Arterial hypertension: drugs ACE inhibitors and sartans

Arterial hypertension is the most common cardiovascular pathology, affecting about 40% of the adult European population [1]. Of course, this leads to high demand for antihypertensive drugs, regardless of the season. And although the chief’s task is, first of all, to offer several drug options according to the INN prescribed in the prescription, he also has to explain side effects, dosage, and sometimes answer questions about the features of the mechanism of action. Therefore, we decided to offer our readers a series of articles about the group of antihypertensive drugs and the features of working with requests for them. Let's start with blockers of the renin-angiotensin-aldosterone system.

RAAS: the basics

Before we begin describing the drugs, let’s dive briefly into the intricacies of pharmacology and once again remember what the mechanism of action of the renin-angiotensin-aldosterone system, or RAAS, is.

The RAAS is a complex hormonal-enzymatic system in which almost all organs and tissues of the body are involved, but the key roles in it belong to the liver, kidneys, adrenal glands and lungs.

Alpha-2‑globulin angiotensinogen is constantly synthesized in the liver. At the same time, the kidneys produce the enzyme renin in response to decreased intrarenal pressure, decreased delivery of sodium and chloride, and hypoxia. It enters, like angiotensinogen, into the systemic circulation, where it binds to it to form angiotensin I.

Angiotensin I is a practically inert substance. It does not act on blood vessels and is only a precursor of the active component angiotensin II. In the formation of the latter, along with angiotensin I, angiotensin-converting enzyme (ACE), which is produced in the lungs, is involved.

Angiotensin II is the main link in the RAAS circuit.

It exhibits a powerful vasoconstrictor effect and affects the target organs in which its receptors are located. First of all, we are talking about the endothelium, heart and kidneys. This is why high levels of angiotensin II are associated not only with increased blood pressure, but also with damage to the vascular wall, myocardium, kidneys, and the development of chronic heart and kidney failure.

In addition, angiotensin II causes increased synthesis of the adrenal hormone aldosterone. The latter is involved in the control of blood pressure (BP) by regulating the homeostasis of potassium, sodium and intracellular fluid volume. Under its influence, blood pressure increases and the sensitivity of vascular smooth muscles to vasoconstrictor substances, including angiotensin II, increases.

Thus, the RAAS is directly involved in the drama called “arterial hypertension”, playing one of the main roles in it. Fortunately, it is possible to block this system. This can be done with drugs of two pharmacological groups - angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs, also known as sartans).

The first class of drugs is ACE inhibitors.

Drugs of this group became one of the first classes of drugs that effectively reduce the activity of the RAAS; their development began in the 60s of the last century [2]. Today they are included in the category of so-called “life-saving drugs” due to their proven ability to improve the prognosis of a number of cardiovascular and renal diseases [2].

ACE inhibitors: mechanism of action and effect

ACE inhibitors reduce the level of circulating angiotensin II by blocking the angiotensin-converting enzyme, which causes a complex pharmacological effect:

antihypertensive;
cardioprotective;
angioprotective;
antiatherosclerotic;
anti-inflammatory.

When taking drugs from the ACE inhibitor group, carbohydrate metabolism also improves: tissue sensitivity to insulin increases and glucose metabolism improves.

Indications and properties

The spectrum of activity of ACE inhibitors allows their use in arterial hypertension, coronary heart disease, chronic heart failure, nephropathies and acute myocardial infarction [3].

ACE inhibitors belong to the group of antihypertensive drugs that specifically lower blood pressure and slow the progression of heart failure, which determines their widespread use in cardiology. Data from a review of 158,998 patients with hypertension showed that taking ACE inhibitors reduces mortality from all of the above causes. This is a significant advantage of ACE inhibitor drugs, including compared to angiotensin II blockers [4].

However, ACE inhibitors are still not able to completely prevent the conversion of angiotensin I to angiotensin II, since there are a number of other enzymes that successfully “replace” ACE. This is exactly how the enzymes chymase, elastase and cathepsin G work, for example [5]. When using ACE inhibitors, these substances are compensatory activated, and the blockade of the RAAS becomes incomplete. This is a significant drawback of ACE inhibitors.

What should I warn the client about?

Important!

During the consultation, it is appropriate to emphasize that drugs that block the activity of the RAAS - ACEIs and ARBs - with constant use, along with an antihypertensive effect, protect the heart and blood vessels, significantly reducing the incidence of cardiovascular accidents. This small note can serve as a convincing argument in favor of regular and disciplined use of such drugs, according to the instructions and recommendations of the doctor.

Use of ACE inhibitors in clinical practice

Angiotensin-converting enzyme (ACE) inhibitors have been used in cardiology for almost 30 years. During this time, thanks to a large number of large studies, the effectiveness of this group of drugs in the treatment of arterial hypertension (AH), heart failure (HF), left ventricular (LV) dysfunction, hypertensive and diabetic nephropathy has been proven.

Currently, ACE inhibitors include a large number of drugs that differ in physicochemical and pharmacokinetic properties. Depending on the nature of the group that directly binds to the active site of ACE, all ACE inhibitors are divided into three categories: sulfhydryl (benazepril, captopril), carboxyl (cilazapril, enalapril, lisinopril, perindopril, ramipril, spirapril, trandolapril) and phosphonyl (fosinopril) . Most ACE inhibitors, except captopril and lisinopril, are prodrugs and are converted to active metabolites in the liver or gastrointestinal tract. Prodrugs are more lipophilic and, after conversion to active metabolites, penetrate better into target organs, however, in patients with diseases and impaired liver function, inhibition of the activation of ACE inhibitors during the first passage through it is observed, which must be taken into account when choosing a drug.

Basically, ACE inhibitors and their metabolites are excreted by the kidneys, and some of them, such as fosinopril, trandolapril and spirapril, are excreted both in urine and bile.

Capoten has a short duration of action, and therefore it must be prescribed 3-4 times a day; other ACE inhibitors are characterized by a prolonged action and can be prescribed 2 or 1 time a day.

All ACE inhibitors have the same mechanism of action - ACE inhibition, which leads to a decrease in the formation of angiotensin II from angiotensin I due to a decrease in its level in the blood and tissues. At the same time, both the secretion of aldosterone and vasopressin and the activity of the sympathetic nervous system decrease. ACE inhibitors suppress kininase II, as a result of which the decay of bradykinis is inhibited.

na - a powerful stimulator of the release of endothelium-dependent relaxation factors: nitric oxide, endothelium-dependent hyperpolarization factor and prostacyclin.

The main therapeutic effects of ACE inhibitors are as follows:

decrease in total peripheral vascular resistance;
reduction of LV pre- and afterload;
increased natriuresis;
reduction of hypertrophy of the vascular wall and myocardium;
improvement of endothelial function;
decreased platelet aggregation.

Side effects with the use of ACE inhibitors occur relatively rarely. Such impacts include:

arterial hypotension;
allergic reactions, including angioedema;
hyperkalemia associated with decreased aldosterone secretion (can be observed in patients with congestive heart failure, in the elderly, in patients with renal failure and diabetes mellitus);
acute renal failure, which often develops during treatment with diuretics in high doses, in elderly patients with heart failure, in the presence of hyponatremia, bilateral renal artery stenosis or stenosis of the artery of a single kidney. In these conditions, ACE inhibitors reduce glomerular filtration, which leads to an increase in creatinine levels;
proteinuria.

The most common side effect of ACE inhibitors is a dry cough, which develops in 5–10% of patients. The cause of this effect has not been established, but it has been suggested that it may be caused by an increase in bradykinin levels in lung tissue. ACE inhibitors do not differ in their ability to cause cough.

Allergy and bilateral renal artery stenosis are absolute contraindications to the use of ACE inhibitors. They should also not be prescribed to patients with hypertrophic cardiomyopathy. ACE inhibitor therapy should be discontinued if potassium levels are greater than 6.0 mmol/L, creatinine levels are greater than 50%, or creatinine levels are greater than 3 mg/dL (256 mmol/L).

ACE inhibitors for hypertension

According to Russian guidelines for hypertension, developed on the basis of the latest European guidelines for the control of hypertension, the main goal of treatment for patients with hypertension is to reduce the risk of developing cardiovascular complications (CVC) and death from them [1]. In this case, one of the most important conditions is to achieve the target level of blood pressure (BP), which is taken to be BP < 140/90 mmHg. Art. When hypertension is combined with diabetes mellitus or kidney damage, it is recommended to reduce blood pressure to a level < 130/80 mm Hg. Art. To date, none of the classes of antihypertensive drugs has a significant advantage in terms of lowering blood pressure and preventing the development of cardiovascular events. With regard to their use, each class of drugs occupies its own niche, determined taking into account indications and contraindications (Table 1).

As can be seen from Table 1, ACE inhibitors firmly occupy a place on the list of first-line antihypertensive drugs and have many niches for use. Based on the results of multicenter randomized trials, it can be concluded that ACE inhibitors are the first choice drugs in patients with heart failure, left ventricular systolic dysfunction or diabetes mellitus, in patients with a history of myocardial infarction or stroke, as well as in patients at high risk of coronary heart disease [ 2, 3].

The first randomized large-scale study to demonstrate the effectiveness of ACE inhibitors in reducing cardiovascular events following diuretics and beta-blockers was the CAPPP study (The Captopril Prevention Project), which compared the effect of ACE inhibitors (captopril 50 mg) and standard therapy (diuretics, beta-blockers). blockers) on morbidity and mortality from cardiovascular diseases in patients with hypertension. The results of a 6-year follow-up demonstrated that the risk of developing cardiovascular complications was the same in both groups. At the same time, the incidence of diabetes decreased with captopril treatment. Also, in patients with concomitant diabetes mellitus, there was a decrease in the incidence of cardiovascular events on the background of ACE inhibitors [6].

In the PROGRESS study, patients who had suffered a stroke or transient ischemic attack, both with and without hypertension, received active treatment with perindopril, 4 mg; if necessary, indapamide, 2.5 mg, was included in the treatment regimen. As a result of a 4-year follow-up, it was found that combination therapy led to a more pronounced reduction in the risk of recurrent stroke and the risk of any vascular complications, however, monotherapy with perindopril made it possible to achieve a clinically significant reduction in the risk of stroke [4].

The ABCD (Appropriate Blood Pressure Control Diabetes) study compared the effectiveness of long-term treatment with enalapril and nisoldipine in patients with hypertension and concomitant diabetes mellitus. After 5 years of observation, it was found that with the same reduction in blood pressure in both groups, the frequency of fatal and non-fatal myocardial infarction was 5 times lower among patients taking enalapril [5].

ACE inhibitors for heart failure

ACE inhibitors are indicated for all patients with systolic dysfunction (ejection fraction 40–45%), regardless of whether it is combined with clinical signs of HF, in the absence of contraindications.

Note that taking ACE inhibitors does not always lead to an improvement in functional class and exercise tolerance. In patients with circulatory failure, the main goal of ACE inhibitor therapy is to reduce mortality, rehospitalization rates, and progression of HF. Not all drugs in this class have been studied in various studies, and adequate dosages have not been established in all cases, so you should start with minimal dosages, gradually increasing them to target values that have been proven to be effective in large controlled studies (Table 2), or to maximum tolerated dose. Such treatment tactics are justified by the fact that low doses of ACE inhibitors do not achieve the main goal of therapy—increasing survival. Therapy with ACE inhibitors should be carried out under the control of blood pressure, creatinine and potassium levels.

Recommended doses of ACE inhibitors for HF

The CONSENSUS and SOLVD studies demonstrated that enalapril significantly reduced mortality in patients with chronic HF, regardless of functional class. The CONSENSUS study included patients with functional class IV. The inclusion of enalapril in the standard regimen of digoxin and diuretics after 6 months led to a significant reduction in mortality [7]. The results of the SOLVD study confirmed the beneficial effect of enalapril on survival in chronic circulatory failure in patients of functional class II–III [8]. The SOLVD study also demonstrated a reduction in mortality and progression of HF in patients who suffered a myocardial infarction with LV dysfunction without clinical signs of HF. Improved survival early after myocardial infarction (days 3 to 15) was demonstrated in the AIRE (Ramipril Therapy) study, which included patients with clinical signs of HF, as well as the SAVE (Capoten therapy) and TRACE studies ( therapy with trandolapril) carried out in patients with LV systolic dysfunction.

The use of ACE inhibitors in high-risk patients

The issue of the appropriateness of prescribing ACE inhibitors to patients with cardiovascular diseases without HF has been discussed for a long time. The final answer to this question was provided by the HOPE (ramipril therapy) and EUROPA (perindopril therapy) studies, which convincingly proved the benefits of using ACE inhibitors in patients with coronary heart disease and other forms of atherosclerosis.

The HOPE study [9] enrolled patients over 55 years of age with various forms of atherosclerosis (coronary heart disease, peripheral artery disease, stroke) or diabetes mellitus and at least one other risk factor. However, there were no clinical signs of HF or decreased LV ejection fraction. For 5 years, patients were prescribed ramipril or placebo. Treatment with ramipril significantly reduced the risk of death from cardiovascular causes, myocardial infarction and stroke. The reduction in blood pressure in the ramipril group was relatively small, so the improvement in long-term outcome in patients at high risk of developing cardiovascular complications, according to the results of this study, cannot be explained only by the hypotensive effect of the drug.

Evidence of the effectiveness of ACE inhibitors in patients with stable coronary heart disease was obtained during the EUROPA study, which included patients suffering from stable coronary heart disease without HF. For 4 years, they were treated with perindopril or placebo, which were added to the standard treatment regimen. When taking perindopril, mortality rates from cardiovascular diseases, myocardial infarction and the number of sudden deaths decreased [10].

The results obtained may be associated with the presence of some additional effects, for example, with an improvement in endothelial function, since endothelial dysfunction is currently considered as an early risk factor for the development of atherosclerosis and atherothrombosis [10].

Thus, summing up all of the above, it can be noted that ACE inhibitors are a class of drugs that are well tolerated by patients, cause the least amount of side effects, and are metabolically neutral. In addition, their effectiveness has been convincingly proven thanks to a huge number of large studies conducted among patients with cardiovascular pathology.

Literature

Russian national recommendations for the diagnosis and treatment of arterial hypertension. Second revision//Cardiovascular therapy and prevention. 2004. No. 6.
Wood D., De Backer G., Faergeman O., Graham I., Mancia G. and Pyorala K. et al. For the Second Joint Task Force of European and other Societies-ton Coronary Prevention: European Society of Cardiology, European Atherosclerosis Society, European Society of Hypertension, International Society of Behavioral Medicine, European Society of General Practice/Family Medicine, European Network. Prevention of coronary heart disease in clinical practice. Eur Hear J. 1998; 19: 1434–1503.
Chobanian AV, Bakris GL, Black HR et al. The seventh report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure. JAMA. 2003; 289:2560–2572.
PROGRESS Collaborative group. Effects of a perindopril-based blood pressure lowering regimen on cardiac outcomes among patients with cerebrovascular disease. Eur Heart J. 2003; 24:475–484.
Estasio RO, Jeffers BW, Hiatt W. et al. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. ABCD Study //N Eng J Med. 1998; 338:645–652.
CAPPP Hansson L., Lindholm L.H., Niskanen L. et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the captopril prevention project (CAPPP) randomized trial // Lancet. 1999; 353:611.
Consensus Trial Study group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med. 1987; 316:1429–1435.
The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Ensi J Med. 1991; 325:293–302.
The HOPE Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on death from cardiovascular causes, myocardial infarction, and stroke in high-risk patients. N Engl J Med. 2000; 342:145–153.
Taddei S., Virdis A., Chiadoni L., Salvetti A. The pivotal role of endothelium in hypertension / Medicographia. Issue 59. 1999; 21:1: 22–29.

D. V. Nebieridze , Doctor of Medical Sciences, Professor F. S. Papova, Candidate of Medical Sciences GNITSPM, Moscow

ACE inhibitors: remember by name

Let's consider the features of some drugs - representatives of the ACE inhibitor group.

Captopril is the first non-peptide ACEI, synthesized in 1975 [2]. The only tableted ACEI used to relieve hypertensive crisis. The dose is prescribed by the doctor (12.5–50 mg).
Lisinopril is the only hydrophilic ACEI that does not accumulate in adipose tissue. Therefore, it is recommended for hypertension against the background of excess body weight and metabolic syndrome [2].
Ramipril is an ACE inhibitor, which in a randomized trial demonstrated a significant reduction in overall mortality from CVD in high-risk patients by 16%, mortality from myocardial infarction by 20%, from stroke by 32%, and from chronic heart failure by 23% [ 6]. In addition, the incidence of new cases of diabetes while taking ramipril was 33% lower than in the placebo group [7].
Fosinopril is an ACE inhibitor that is suitable for patients with hypertension due to severe renal failure, since it is eliminated in two interchangeable ways: through the liver and kidneys.
Enalapril is the only ACEI that has a parenteral form (the active metabolite of enalapril is enalaprilat). Enalaprilat, like captopril, is used to relieve hypertensive crisis.
Zofenopril is one of the most lipophilic ACE inhibitors. Due to its high lipophilicity, it easily penetrates into organs and tissues, showing a special affinity for the heart and blood vessels. It has a long-term anti-ischemic and cardioprotective effect, and exhibits an antioxidant effect [8].
Spirapril has a long half-life, which provides a long-lasting and uniform antihypertensive effect. Does not require dose titration [9].
Quinapril has high tissue specificity - it suppresses ACE in the plasma, lungs, kidneys, heart, and vascular walls. Improves the function of the vascular endothelium, providing an antiatherosclerotic effect [10].

Tolerability of ACE inhibitors

The subject of special attention of pervostolniks, as specialists dispensing the drug, is the side effects of ACE inhibitors. Despite the generally favorable safety profile, adverse reactions are the weak link of drugs in this group.

What should I warn the client about?

While taking ACE inhibitors, a dry cough develops in 1–10% of cases [6]. Different members of the group practically do not differ from each other in their ability to cause it, and replacing one ACE inhibitor with another does not improve tolerability in this regard [11].
When taking single-agent ACEIs, Quincke's edema can extremely rarely occur (but more often than when taking other antihypertensive drugs) [2]. It is believed that drugs in this group do not cause this complication, but alleviate its occurrence in predisposed patients. When releasing ACE inhibitors, it is appropriate to emphasize that if difficulty breathing and shortness of breath occur, you should immediately contact your doctor [11].

The cause of cough while taking ACE inhibitors has not been fully determined. It is assumed that the leading role is played by the accumulation of bradykinin in the bronchial mucosa, which is activated by blockade of angiotensin II [11].

Diagnosis of sarcoidosis (angiotensin-converting enzyme (ACE) activity)

Sarcoidosis

- a systemic disease with a chronic course, in which the lymph nodes of the mediastinum can be affected, characterized by the formation of granulomas (limited foci of inflammation, consisting of an accumulation of normal and modified cells) in the affected tissues.
In addition to lung lesions, extrapulmonary symptoms are often observed, such as eye lesions (uveitis), erythema nodosum, arthritis, and the formation of granulomas in the central nervous system, reminiscent of multiple sclerosis. The cause of sarcoid granulomas is unknown. Granulomas, consisting of inflammatory cells, are metabolically active and produce mediators of the immune response. One of the products of sarcoid granulomas is ACE. The activity of angiotensin-converting enzyme (AFP)
is a regulator of the activity of the renin-angiotensin system, which plays a key role in the regulation of blood pressure, water and electrolyte metabolism in humans.

ACE is found mainly in lung tissue. It is found in small quantities in the epithelium of the proximal tubules of the kidneys and vascular endothelium. Currently found in almost all tissues. ACE is involved in the formation of angiotensin II from angiotensin I.

Under the influence of the kidney enzyme renin, the decapeptide angiotensin I is split off from angiotensinogen. Further, under the action of the ACE enzyme in the blood serum, a dipeptide is split off from angiotensin I and a powerful blood pressure regulator is formed - angiotensin II, the excess of which causes essential hypertension. In addition, ACE destroys bradykinin, a low molecular weight peptide that leads to a decrease in blood pressure.

ACE in sarcoidosis is balanced by other blood pressure regulation systems, so there is no significant increase in blood pressure in this disease. The synthesis of ACE in sarcoidosis depends on the total number of sarcoid granulomas: its content is higher in extrapulmonary manifestations of the disease. In sarcoidosis, high ACE activity is observed in 70% of patients, more often with extrapulmonary lesions. An increase in ACE activity in the blood serum may indicate an exacerbation of the disease. The administration of steroid hormones significantly reduces the synthesis of ACE. Increased ACE activity is found in cardiovascular diseases, primarily in heart failure. An increase in enzyme activity is a risk factor for heart attack. ACE inhibitors are often used in the treatment of hypertension and diabetes; the use of these drugs affects test results. Enzyme activity may be nonspecifically increased in asthma, steroid hormones, berylliosis, asbestosis, silicosis, tuberculosis, emphysema, lymphogranulomatosis, hyperthyroidism, idiopathic pulmonary fibrosis, diabetes and a number of other conditions. Often high activity can be detected in Gaucher disease. In children, ACE levels are higher than in adults (reaching adult levels by the end of adolescence).

Indications:

diagnosis and differential diagnosis of sarcoidosis;
diagnosis of neurosarcoidosis;
monitoring the course of sarcoidosis;
assessment of the severity of heart failure.

Preparation
Before drawing blood, it is recommended that you fast for 12 hours and limit your fluid intake. Taking steroid hormones should be interrupted 2 days before the study. Taking ACE inhibitors affects the study results.

You should discuss with your doctor the advisability of examination while taking these drugs or their temporary withdrawal (the period of withdrawal depends on the half-life of the drug).

Interpretation of results

Units of measurement: Unit. ACE Unit.

Reference values:

Children from 6 months to 18 years: 29–112 units. APF.
Adults from 18 to 120 years: 20–70 units. APF.

Promotion:

sarcoidosis (high ACE activity in 70% of patients);
cardiovascular diseases, heart failure;
Enzyme activity may be nonspecifically increased in asthma, steroid hormone use, berylliosis, asbestosis, silicosis, tuberculosis, emphysema, lymphogranulomatosis, hyperthyroidism, idiopathic pulmonary fibrosis, diabetes and a number of other conditions. Often high activity can be detected in Gaucher disease.

Note. Taking medications may affect test results. ACE inhibitors (captopril, enalapril, ramipril, etc.) interfere with the test result in the direction of reducing the result. The use of steroids in patients with sarcoidosis leads to a decrease in serum ACE activity.

The second class of drugs is angiotensin II receptor blockers.

Research that has focused on studying the possibilities of blocking the RAAS has led to the discovery of a group of drugs that do not have the classic disadvantage of ACE inhibitors - the side effect of cough. ARBs, or sartans, block the RAAS more completely, resulting in better tolerability than their predecessors. Despite their relatively recent introduction into clinical practice - sartans began to be used for long-term treatment of hypertension only in 1999 - representatives of this group have today become one of the most popular antihypertensive drugs [12].

Sartans: mechanism of action and effect

The pharmacological effect of sartans is identical to the effect of ACE inhibitors. Due to competitive blockade of angiotensin II receptors, they suppress vasoconstriction, aldosterone secretion, reduce myocardial hypertrophy, and also improve endothelial function.

The mechanism of action of ARBs is not the blockade of angiotensin-converting enzyme, as is the case with ACE inhibitors, but the blockade of angiotensin AT1 receptors, through which the vast majority of the physiological effects of angiotensin II are realized (vasoconstriction, etc.). AT1 receptors are located predominantly in vascular smooth muscle, heart, liver, adrenal cortex, kidneys, lungs and brain.

Over the past 10 years, drugs have appeared that some experts propose to separate into a separate, second generation of ARBs. They not only block AT1 receptors, but also help normalize carbohydrate and lipid metabolism.

Indications and properties

Sartans, like ACE inhibitors, are prescribed for a number of diseases, including arterial hypertension, chronic heart failure, previous myocardial infarction, diabetic nephropathy, atrial fibrillation and metabolic syndrome. In addition, ARBs become the drugs of choice in situations where cough develops while taking ACE inhibitors [13].

The effectiveness of sartans has been proven to significantly reduce blood pressure and have a cardioprotective effect [13, 14], as well as:

reduce the incidence of myocardial infarction and stroke;
reduce the frequency of hospitalizations due to chronic heart failure;
reduce the severity of symptoms of CHF;

In addition, some ARBs, like ACEIs, reduce the likelihood of developing diabetes and exhibit nephroprotective effects.

The place of angiotensin receptor blockers in the treatment of arterial hypertension. Answers on questions.

- Dear Colleagues! Today we started with cardiology, and we are again moving into this very interesting area. Our program will be continued by Professor Maksim Leonidovich Maksimov, “The place of angiotensin II receptor blockers in the treatment of arterial hypertension.” Please, Maxim Leonidovich.

Maxim Leonidovich Maksimov , professor:

– Good evening, dear colleagues! I think that today my topic “The place of angiotensin II receptor blockers in the treatment of arterial hypertension” should not begin in such a high society with the relevance of the treatment of arterial hypertension, in general. We are all well aware of the relevance of the problem of treating arterial hypertension, and we know the dangers of this disease and the risks. Therefore, I would like to focus on those drugs that are most modern and most relevant to use in this category of patients today.

Angiotensin II receptor blockers belong to the main group of antihypertensive drugs along with angiotensin-converting enzyme inhibitors, along with thiazide and thiazide-like diuretics, and calcium antagonists. But I would like to note that the most important thing is that angiotensin receptor blockers are among the three most relevant drugs that can not only attract the patient to good treatment results, but prolong the patient’s life, improve the prognosis of the patient with arterial hypertension, and not only with arterial hypertension.

ACE inhibitors, angiotensin receptor blockers and β-blockers are used today for almost any cardiovascular disease.

If we pay attention to the recommendations (Russian and European) for the diagnosis and treatment of arterial hypertension, we will see that the primary indications for prescribing angiotensin receptor blockers are almost in a leading position along with the often used angiotensin-converting enzyme inhibitors. The indications are much superior to those of β-blockers and calcium antagonists.

Of course, we began our acquaintance with angiotensin receptor blockers with a single indication - cough when taking ACE inhibitors. Today, sartans have their own advantages, their own evidentiary values, their own data from clinical studies showing that this group of drugs has its own irreplaceable emphasis on each of the pathologies. Take, for example, metabolic syndrome (diabetes mellitus), pay attention to diabetic and non-diabetic nephropathy and other diseases.

Recommendations for the selection of medications for the treatment of patients with arterial hypertension. When we look at this table, we can pay attention to the fact that angiotensin receptor blockers - in almost the majority of clinical cases of diseases associated with arterial hypertension, we can start therapy with this group of drugs along with ACE inhibitors, along with β-blockers and to some extent with thiazide diuretics.

Angiotensin II receptor antagonists are today the world leaders among antihypertensive drugs. For many years, drugs such as calcium antagonists and ACE inhibitors were in the leading position. But today, the safest and most effective drugs for the treatment of arterial hypertension, which are famous not only for their main hypotensive effect, but also for their so-called side effects, are becoming the leaders on the world market. These are cardioprotective, vasoprotective, cerebroprotective, nephroprotective effects that can be useful in a fairly wide group of different patients.

The mechanism of action of sartans is fundamentally different from ACE inhibitors, although, at first glance, we can say that these drugs are quite similar to each other. What is the difference between sartans and ACE inhibitors? The fact is that ACE inhibitors affect the transition of angiotensin I to angiotensin II through the angiotensin-converting enzyme. This reduces the content of angiotensin II in the blood plasma and tissues. But sartans block angiotensin type I receptors, thereby, without reducing the level of angiotensin II, they block its entry into this type of receptor.

Please note that along with ACE inhibitors, which may not be entirely competent in reducing the concentration of angiotensin II, which appears through alternative tissue pathways. This is the first difference. On the other hand, sartans do not reduce the amount of angiotensin II, which reaches other types of angiotensin receptors, in particular, angiotensin receptors of the second, third and other types.

If you look at the effects of blockade of AT 1 receptors, which precisely reduce, level out, blockade of angiotensin receptors, this is a decrease in the manifestations of myocardial hypertrophy, a decrease in the risk of developing arrhythmias. This is a vasoprotective effect, in particular, a decrease in the manifestation of vasoconstriction, a decrease in the activation of lipid peroxidation, and a decrease in the stimulation of atherogenesis. It is necessary to pay attention to a decrease in general neurohumoral regulation. And of course, a nephroprotective effect, such as: a decrease in fluid and sodium retention, an increase in renal blood flow, and a decrease in the phenomenon of nephroangiosclerosis.

On the other hand, β-blockers open the way to excite angiotensin type II receptors, where angiotensin II is fully revealed in effects such as preventing activation of the sympathoadrenal system, reducing insulin resistance, blocking aldosterone synthesis, preventing hypertrophy and fibrosis. In the vascular bed, vasodilation and improvement of endothelial function are noted, and the development of atherogenesis is prevented. It is important in the nephroprotective function - we see a decrease in albuminuria, a decrease in pressure in the renal glomerulus, an increase in natriuresis and also a decrease in new cases of type 2 diabetes mellitus.

Valsartan is one of the leading drugs in the group of angiotensin receptor blockers. Today it is the world leader among sartans. “Valsartan” is a drug that has a fairly serious history, both in terms of the time of its discovery and synthesis, and in the studies that have been and are being carried out on this drug all over the world. Today, Valsartan is the most studied angiotensin receptor blocker, ahead of Telmisartan and far ahead of other groups of sartans, such as Lazortan, Candesartan and other sartans.

Today, Valsartan has noted its positive presence in more than 150 clinical studies, almost 100 thousand patients are participants in international clinical randomized studies. Therefore, we can say with absolute certainty that Valsartan is of significant interest for modern cardiology and therapy. Unlike other sartans and, in particular, ACE inhibitors, Valsartan blocks the effects of AT1 receptors most pronouncedly, 20 thousand times more than it blocks AT2 receptors. That is, it is a highly selective blocker of type 1 angiotensin receptors. This is a non-competitive drug, therefore, it does not change its action depending on the level of angiotensin II. And also its action determines the two-hour presence of the effects of blockade of angiotensin receptors, in contrast to ACE inhibitors, which cannot block all pathways of AT2 formation. This effect is also called the “ACE inhibitor escape effect.” We can clearly note that sartans are their class, their effect, but “Valsartan” here, today, has the largest evidence base and the largest points for monitoring effectiveness.

Valsartan clearly reduces the risk of cardiovascular complications such as stroke, such as new cases of diabetes. Please note - these are very interesting numbers. Valsartan seriously and significantly reduces the risk of developing the first and subsequent heart attacks and strokes. Valsartan reduces the frequency of hospitalizations due to angina pectoris. The pharmacodynamics and pharmacokinetics of Valsartan also have their own specific characteristics. When taking sartans, there is no effect of hypotension of the first dose; accordingly, it is quite safe at the start of therapy. It is quite safe for long-term therapy, especially in elderly patients. Sudden o is not accompanied by the development of rebound hypertension. Valsartan has two routes of elimination: 70% through the liver and 30% through the kidneys. Accordingly, this will also be a positive feature of this drug for the treatment of high-risk patients. Metabolism of one of the well-known generics “Valsartan” is not carried out through the cytochrome P450 system. This ensures there are no interactions.

Thus, I would like to emphasize that today Valsartan and angiotensin receptor blockers are not only effective and safe drugs in monotherapy, but, of course, these drugs are important and must be taken in combination with other hypertensive drugs, such as thiazide diuretics . And we know not only the combination, but also fixed combinations of such drugs - these are drugs combined with dihydropyridine calcium antagonists, in particular, with Amlodipine. We are well aware of the fixed combination drugs “Valsartan” plus “Amlodipine”, “Valsartan” plus non-dihydropyridine calcium antagonists. Green arrows in this diagram indicate rational, complete combinations that not only have the ability to significantly reduce arterial hypertension. Also, these combinations are characterized by a small number of side effects and, most importantly, can significantly reduce the risk of cardiovascular events and protect target organs from quite serious damage, which is dangerous for the development of arterial hypertension.

The blood pressure of a healthy person has daily peaks and valleys, and, interestingly, all sartans, and Valsartan, in particular, have the ability to normalize the daily rhythm of blood pressure. This slide presents our own studies of one of Valsartan’s generic drugs, Valsacor, which shows that the number of normal blood pressure profiles based on 24-hour monitoring looks quite significant compared to the number of pathological profiles. This shows not so much the effectiveness as the safety of this drug in treating patients every day for many months and years. Blood pressure variability also affects the prognosis of patient treatment, accordingly, we can understand that Valsartan is able to positively adjust and reduce the number of unregulated increases in blood pressure. It has been proven that blood pressure variability is a factor that determines myocardial mass, creatinine level and changes in the fundus over 7 years, that is, the higher the variability, the higher the damage to target organs. If a drug is able to reduce this variability, reduce these peaks of decrease and increase in blood pressure, there is a clear effect on the prognosis and condition of target organs.

What is positive and why did I choose for today’s presentation one of the main generic drugs of Valsartan - Valsacor? The fact is that, along with the data of Valsartan itself, Valsacor has its own data from clinical studies, such as the use of Valsartan in weightlifters, showing, first of all, the safety of the drug and the normalization of blood pressure variability. Not a single patient noted poor tolerability, which, of course, is characteristic not only of the entire class of sartans, but also of Valsartan, first of all.

As a final slide... I'll skim a little bit. I would like to emphasize the need to combine even such an effective class of drugs as sartans with other antihypertensive drugs. For example, hydrochlorothiazide. It has been clearly proven that, firstly, the combinations are most acceptable in patients with a high risk of second and third degree arterial hypertension. On the other hand, the presence of the most combinable class of drugs, which are thiazide diuretics, we can say that the fixed combination of Valsartan plus hydrochlorothiazide, the fixed combination of sartans, in principle, with thiazide diuretics today has shown the ease of use for both the patient, which determines compliance And, of course, the convenience of dose titration, which determines the convenience for the doctor, as well.

- Look what they write. “It’s a terrible combination, the combination of an ACE inhibitor and sartan is terrible.” We're not saying it's good.

Maksimov M.L.:

– We didn’t even talk. I’m ready to show a slide, there was a combination with thiazide diuretics, with calcium antagonists and with non-dihydropyridine calcium antagonists. It is not rational to combine sartans with ACE inhibitors. There have been articles on the combination of ACE inhibitors with sartans in the treatment of chronic heart failure. This combination, of course, is not indicated either in the treatment of coronary artery disease or in the treatment of arterial hypertension. I absolutely agree with you.

– I want to say, I’ll also add, we’ll talk a little about this topic. Indeed, hypotheses were tested, for example, in the ONTARGET study, which is better? It would seem that if we block the renin-angiotensin-aldosterone system at all levels, wherever possible, then we will get many benefits, no. We do not receive any special benefits, although the combination of aldosterone blockers, such as speronolactone and ACE inhibitors or sartans, is important, especially in patients with heart failure. Look how interesting some sensational phenomena really are. Here are the questions again. Tell me, what do you think about the increased cancer risk of sartans?

Maksimov M.L.:

– The increased cancer risk of sartans is more likely some kind of remnant of marketing wars than scientific data. To date, sartans have not been proven to have cancer risks or have been confirmed by any research.

– Again, different listeners and viewers write. What is your attitude to the simultaneous administration of ACE inhibitors and sartan?

Maksimov M.L.:

– It is not advisable to prescribe ACE inhibitors and sartans at the same time for arterial hypertension.

– We received a message from Ismail-ala from Bishkek. Thank you very much, wonderful program, especially sartans and the modern view of nephroprotection.

Individual representatives of sartans

Most sartans have similar properties and differ little from each other both in pharmacokinetic parameters and in hypotensive and cardioprotective activity. But still, some ARBs have features:

Losartan, the first synthesized sartan, has a uricosuric effect, that is, it increases the excretion of uric acid. Therefore, it is advisable to use it for concomitant gout [4].
Valsartan blocks, along with AT1 receptors, AT2 receptors located in blood vessels. Due to the blockade of the latter, the drug has a vasodilating effect [13].
Telmisartan increases tissue sensitivity to insulin and enhances glucose utilization in muscles and tissues. At the dosages used for the treatment of hypertension, the drug acts similarly to hypoglycemic drugs - thiazolidinedione derivatives (pioglitazone, rosiglitazone). It is this drug that some experts consider to be a representative of the second generation sartans [13].
Azilsartan medoxomil is a new sartan that binds more tightly to AT1 receptors compared to other ARBs, due to which it has a powerful and long-lasting antihypertensive effect that is superior to the effect of other sartans. The drug increases tissue sensitivity to insulin and affects the mass of adipose tissue, reducing it. The drug is promising for patients with hypertension and metabolic disorders [14].
Fimasartan is another new ARB inhibitor developed by a Korean company. It is used only as an antihypertensive agent [15].