conditions [1].

Depending on the chemical structure of the active part of the molecule that binds to ACE, drugs of this class are divided into 3 groups [2]:

• ACE inhibitors containing a sulfhydryl group (captopril); • ACE inhibitors containing a carboxyl group or carboxyl dipeptides (enalapril, lisinopril, ramipril, perindopril, cilazapril, benazepril, quinapril, trandolapril, spirapril); • ACE inhibitors containing a phosphoryl group (fosinopril).

The effectiveness of therapy is significantly influenced by such parameters of the pharmacokinetics of ACE inhibitors as bioavailability, biotransformation (whether the drug is an active substance or a prodrug that is converted into active metabolites in the body), elimination routes and the duration of inhibition of ACE activity. Based on this, ACE inhibitors are divided into 2 groups according to their pharmacokinetic properties:

• active substances (captopril, lisinopril); • prodrugs: precursors of ACE inhibitors (fosinopril, all carboxyl dipeptides except lisinopril). Prodrugs are converted to their active form by hydrolysis of the ester linkage as they pass through the gastrointestinal mucosa and in the liver (for example, enalapril is converted to enalaprilat). The action of drugs in this group is realized more slowly, and the effect lasts longer. If liver function is impaired (liver cirrhosis, severe hepatitis, etc.), their effectiveness decreases, which requires dose adjustment [2].

Among the drugs in this group, fosinopril occupies a special place. A special feature of the drug is a dual balanced route of elimination - through the liver and through the kidneys (in a ratio of approximately 50:50). This means that in patients with impaired liver function, this fosinopril will be excreted through the kidneys, and in patients with impaired renal function, through the liver (gastrointestinal tract) [2]. In clinical practice, this provides the advantage of the drug, which is expressed in the absence of the need for dose adjustment in patients with concomitant renal or liver failure [2].

ACE inhibitors have proven effective in reducing the rate of progression of POM and reducing the degree of pathological changes. ACEI therapy leads to a decrease in the severity of left ventricular myocardial hypertrophy (LVMH), including the fibrous component, a significant decrease in the level of microalbuminuria (MAU) and proteinuria, and prevents deterioration of renal function [1]. The most pronounced antihypertensive effect of ACE inhibitors was observed in patients with increased activity of the RAAS [1,2]. In addition, ACE inhibitors slow down the degradation of bradykinin, which, on the one hand, enhances their antihypertensive effectiveness, and on the other hand, contributes to the development of such characteristic side effects as dry cough and angioedema.

As is known, in patients with diabetes, hypertension greatly increases the risk of developing both macrovascular (myocardial infarction, stroke) and microvascular (angiopathy, retinopathy, nephropathy) complications. It was found that ACE inhibitors have additional advantages for this group of patients compared to other classes of antihypertensive drugs: they largely reduce the risk of all complications and inhibit the development of chronic renal failure (CRF), i.e., they have a nephroprotective effect [1]. The use of ACE inhibitors significantly slows down the onset of “renal death” (dialysis or kidney transplantation) both in diabetic nephropathy and in hypertension with proteinuria without diabetes [3]. That is why they are indicated for all patients with a combination of diabetes and hypertension, as well as for patients with hypertension and microalbuminuria without diabetes [1].

A reliable clinical marker of an increased risk of complications, both cardiovascular and renal, in patients with hypertension, especially in combination with diabetes, is microalbuminuria [1]. By the degree of reduction of microalbuminuria during treatment, one can judge the reduction in the risk of complications. The effectiveness of ACE inhibitors in patients with microalbuminuria is due to the fact that angiotensin II plays a key role in the development of organ damage in hypertension, especially nephropathy and chronic renal failure. Angiotensin II stimulates the activity of the sympathetic nervous system, which entails an increase in the production of angiotensin II by the kidneys, activation of the RAAS, triggering a cascade of neurohumoral and structural-functional changes that lead to the development of proteinuria, cell proliferation, matrix accumulation and ultimately the formation of glomerulosclerosis [3 ].

The ACE inhibitor lisinopril has been found to reduce the level of microalbuminuria by 48% [4]. In addition, in patients with hypertension and diabetes, lisinopril has a number of additional positive effects on carbohydrate metabolism, in particular, it reduces the level of glycosylated hemoglobin and increases tissue sensitivity to insulin [5].

Of interest are the results of a study examining the effect of another ACE inhibitor, fosinopril, on the risk of micro- and macrovascular complications.

In the PREVEND-IT study (n = 864), it was proven that therapy with another ACE inhibitor, fosinopril, prevents the progression of microalbuminuria, as well as the development of cardiovascular complications in patients with hypertension [6, 7]. During therapy with fosinopril at a dose of 20 mg/day for 46 months in patients with hypertension and microalbuminuria, the level of urinary albumin excretion decreased by 26% compared with placebo, and the main combined indicator of cardiovascular mortality and hospitalization for heart disease was - by 40%. The use of pravastatin in this category of patients did not affect the level of microalbuminuria, and the rate of cardiovascular mortality and hospitalization decreased by 13% [6, 7].

One of the current problems is the treatment of hypertension in patients with MS. As is known, abdominal obesity is an independent risk factor for the development of complications in patients with hypertension [1, 8]. It has been established that in middle-aged patients with excess body weight, the risk of developing hypertension increases by 3 times, and in young people - by 6 times. According to the Framingham study, every 4.5 kg of excess weight increases systolic blood pressure in men by 4.4 mmHg. Art., and in women by 4.2 mm Hg. Art. Treatment of such patients poses certain difficulties [8].

According to the TROPHY study, the number of patients in whom it was possible to achieve normalization of blood pressure was significantly greater in the lisinopril group compared with the hydrochlorothiazide group (when using the drug in doses of up to 50 mg/day) [9]. At the same time, the level of glucose in the blood serum decreased in the lisinopril group, and increased in the hydrochlorothiazide group. The potassium level in the lisinopril group remained virtually unchanged, whereas in the hydrochlorothiazide group it decreased significantly. These properties convincingly demonstrate the feasibility of using lisinopril in obese patients with hypertension.

Another important property of ICE is its antiatherosclerotic effect. Thus, the results of the PHYLLIS study [10] showed a slowdown in the progression of atherosclerosis of the carotid arteries in patients with hypertension during therapy with fosinopril. The study involved 508 patients with hypertension and asymptomatic atherosclerotic lesions of the carotid arteries. Patients were divided into groups depending on the therapy: 127 patients received hydrochlorothiazide at a dose of 25 mg/day, 127 - fosinopril at a dose of 20 mg/day, 126 - 25 mg of hydrochlorothiazide and an additional 40 mg of pravastatin, 128 - 20 mg of fosinopril and 40 mg pravastatin. The average follow-up period was 2.6 years [12, 13]. The level of blood pressure achieved during treatment when measured in the clinic and on an outpatient basis in patients did not differ between groups. Intima-media thickness (IMT) significantly increased in the group of patients receiving only hydrochlorothiazide. In groups of patients taking fosinopril, a significant decrease in IMT thickness was observed [10]. Thus, it has been shown that fosinopril has an antiatherogenic effect in patients with hypertension.

Angiotensin II receptor blockers

There are two mechanisms in the action of angiotensin II (AII) on blood vessels: pressor and depressor. The first is mediated by the effect of AII on type 1 receptors and leads to vasoconstriction, sodium and fluid retention, increased sympathetic activity, decreased vagal tone, cell proliferation and a positive inotropic effect. The depressor effect of AII is realized through stimulation of type 2 receptors, which leads to vasodilation, especially pronounced in the vessels of the brain and kidneys, natriuretic effect, antiproliferative effect, activation of kininogen, release of nitric oxide and prostaglandin I2 [1, 2]. The antihypertensive effect and other pharmacological effects of AT1 receptor blockers (ARBs, sartans) are based on two mechanisms - direct and indirect. The first is associated with a weakening of the effects of AII under conditions of selective blockade of AT1 receptors. The second is due to reactive hyperactivation of the RAAS under conditions of blockade of AT1 receptors and additional stimulation of AT2 receptors [1, 2]. The antihypertensive effectiveness of ARBs is not influenced by the activity of the RAAS, gender and age of the patient.

ARBs have been proven to have a positive effect on the condition of target organs and reduce the risk of developing all cardiovascular complications [1, 2]. In addition, drugs in this group are characterized by the highest patient adherence to treatment due to high efficiency and the best treatment tolerability among all classes of antihypertensive drugs [1, 2]. In recent years, the scope of application of ARBs has expanded significantly. IHD, nondiabetic nephropathy, left ventricular dysfunction were added to the list of indications (diabetic nephropathy, proteinuria/MAU, chronic heart failure, LVMH, paroxysmal atrial fibrillation, cough while taking ACE inhibitors, etc.); In addition, ARBs can now be prescribed to older patients [1].

The first and extremely important study confirming the enormous potential of sartans in the treatment of hypertension was the LIFE study (Losartan Intervention For Endpoint reduction in hypertension study) [11]. More than 9,000 patients with hypertension and LVMH took part in it. Patients received either losartan 50 mg or atenolol 50 mg, with the option of adding 12.5 mg hydrochlorothiazide and subsequently increasing the dose of the drugs until the target blood pressure level was achieved. During the 5-year follow-up, patients receiving losartan, compared with the atenolol group, had a 13% reduction in the incidence of major cardiovascular events (primary endpoint), including a 25% difference in the incidence of strokes. Of course, the main mechanism for this effectiveness of losartan is its ability to reduce the severity of LVMH (p < 0.0001 for the Sokolow-Lyon index and for the Cornell product) [11]. It is known that LV hypertrophy is an independent serious risk factor for cardiovascular events [1]. The same study demonstrated a decrease in the incidence of new cases of type 2 diabetes (by 25%) and a decrease in the severity of insulin resistance when treated with losartan [11].

It is worth noting that among all ARBs, only losartan with proven effectiveness significantly increases uric acid excretion (up to 300%), which makes its use attractive in patients with gout [13]. As is known, hyperuricemia is one of the components of metabolic syndrome and an independent risk factor for CVD. The experiment showed that losartan has the ability to block the transport of urate through membranes in the proximal renal tubules [2]. Thus, ARBs reduce the risk of developing diabetes mellitus, making their use especially relevant in patients with hypertension and MS [1].

ARBs are also characterized by a pronounced nephroprotective effect, which was proven by the results of the large RENAAL study (n = 1,513), which assessed the effectiveness of losartan in patients with hypertension, type 2 diabetes mellitus and diabetic nephropathy. As a result of taking losartan (50–100 mg/day), the risk of a double increase in plasma creatinine concentration was reduced by 25%, and the risk of developing end-stage chronic renal failure was reduced by 28%. In addition, compared with the placebo group, patients in the losartan group had a statistically significant reduction in the level of proteinuria and the frequency of initial hospitalization [12].

Thus, ARBs have established themselves as indispensable drugs in the treatment of such a socially significant disease as hypertension. Their effect is multifaceted and is determined not only by the effect on blood pressure, but also by the normalization of the functioning of the RAAS and the organoprotective effect; The drugs have a favorable metabolic profile and an extremely low incidence of side effects.

Calcium antagonists

The effectiveness of AKs as antihypertensive agents is due to a slowdown in Ca current through the α1- and α2-adrenergic pathways and calcium channels of peripheral vessels, a decrease in the sensitivity of arterial vessels to the endogenous influences of norepinephrine, vasopressin, histamine, serotonin, acetylcholine, which leads to a decrease in total peripheral vascular resistance and BP [1, 2, 14]. AAs are divided into 3 subgroups depending on the chemical structure [1, 2, 14]:

1) dihydropyridines (nifedipine, amlodipine, felodipine, etc.); 2) phenylalkylamines (verapamil); 3) benzodipines (diltiazem).

There are significant differences in the ability of AA to affect the myocardium, vascular wall and cardiac conduction system. Dihydropyridines have a pronounced selective effect on the vascular muscles, leading to dilation of peripheral arteries, do not affect the conduction system of the heart and practically do not cause a decrease in the contractile function of the myocardium [1, 2, 14]. Non-dihydropyridine AKs (verapamil and diltiazem) are characterized by negative ino- and dromotropic effects. All AAs are metabolically neutral and do not have a negative effect on carbohydrate, lipid and purine metabolism. In addition to the antihypertensive effect, ACs have organoprotective and antianginal properties, inhibit platelet aggregation, significantly reduce the risk of stroke, and are the first choice drugs in elderly patients and patients with isolated systolic hypertension [1, 2, 14].

The most important characteristic of AKs is their ability to inhibit the progression of atherosclerosis [14]. The mechanisms of the anti-atherosclerotic effect are to slow down the proliferation of smooth muscle cells by suppressing the release of the corresponding growth factor, inhibiting vascular intimal hyperplasia, reducing the adhesion of monocytes and the uptake of cholesterol esters by macrophages, inhibiting the expression of the HMG-CoA reductase gene, a beneficial effect on the HDL/LDL ratio, stabilization of the plasma membrane , which prevents the penetration of free cholesterol into the vessel wall, and the antioxidant effect of AA [14]. The prospective, randomized, double-blind study of the vascular effects of amlodipine (PREVENT) assessed the effect of the drug on the progression of early atherosclerosis [15]. The results of treatment with amlodipine besilate 10 mg once daily were compared with the effect of usual therapy (clinicians were allowed to use any drugs or interventions they considered necessary). The study involved 825 patients; the follow-up period was 3 years. The primary end point was the dynamics of the condition of the coronary arteries with initial atherosclerotic changes (initial stenosis 30%), which was assessed using quantitative coronary angiography (QCA). Other endpoints included the dynamics of changes in the diameter of segments of coronary arteries affected by atherosclerosis according to CCA data, the rate of progression of carotid atherosclerosis, which was determined using two-dimensional echography, and clinical outcomes. Amlodipine was prescribed at a dose of 5 mg/day, then increased to 10 mg/day for 4 weeks. The study included patients aged 30–80 years with a left ventricular ejection fraction of 40% or more.

Ultrasound examination of the carotid arteries showed that in patients with coronary atherosclerosis, long-term therapy with amlodipine significantly slows down the progression of carotid atherosclerosis [15]. Measurements in 12 carotid artery segments were taken before treatment, at the end of the 4-week dose titration period, and at 6, 12, 24, 30, and 36 months (final visit). In patients receiving amlodipine, the thickness of the intima-media complex decreased by 0.013 mm over 3 years, and in the placebo group it increased by 0.033 mm (p = 0.007).

In the PREVENT study, 3 years of amlodipine therapy led to a significant reduction in the incidence of adverse clinical outcomes in patients with coronary atherosclerosis. With long-term treatment with amlodipine, the incidence of hospitalization for unstable angina and congestive heart failure decreased by 35% compared with that in the placebo group (p = 0.01). The incidence of coronary artery surgery in the amlodipine group decreased by 43% compared with that in the placebo group (p = 0.001) [15]. After 36 months, amlodipine therapy led to a reduction in the total incidence of any CV events or interventions on the coronary arteries by 31% (p = 0.01), mainly due to a significant reduction (by 33%) in the frequency of hospitalizations for unstable angina and surgical interventions on the coronary arteries arteries (by 43%) [15].

AKs are indicated for a combination of hypertension and coronary artery disease [1]. In these patients, third-generation dihydropyridine AKs (primarily amlodipine) are indicated in the following situations [1, 14]:

• as first-line drugs for variant angina; • in patients with angina pectoris in case of persistent angina attacks during therapy with beta blockers, their combination with prolonged dihydropyridines is indicated.

It should be noted that retrospective case-control studies have shown that the relative risk of developing cardiovascular events or death in patients with hypertension when treated with short-acting nifedipine is significantly higher than when treated with diuretics or beta blockers [14]. At the same time, the use of long-acting dihydropyridines does not lead to an increase in the risk of myocardial infarction compared with that when using diuretics, beta blockers, ACEIs and ARBs [14]. Therefore, in clinical practice, the use of prolonged dihydropyridine AA (IIb and especially III generation) is preferable.

Thiazide and thiazide-like diuretics

Thiazide and thiazide-like diuretics (TD) have a pronounced antihypertensive effect. The effectiveness of TD treatment in lowering blood pressure and reducing cardiovascular mortality has been proven in numerous controlled comparative randomized studies, as well as the results of meta-analyses [1].

TDs act on the cortical segment of the loop of Henle and in the initial region of the distal tubules, where in healthy people up to 5–8% of filtered sodium is reabsorbed, they inhibit the activity of a special sodium-chlorine transporter and promote increased excretion of sodium and chlorine ions, as well as water and potassium ions and magnesium [2].

Due to the direct and indirect vasodilating effect of diuretics, a decrease in blood pressure, a decrease in total peripheral vascular resistance, and a decrease in venous return to the heart are noted. The action of thiazide and thiazide-like diuretics begins 1-2 hours after oral administration and lasts for 12-24 hours in most patients (24 hours for the thiazide-like diuretic indapamide).

It should be noted that most TDs are characterized by unfavorable metabolic effects. Treatment with high doses of TD (hydrochlorothiazide 50–100 mg/day) can worsen carbohydrate, lipid, and purine metabolism and reduce the amount of potassium in the blood plasma [1]. This circumstance limits the use of drugs of this group in patients with MS and a high risk of diabetes mellitus. The drug of choice in such cases is the thiazide-like diuretic indapamide: it is metabolically neutral and does not have a negative effect on carbohydrate and lipid metabolism [2].

Indapamide occupies a special place in the group of diuretics. The therapeutic effectiveness of the drug is due to its dual action. Firstly, it inhibits the reabsorption of sodium, chlorine, and, to a lesser extent, potassium and magnesium ions in the proximal and distal tubules of the short segment of the nephron; secondly, it eliminates the excess content of sodium ions in the vascular wall, increases the synthesis of prostaglandin E2 and J2, inhibits the influx of calcium ions into the smooth muscle cells of the vascular wall, resulting in vasodilatation and a decrease in their sensitivity to vasopressor agents (catecholamines, thromboxane) [2 , 16, 17]. Indapamide has a diuretic effect when using a dose of 5 mg/day, daily diuresis increases by 20%. At doses of 1.25–2.5 mg/day, the drug acts primarily as a peripheral arterial vasodilator. Moreover, the antihypertensive effectiveness of indapamide at a dose of 2.5 mg/day is comparable to the effect of 20 mg/day enalapril or 5 mg/day amlodipine [3, 9].

Total peripheral vascular resistance during treatment with indapamide 2.5 mg/day is reduced by 10–15%. According to 24-hour Holter blood pressure monitoring, during treatment with indapamide, there is a uniform decrease in blood pressure throughout the day, without a rise in the early morning hours [1]. The drug is effective for normal and impaired renal function.

The antihypertensive effect of indapamide is observed in mild hypertension in approximately 70% of patients. The effect appears after a few days of treatment and gradually increases. With long-term therapy, the antihypertensive effect of this drug remains in 60% of patients [2, 16].

A unique property of indapamide as a diuretic is its positive effect on lipid metabolism. Thus, it was noted that during treatment with indapamide, the level of low-density lipoprotein cholesterol and triglycerides decreases and the level of high-density lipoprotein cholesterol increases [16].

In addition to the antihypertensive effect, indapamide helps reduce left ventricular hypertrophy in patients with hypertension. Six-month therapy with indapamide 2.5 mg/day resulted in a decrease in left ventricular mass index by 13.3% [16].

Unlike thiazide diuretics, indapamide has a nephroprotective effect. Long-term (for 2 years) treatment with this drug in patients with hypertension and functional renal failure was accompanied by an increase in glomerular filtration rate by 28% [16]. Thus, among thiazide diuretics, indapamide is the drug of choice for the treatment of patients with hypertension and dyslipoproteinemia, MS, diabetes mellitus and early renal failure.

Beta blockers

BABs have been proven to be highly effective in reducing the risk of CV events in the treatment of patients with hypertension [1]. Currently, indications for prescribing beta blockers in patients with hypertension are stable angina, previous myocardial infarction, chronic heart failure, tachyarrhythmia, glaucoma and pregnancy.

BBs compete with catecholamines for binding to beta-adrenergic receptors of the heart. The main effects of beta blockers - a decrease in the frequency and strength of heart contractions, antiarrhythmic and hypotensive effects - are due to blocking the influence of mediators on beta1-adrenergic receptors.

The problem that arises when using beta blockers is the unfavorable metabolic effect of a number of representatives of this class on carbohydrate and lipid metabolism, which limits their use as monotherapy in people with MS and a high risk of developing diabetes mellitus. It is worth emphasizing that data on the negative metabolic effects of beta blockers were obtained from the analysis of studies in which atenolol was mainly used. These restrictions do not apply to highly selective blockers (bisoprolol, nebivolol), as well as the third generation drug carvedilol, which, in addition to a pronounced vasodilating effect, also has a cardioprotective effect due to its antioxidant properties [1].

Thus, a differentiated approach to the selection of a class of antihypertensive drugs and a drug within a class will allow individualizing the treatment of a particular patient and increasing its effectiveness.

Literature

1. Diagnosis and treatment of arterial hypertension. Russian recommendations (fourth revision). Systemic Hypertension 2010; 3:5–26. 2. Clinical pharmacology. Ed. V.G. Kukesa, edition 4, M.: “GEOTAR-Media”, 2008. pp. 321–396, 458–479. 3. Rizzoni D., Muiesan ML, Porteri E. Effects of long-term antihypertensive treatment with lisinopril on resistance arteries in hypertensive patients with left ventricular hypertrophy. J. Hypertens., 1997; 15 (2): 197-204. 4. Balázsi I., Takács J. The effect of lisinopril on hypertensive patients suffering in diabetic nephropathy Diabetologia Hungarica, 1999; 7.(N2.): 101-106. 5. Kawahara J., Hsieh ST., Tanaka S. et al. Effects of lisinopril on lipid peroxidation, cell membrane fatty acids, and insulin sensitivity in essential hypertension with impaired glucose tolerance. Am J Hypertens 1994; 7:23A. 6. Asselbergs FW, Diercks GFH, Hillege HL et al. for the Prevention of Renal and Vascular Endstage Disease Interventional Trial (PREVEND IT) Investigators. Effect of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria // Circulation. – 2004. – Vol. 110. – P. 2809-2816. 7. Diercks GF, Janssen WM, van Boven AJ et al. Rationale, design, and baseline characteristics of a trial of prevention of cardiovascular and renal disease with fosinopril and pravastatin in nonhypertensive, nonhypercholesterolemic subjects with microalbuminuria (the Prevention of REnal and Vascular ENDstage Disease Intervention Trial) // Amer. J. Cardiology. – 2000. – Vol. 86. – P. 635-638. 8. Chazova I.E., Mychka V.B. Metabolic syndrome. M.: Media Medica, 2004. – 163c. 9. Reisin E. TROPHY study. Hypertens. 1997; 30: P.140-145. 10. Zancetti A., Crepaldi G., Bond G. et al. on behalf of PHYLLYS Investigators. Different effects of antihypertensive regimens based on fosinopril or hydrochlorthiazide with or without lipid lowering with pravastatin on progression of asymptomatic carotid atherosclerosis. Princioal results of PHYLLIS – a randomized double-blind trial // Stroke. – 2004. – Vol. 35. – P. 2807-2812. 11. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. //Lancet.– 2002– 359(9311) – P. 995–1003. 12. Brenner B.M., Cooper M.E., de Zeeuw D., Grunfeld J.–P., Keane W.F., Kurokawa K., McGill J.B., Mitch WE., Parving H.H., Remuzzi G., Ribeiro A.B., Schluchter M.D., Snavely D., Zhang Z, Simpson R, Ramjit D, Shahinfar S: Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL). JRAAS 2000;1:328–35. 13. Dang A., Zhang Y., Liu G. et al: Effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia in Chinese population. J hum Hypertense 2006; 20:45–49. 14. Kukes V.G., Ostroumova O.D., Starodubtsev A.K. Calcium antagonists: modern aspects of application in cardiology. Consilium medicum, 2006; Vol. 8 (No. 11): 113–117. 15. Pitt B, Byington RP, Furberg CD et al. (for the PREVENT investigators). Effect of amlodipine on progression of atherosclerosis and the occurrence of clinical events. Circulation 2000; 102(13):1503–10. 16. Preobrazhensky D.V., Sidorenko B.A. Differential drug therapy for arterial hypertension. Consilium Medicum. 2001; Volume 3 (10): 83–87. 17. Passeron J., Panly N., Despart J. International multicentre study of indapamide in the treatment of essential arterial hypertension. Postgrad. Med. J., 1981; 57:53–64.

Despite the efforts of scientists, doctors and health authorities, arterial hypertension (HTN) in the Russian Federation remains one of the most significant medical and social problems. This is due to both the widespread prevalence of this disease (about 40% of the adult population of the Russian Federation has elevated blood pressure [BP]), and the fact that hypertension is the most important risk factor for major cardiovascular diseases - myocardial infarction and cerebral stroke, which mainly determine high blood pressure. mortality in our country [1].

According to modern concepts, the main goal of antihypertensive therapy (AHT) is to reduce mortality and the incidence of complications. Therefore, the goals of treatment include not only achieving the target blood pressure level, but also protecting target organs (heart, brain, kidneys) [1]. As large clinical studies have shown, to solve this problem, most patients with hypertension required the use of a combination of two or more drugs [2]. Currently, combined AHT is becoming one of the main directions in the treatment of hypertension. Modern approaches to the treatment of hypertension have significantly expanded the indications for combined antihypertensive therapy: according to the Russian recommendations for the diagnosis and treatment of hypertension, 4th revision (2010), it is recommended to begin treatment with it, bypassing the stage of monotherapy, in patients with hypertension not only II–III, but even I degree in the presence of a high and very high risk of developing cardiovascular complications. In this case, priority is given to the use of fixed combinations containing two antihypertensive drugs (AGDs) in one tablet [1]. However, studies examining the antihypertensive effectiveness and safety of various fixed combinations are scarce. In the last decade, the organoprotective effects of various antihypertensive drugs have been actively studied. Many studies have been presented that prove the ability of almost all groups of antihypertensive drugs to cause regression of target organ damage (heart, kidneys, brain), including correction of endothelial dysfunction. However, the study of the organoprotective effect of fixed combinations of antihypertensive drugs is just beginning. In table 1 shows rational combinations of AGP and some currently existing fixed combinations.

. Some rational combinations of AGP and fixed combinations of AGP used in Russia.

All currently available guidelines for the treatment of hypertension (American, European, Russian) have developed approaches to selecting a group of antihypertensive drugs in different clinical situations, while approaches to choosing rational combinations for different subgroups of patients with hypertension have not been developed at all [1, 3, 4 ]. And this despite the fact that in all recommendations for the treatment of hypertension, priority is given to combination therapy. In this regard, in the upcoming 4th edition of the Russian recommendations for the diagnosis and treatment of hypertension (2010), for the first time in the world, an attempt is being made to develop indications for the selection of two-component antihypertensive combinations in specific clinical situations. The main indications for prescribing rational combinations of antihypertensive drugs are presented in table. 2 and 3.

. Preferred indications for prescribing rational combinations of antihypertensive drugs.

Recommendations for the selection of rational and possible combinations of antihypertensive drugs for the treatment of patients with hypertension, depending on the clinical situation

Target organ damage:

• LVH – ARA-II/ACEI with TD or AC;
• asymptomatic atherosclerosis – ARA-II/ACEI with AK;
• microalbuminuria – ARA-II/ACEI with TD;
• kidney damage – ARA-II/ACEI with TD;

Associated clinical conditions:

• previous cerebral stroke - any rational combinations of antihypertensive drugs;
• previous MI – β-AB/AC with ARA-II/ACEI, β-AB with AC;
• IHD – β-AB or AK with ARA-II or ACEI;
• CHF – ARA-II/ACEI with β-AB and TD;
• renal failure/proteinuria - ARA-II/ACEI with loop diuretic;
• peripheral arterial diseases – AK with ARA-II/ACEI;

Special clinical situations:

• elderly – ARA-II/ACEI with AK/TD;
• ISAG – AC with TD, AC or TD with ARAII/ACEI;
• metabolic syndrome – ARA-II/ACEI with AK/TD;
• diabetes mellitus – ARA-II/ACEI with AK/TD;
• pregnancy - methyldopa with AK/β-AB.

In this article, we will focus on the possibility of using the most commonly used combination in our country, an antihypertensive-ACEI with a TD (thiazide diuretic).

Currently, the combination of ACEI and TD is still the most frequently prescribed of all non-fixed and fixed combinations of AGP, not only in our country. The high effectiveness and safety of this combination in the treatment of hypertension is noted in the recommendations of the GFOC, EOC-EOG and JNC VII [1, 3, 4]. The rationality of combining an ACE inhibitor with a diuretic for the treatment of patients with hypertension is fully justified. Thus, the antihypertensive effect of ACE inhibitors is based primarily on a decrease in the production of angiotensin II, so they have the most pronounced antihypertensive effect on patients with increased activity of the renin-angiotensin-aldosterone system (RAAS), which has been shown in a number of studies [5]. At the same time, the antihypertensive effect of all diuretics is limited by the inevitable reactive hyperreninemia and secondary hyperaldosteronemia associated with the activation of the RAAS, which inevitably arise during their use, the severity of which is significantly reduced with the simultaneous administration of ACE inhibitors. The combined use of ACE inhibitors and diuretics can significantly increase the effectiveness of both drugs, which leads to an expansion of the range of patients responding to therapy, allowing the target blood pressure level to be achieved more often [5]. In patients with normal and low-renin hypertension, the effectiveness of ACEIs is low, but the addition of a diuretic helps to increase renin activity, restoring sensitivity to ACEIs. As a result, this combination effectively reduces blood pressure in almost all patients, regardless of the initial activity of the RAAS, which allows its use in normo- and even hyporenin forms of hypertension [5]. This is extremely important for the treatment of elderly patients, since normo- and hyporenin forms are very common in them.

An additional decrease in blood pressure during combination therapy with a diuretic and ACE inhibitors is also due to the fact that the latter potentiate the natriuretic effect of diuretics, increasing their effectiveness. The combined use of ACE inhibitors and diuretics leads to an additive antihypertensive effect when using lower doses of both antihypertensive drugs [5].

ACEIs prevent the development of hypokalemia resulting from stimulation of aldosterone production by diuretics by reducing the activity of angiotensin II and reducing the concentration of aldosterone, which promotes the reabsorption of potassium lost when diuretics are prescribed. At the same time, the combined use of ACE inhibitors and diuretics promotes increased sodium excretion from the body, thereby reducing the volume load [5]. When carrying out combination therapy, the metabolic effects of TD and ACEI are very important, especially the effect on insulin resistance, since its presence is associated with an increase in cardiovascular risk in patients with hypertension [2]. The use of diuretics is associated with a negative effect on carbohydrate, lipid and purine metabolism, contributing to an increase in the levels of uric acid, glucose and cholesterol in the blood, which is significantly limited when used together with ACE inhibitors, which counteract the adverse effects of diuretics [5].

While there are many positive aspects, there are several problems associated with the use of an ACEI and diuretic combination. When using this combination as a first choice, there may be concern for the development of hypotension due to the effect of the first dose. The addition of an ACEI to a diuretic may worsen renal function in patients with heart failure, but these problems can be overcome by careful monitoring of the patient in the first days of treatment and gradual titration of the ACEI dose [5].

Reducing the doses of a diuretic and ACEI in a rational combination occurs not only without loss, but even with an increase in the antihypertensive effect, as well as a decrease in the risk of side effects when treated with this combination of drugs. The use of a combination of ACEI + diuretic makes it possible to achieve the target blood pressure level in more than 80% of patients with hypertension: having high antihypertensive effectiveness, this combination has proven a diverse organoprotective effect in the form of reducing the severity of left ventricular myocardial hypertrophy (LVMH), nephroprotection and the ability to restore impaired endothelial function [5 ]. This combination of antihypertensive drugs is intended primarily for patients with chronic heart failure, LVMH, diabetic and non-diabetic nephropathy. It is also very effective in elderly patients with isolated systolic hypertension (ISAH), when monotherapy with ACE inhibitors or diuretics is ineffective (Tables 2, 3).

With combined AHT using an ACE inhibitor and a diuretic, the question of a safe dose of TD remains fundamentally important, since back in 1959 the first report appeared that HCTZ can cause impaired glucose tolerance. Since that time, a lot of evidence has accumulated about the unfavorable effect of TD on carbohydrate metabolism in patients with hypertension, regardless of the presence or absence of diabetes mellitus [5]. In addition to the adverse effect on carbohydrate metabolism, TDs can negatively affect lipid metabolism. The results of a number of clinical studies have shown that the use of TD leads to an increase in total cholesterol levels by 5–20% and triglycerides by 15–30% from the initial level [6]. It has now been proven that only low doses of TD (no more than 12.5–25.0 mg of HCTZ per day) can be used for the permanent treatment of patients with hypertension, even in combination with ACE inhibitors. The safety of low doses of HCTZ in combination with ACE inhibitors has been demonstrated in a number of studies. For example, in a multicenter study that included 505 patients, the use of 12.5 mg of HCTZ in combination with 10 mg of lisinopril reduced blood pressure as effectively as 25 mg of HCTZ [7]. But the higher dose of TD resulted in decreased potassium levels and increased plasma glucose levels. The authors of this study concluded that if monotherapy is ineffective, it is preferable to transfer the patient to combination therapy instead of increasing the dose of TD. In another multicenter study involving 402 patients, HCTZ (6.25 or 12.50 mg/day) was added to enalapril (20 mg/day) [8]. The addition of both doses of TD led to an almost twofold increase in the antihypertensive effect compared to monotherapy with enalapril, but a higher dose of HCTZ did not have a clear advantage. Both doses of HCTZ showed equal safety in terms of side effects and did not lead to metabolic disorders [8]. Based on the current evidence, it is optimal to initiate treatment with low doses of ACEI (eg, lisinopril 10 mg/day) and TD (6.25–12.5 mg/day HCTZ), with a possible subsequent doubling of the doses of one or both drugs (preferably first double the dose of ACEI, and then, if the target blood pressure is not achieved, double the dose of HCTZ). This property of the combination of ACEI and HCTZ in doses of no more than 12.5 mg is of particular importance in geriatric practice, since almost all elderly patients have concomitant atherosclerosis of the coronary, carotid and femoral arteries.

The antihypertensive effectiveness of combinations of various ACE inhibitors with diuretics has been confirmed by a number of studies, including Russian ones [9–13]. For example, one of the representatives of the ACEI class is lisinopril. A multicenter study examined the antihypertensive efficacy and effect on renal function of lisinopril therapy and its fixed combination with the diuretic HCTZ in patients with hypertension [13]. The study included 58 patients (27 men and 31 women) aged 33–75 years (55.0 ± 1.5 years) with an average duration of hypertension of 12.3 ± 1.4 years. 61% of patients had hypertension of I degree and 39% of II degree of severity according to the 2007 VNOK classification based on blood pressure level. After 2 weeks of “clean background,” all patients began treatment with lisinopril at a dose of 10 mg/day once in the morning. After 2 weeks, in patients who did not reach the target blood pressure level (≤ 140/90 mm Hg, and in the presence of diabetes mellitus ≤ 130/80 mm Hg), the dose of lisinopril was doubled (20 mg/day). If monotherapy with lisinopril did not allow achieving the target blood pressure level, the diuretic HCTZ was added to the treatment in the form of a fixed combination with lisinopril (20 mg lisinopril/12.5 mg HCTZ) one tablet once in the morning and an additional visit was scheduled after 2 weeks to assess the effectiveness of the drug. If the target blood pressure level was not achieved during combination therapy, the dose of this fixed combination was doubled (40 mg lisinopril/25 mg HCTZ). The state of kidney function as a target organ in hypertension and its dynamics were assessed using the Reberg test with calculation of glomerular filtration rate (GFR) and determination of microalbuminuria (MAU) in 24-hour urine [13].

The authors note that during monotherapy with lisinopril at a dose of 10–20 mg/day, in the whole group after 4 weeks of therapy there was a significant decrease in blood pressure from 151.2 ± 1.2/92.2 ± 1.2 to 137.2 ± / 85.8 ± 1.2 mm Hg. Art. (Δ -14.0 ± 1.0/-6.4 ± 0.8; p < 0.001). 37% of patients reached the target blood pressure level; the remaining patients were transferred to a fixed combination with 12.5 mg of HCTZ. Over 16 weeks of treatment, the average blood pressure in the group decreased from 151.2 ± 1.2/92.2 ± 1.2 to 127.4 ± 1.0/79.2 ± 0.9 mm Hg. Art. (Δ -23.8 ± 1.5/-13.0 ± 1.1; p < 0.001). No significant dynamics of heart rate were noted. 98% of patients achieved target BP [13].

Since patients with renal failure were not included in the study, the blood creatinine level in all patients remained within the range of 63.7–140.0 (89.2 ± 2.4) μmol/L. GFR ranged from 69.8 to 187.1 (98.7 ± 4.5) ml/min. In 28% of patients, hyperfiltration was detected, which is the main non-immune mechanism of progression of hypertensive nephropathy, eventually leading to a decrease in GFR and an increase in the level of nitrogenous wastes in the blood [14], which is confirmed by the presence of a negative correlation between the level of creatinine and GFR. MAU was detected in 72% of patients. Daily albumin excretion was 5–290 (45.3 ± 6.0) mg/day. The severity of MAU increased with increasing severity of hypertension (r = 0.57, p = 0.003) from 37.1 ± 4.4 mg/day at grade I to 58.8 ± 13.9 mg/day at grade II hypertension (p = 0.003) [13].

The authors also noted that treatment with lisinopril as monotherapy and its fixed combination with HCTZ led to a decrease in MAU levels by more than 2 times (ΔMAU -28.6 ± 3.9 mg/day; p < 0.001), as well as an increase in GFR with 80.8 ± 2.6 to 97.7 ± 3.0 ml/min (ΔGFR 20.7 ± 3.4 ml/min, p < 0.001) in patients with initially normal and reduced GFR and a decrease in GFR from 145.7 ± 5.1 to 120.2 ± 7.3 ml/min (ΔGFR -26.9 ± 7.3 ml/min; p = 0.005) with initial hyperfiltration. The multidirectional effect of therapy on GFR in patients with initially normal and elevated GFR is a positive development, since hyperfiltration is currently considered as the main non-immune mechanism for the development of nephrosclerosis, which leads to the progression of hypertension and the development of renal failure [2, 5, 14]. The absence of a decrease in GFR during ADT in patients without hyperfiltration indicates a clear nephroprotective effect of therapy. A decrease in MAU levels over 16 weeks of therapy occurred in all (100%) patients, with normalization in 88% of patients with initially elevated MAU [13].

According to the researchers, in the group of patients who were “insensitive” to lisinopril monotherapy, who initially had a significantly higher level of blood creatinine and a lower GFR, combination therapy with lisinopril with HCTZ had a beneficial effect on renal function in the form of a statistically significant decrease in MAU levels from 53.1 ± 9.2 to 20.4 ± 5.4 mg/day (ΔMAU -32.7 ± 5.8 mg/day, p < 0.001) and an increase in GFR from 87.4 ± 4.2 to 113.3 ± 3 .5 ml/min (ΔGFR 25.9 ± 3.1 ml/min, p < 0.001) [13].

Attention should be paid to the fact that biochemical blood parameters (potassium, sodium, glucose, alanine aminotransferase, aspartate aminotransferase) did not change significantly during therapy with both drugs. Tolerability of lisinopril and its fixed combination with HCTZ was good; no differences in tolerability were identified. Adverse events in the form of a dry cough were noted in one patient; they were mild and went away on their own after discontinuation of the drug [13].

There is also data on the effectiveness and safety of combinations of other ACE inhibitors, such as enalapril, perindopril, moexipril, fosinopril, with thiazide and thiazide-like diuretics [9–12]. However, almost all studies using ACE inhibitors and a diuretic, with rare exceptions [9, 12], did not aim to evaluate the effectiveness and safety of treatment with a combination of drugs. As a rule, it was either an ACEI or a diuretic, and the second drug was added only if the first was ineffective, which dictates the need for further research.

The problem of hypertension is especially relevant for elderly patients, since the prevalence of hypertension increases with age and after 50 years of age exceeds 50%, and in people over 80 years of age – 80% [15]. In addition, the presence of hypertension has a significant impact on the health status, duration and quality of life of elderly patients, since it is an independent prognostically independent risk factor for the development of cardiovascular diseases such as stroke, coronary artery disease, and premature death. Thus, age over 55 years for men and over 65 years for women is one of the additional risk factors when stratifying the risk of cardiovascular complications [16]. In other words, at the same level of blood pressure, both systolic and diastolic, the risk of developing coronary artery disease (Fig. 1) and stroke is always higher in elderly patients compared to younger patients. Therefore, when treating elderly patients, achieving target blood pressure levels is especially important. In this regard, the high antihypertensive effectiveness of the combination of an ACE inhibitor and a diuretic, in particular lisinopril and HCTZ, is very significant.

This pronounced increase in the frequency of hypertension in elderly people has its explanation from the point of view of pathogenesis. With age (after 60 years), even in practically healthy people, the number of functioning nephrons decreases by 2 times [17]. Accordingly, the filtration area decreases and volume-dependent increases in blood pressure occur. This creates conditions for increasing the effectiveness of diuretics in the treatment of hypertension in people of this age group. With age, the distensibility of the aorta also decreases, which is currently considered the main mechanism for the development of ISAH in the elderly [18, 19], sensitivity to table salt increases [20], and endothelial dysfunction develops (the production of vasodilatory factors, in particular nitric oxide, decreases and vasoconstrictor increases). ) [21].

The incidence of ISAH increases with age, exceeding 40% in patients over 60 years of age [22]. ISAH refers to an increase in systolic blood pressure (SBP) to 140 mmHg. Art. and higher with diastolic blood pressure (DBP) less than 90 mm Hg. Art. [1]. On the other hand, among patients with ISAH, people over 60 years of age predominate: in this age subgroup, ISAH accounts for 65–75% of all cases of hypertension [22]. This is apparently due to the fact that the increase in SBP occurs at least until the age of 80, while the increase in diastolic blood pressure occurs only until the age of 50, and then it either levels off or tends to decrease (Fig. 2 ) [23].

The importance of highlighting the problem of ISAH is due to the fact that an increase in SBP, including an isolated increase (with normal DBP), is an important risk factor for the development of cardiovascular, cerebral complications and chronic renal failure [24, 25]. Therefore, to regard an increase in SBP as a manifestation of the age norm, as was the case about 10 years ago, is a serious mistake, which has the most serious consequences for the patient. Increases in SBP and DBP as risk factors for the development of all complications of hypertension are at least equivalent, and it is necessary to achieve their complete normalization. Moreover, in many cases, an increase in SBP plays an even greater role in the development of cardiovascular complications: people of all age groups are at risk of developing all cardiovascular complications of hypertension (CHD, including myocardial infarction, stroke, heart failure, atherosclerosis of peripheral arteries) correlated more strongly with SBP rather than DBP [24, 25]. It has been established that ISAH increases mortality from cardiovascular pathology by 2–5 times and overall mortality by 51% compared with that in individuals with normal blood pressure [24].

The first choice for the treatment of ISAH includes thiazide and thiazide-like diuretics [1]. Their use in patients with ISAH leads not only to normalization of blood pressure, but also to a reduction in mortality and the risk of complications (heart attack, stroke, heart and kidney failure, dementia). So, if you reduce SBP by at least 12–13 mm Hg. Art., this will lead to a reduction in the risk of developing coronary artery disease and stroke (by 21 and 37%, respectively) and mortality from these causes (by 27 and 36%, respectively) [25]. In this regard, the use of fixed combinations, which include diuretics, is especially important in real clinical practice. The differences among the many fixed combinations containing the combination of ACEI and HCTZ are based, of course, on differences in the properties of the ACEI.

Particular attention has been paid to the treatment of hypertension in the elderly by drugs whose metabolism does not depend on a number of factors, including liver function. It is well known that patients over 60 years of age have many concomitant diseases, and one of the most common is various liver pathologies. Therefore, lisinopril deserves special attention when choosing an ACE inhibitor for this category of patients. Its distinctive pharmacokinetic features are very low lipophilicity and lack of metabolism in the body [26]. Eating does not affect the absorption of the drug. It is the only(!) of the ACE inhibitors that is not metabolized in the liver. Peak concentrations in the blood are observed 7 hours after taking the drug. The half-life is 12 hours; lisinopril is prescribed once a day. Excreted by the kidneys. This drug, unlike all other long-acting ACE inhibitors, is an active substance, and not a prodrug that requires metabolic changes. This is a great clinical advantage of lisinopril, since it can be prescribed at the same dose to patients with any concomitant liver pathology without loss of clinical effect, unlike all other ACE inhibitors.

Therefore, fixed combinations containing lisinopril and HCTZ are common in Russia. I would like to draw your attention to the drug Liten H, which is available in two versions: lisinopril 10 mg + HCTZ 12.5 and lisinopril 20 mg + HCTZ 12.5 mg. The presence of two dosages allows the doctor to more individually select treatment for each patient. Thus, for grade I hypertension (BP 140–159 and/or 90–99 mm Hg), treatment should begin with lisinopril 10 mg + HCTZ 12.5 mg, and if necessary, especially with a high and very high risk of complications. , in the future switch to the option of lisinopril 20 mg + HCTZ 12.5 mg. For grade II hypertension (BP – 160–179 and/or 100–109 mm Hg), it is immediately recommended to prescribe lisinopril 20 mg + HCTZ 12.5 mg.

Thus, combination therapy, primarily fixed combinations of antihypertensive drugs, is currently the first-line therapy in the treatment of hypertension. Currently, the combination of ACEI and TD HCTZ is still the most frequently prescribed combination in a very large number of clinical situations, including in the treatment of hypertension in the elderly and ISAH. Its distinctive features are high antihypertensive effectiveness, low frequency of side effects (including due to neutralization of each other's side effects), the presence of organoprotective properties, metabolic neutrality (provided the dose of HCTZ is not more than 12.5 mg). The additional properties of ACE inhibitors, in particular lisinopril, are also of great importance for clinical practice. Wider and more rational use of these fixed combinations will improve the effectiveness of hypertension treatment and reduce the risk of cardiovascular complications and death.