Selective antagonist of angiotensin II type receptors at1. The use of AT1-receptor angiotensin blockers in the pathogenetic therapy of arterial hypertension. Side effects and contraindications

Catad_tema Heart failure - articles

Achievements in drug therapy of chronic heart failure. Part II

»» № 1 "2000

LITERATURE REVIEWS Sidorenko B.A., Preobrazhensky D.V.
Medical Center of the Office of the President of the Russian Federation, Moscow

The desire to increase the effectiveness of drug therapy for chronic heart failure (CHF) forces the use of other drugs in combination with angiotensin-converting enzyme (ACE) inhibitors, diuretics, cardiac glycosides and beta-blockers. In the 1980s, randomized trials were conducted to evaluate the efficacy and safety in patients with CHF of drugs belonging to the classes of aldosterone receptor blockers, antiarrhythmic drugs, AT1-angiotensin receptor blockers, vasodilators and non-glycoside inotropic drugs.

Aldosterone receptor blockers

A new approach to the treatment of CHF is associated with the use of aldosterone (mineralocorticoid) receptor blockers - spironolactone and eplerenone, which in the past were considered only as representatives of one of the subgroups of potassium-sparing diuretics.

Until recently, the aldosterone receptor blocker spironoloctone (aldactone, veroshpiron, spironol) in CHF was used only as a potassium-sparing agent to correct hypokalemia caused by loop and thiazide diuretics. In the 90s, in the treatment of CHF, ACE inhibitors began to be widely used, which can effectively prevent the development of hypokalemia in patients receiving loop and thiazide diuretics. As a result, in patients with CHF, hyperkalemia is now much more common than hypokalemia. And therefore, in the vast majority of cases, in patients with CHF receiving ACE inhibitors, there is no reason to fear the development of hypokalemia, and therefore prescribe potassium-sparing diuretics.

CHF is characterized by elevated plasma aldosterone concentrations. According to some observations, in CHF, hyperaldosteronemia is a prognostically unfavorable sign.

Hyperaldosteronemia in patients with CHF is associated not only with increased secretion of aldosterone as a result of hyperactivity of the renin-angiogensin system (RAS), but also with a decrease in its inactivation in the liver. In turn, a violation of aldosterone inactivation can be a consequence of both a decrease in hepatic blood flow and a violation of its uptake by hepatocytes. It is known that a violation of the degradation of aldosterone in the liver, in itself, can cause a 3-4-fold increase in its plasma concentrations due to a significant lengthening of the half-life of aldosterone in blood plasma from 30-35 to 70-100 minutes. Recently, aldosterone has been found to play an important role in the pathogenesis of CHF. Aldosterone not only regulates water and electrolyte homeostasis by promoting sodium retention and increasing the excretion of potassium and magnesium by the kidneys. Prolonged hyperaldosteronism, as it turned out, causes structural changes in the cardiovascular system. In particular, hyperaldosteronism contributes to the development of cardiomyocyte hypertrophy, fibroblast proliferation, and increased collagen synthesis in the heart and arterial wall. It is believed that elevated plasma aldosterone concentrations are one of the reasons for the development of hypertrophy and diffuse interstitial myocardial fibrosis, as well as thickening of the middle lining of the arteries and perivascular fibrosis in patients with CHF.

The dual mechanism of hyperaldosteronemia in patients with CHF explains why suppression of excessive RAS activity with ACE inhibitors does not lead to normalization of plasma aldosterone concentrations. To reduce the undesirable effects of hyperaldosteronemia requires the use of specific aldosterone antagonists, among which the best known is spironolactone.

Spironolactone is a specific blocker of aldosterone (mineralocorticoid) receptors, which, in addition to the renal tubules and adrenal glands, are found in the heart and arterial wall. Spironolactone can also inhibit the activity of aldosterone synthetase and thus reduce aldosterone synthesis. In addition, it inhibits the activity of 5alpha reductase. As a result, the formation of the alpha isomer of aldosterone, which has a greater mineralocorticoid activity than its beta isomer, is reduced.

Recently, an experiment has shown that spironolactone prevents aldosterone-induced remodeling of the cardiovascular system. With the joint appointment of aldosterone and spironolactone, neither left ventricular hypertrophy nor myocardiofibrosis develops.

Given the antagonism of spironolactone in relation to the adverse effects of aldosterone in patients with CHF, a randomized, placebo-controlled study, the RALES Mortality Trial, was undertaken.

The aim of this study was to evaluate the effect of low-dose spironolactone on mortality in patients with class III-IV CHF and with a left ventricular ejection fraction of less than 35% who received standard therapy, including ACE inhibitors, loop diuretics, and cardiac glycosides. After randomization, 822 patients additionally received spironolactone (25 mg/day) and 841 patients - placebo.

In August 1998, the RALES Mortality Trial was suspended early after a significantly lower mortality was found in the spironolactone-treated group compared to the control group. Mortality from all causes in the group of patients treated with spironolactone was 27% lower than among patients treated with placebo (95% confidence interval from 14 to 37%; p = 0.0001). Mortality from cardiac causes decreased by 31%, the total number of hospitalizations - by about 17%, and hospitalizations due to decompensation of CHF - by about 36%. The total number of deaths and hospitalizations decreased by about 22% with the addition of spironolactone (p<0,0002). Не было значительных различий между группами в средних уровнях калия или частоте выраженной гиперкалиемии. Лишь у 15% больных, леченных спиронолактоном, отмечались признаки гиперкалиемии, которые потребовали снижения дозы препарата. Единственным существенным побочным эффектом была гинекомастия, которая встречалась у 10% мужчин, получавших спиронолактон .

Thus, the RALES Mortality Trial showed that the use of the aldosterone receptor blocker spironolactone can significantly improve the survival of patients with severe CHF.

Eplerenone is a more selective blocker of aldosterone (mineralocorticoid) receptors than spironolactone, so the likelihood of developing gynecomastia with its use is much lower than with spironolactone.

amiodarone and dofetilide

Apart from beta-blockers, amiodarone is essentially the only antiarrhythmic drug that can be used for long-term therapy of ventricular arrhythmias, and hence for the prevention of sudden death in patients with CHF. The use of dofetilide, a new antiarrhythmic drug belonging to class III according to the classification of E. Vaughan Williams-B, also seems promising. Singh D. Harrison.

In the early 90s, two large placebo-controlled studies were performed that evaluated the efficacy and safety of amiodarone in patients with CHF.

In the study GESICA in patients with CHF II-IV FC, mortality in the group of patients treated with amiodarone was significantly lower (by 28%) than in the control group (p = 0.024). There was an insignificant decrease in both cases of sudden death (by 27%) and deaths from progressive heart failure (by 23%). Amiodarone was especially effective in women (decrease in mortality by 48%) and in patients with non-sustained ventricular tachycardia (decrease in mortality by 34%).

Somewhat different data regarding the efficacy of amiodarone in patients with CHF were obtained in a placebo-controlled randomized study of CHF-STAT. In this study, amiodarone did not have a significant effect on the prognosis of life in patients with CHF II-IV FC. At the same time, the dependence of the effectiveness of long-term amiodarone therapy on the etiology of CHF was noted. Thus, there was a clear trend towards improved survival in patients treated with amiodarone with CHF of non-ischemic etiology, which accounted for about 30% of all patients included in the study (p = 0.07).

According to the summary data of five randomized trials, in patients with CHF, amiodarone significantly reduces mortality - by an average of 17%.

The reasons for the discrepancy between the results of the GESICA and CHF-STAT studies are not entirely clear. This may be due to differences in the composition of patients included in the study. For example, the GESICA study was dominated (about 60%) by patients with non-ischemic HF, in whom, according to the CHF-STAT study, amiodarone appears to increase survival. In the GESICA study, amiodarone significantly improved survival only in women (48% reduction in mortality), who accounted for about 20% of all patients. It was much less effective in men - reducing mortality by an average of 26% (5% confidence interval from -2 to + 46%). Meanwhile, in the CHF-STAT study, only 1% of patients were women.

Despite the contradictory results of the GESICA and CHF-STAT studies, it is clear that amiodarone at a dose of up to 300 mg / day can improve the long-term prognosis in patients with CHF of non-ischemic etiology, i.e., first of all, in patients with dilated cardiomyopathy. Amiodarone appears to be particularly effective in women, as well as in patients with baseline tachycardia (HR>90 bpm) and episodes of nonsustained ventricular tachycardia as measured by 24-hour ECG monitoring.

Thus, at present, amiodarone should not be widely used for the treatment of asymptomatic and asymptomatic ventricular arrhythmias in patients with left ventricular systolic dysfunction in order to prevent sudden death.

In the multicenter, placebo-controlled DIAMOND study in patients with postinfarction left ventricular systolic dysfunction, dofetilide did not significantly reduce all-cause and cardiac mortality by an average of 6% and 7%. At the same time, dofetilide reduced the need for hospitalization of patients due to heart failure, which is explained by the ability of the drug to prevent the development of atrial fibrillation paroxysms.

Therefore, along with beta-blockers, amiodarone and dofetilide can be used to improve the prognosis in patients with postinfarction left ventricular systolic dysfunction and ventricular arrhythmias.

AT1-angiotensin receptor blockers

AT1-angiotensin receptor blockers are a new group of drugs, the use of which is considered promising in the treatment of CHF.

AT1-angiotensin receptor blockers have important advantages over ACE inhibitors: (1) they are more effective than ACE inhibitors in suppressing RAS activity, since they act at a lower level - at the level of cellular receptors; (2) their action is more selective, since they only suppress the activity of the RAS, but do not affect the kallikrein-kinin and other neurohumoral systems that play a role in the pathogenesis of CHF; and (3) AT1-angiotensin receptor blockers are much better tolerated than ACE inhibitors.

Thus, AT1-angiotensin receptor blockers provide a more effective, more selective (selective) and more specific approach to inhibition of excessive activity of the RAS than ACE inhibitors, and, in addition, are excellent tolerability.

The first AT1-angiotensin receptor blocker effective when taken orally is losartan (cozaar), which was synthesized in 1988. In the mid-90s, clinical trials of other AT1-angiotensin receptor blockers, such as valsargan, zolarsartan, irbesartan, candesartan, were completed. , losartan, tazozartan, telmisartan and eprosartan.

In total, two long-term randomized trials have studied the efficacy and safety of AT1-angiotensin receptor blockers during long-term use in patients with CHF.

In the ELITE multicenter study, mortality in the group of patients with CHF II-IV FC and with a left ventricular ejection fraction of not more than 40%, treated with losartan, was approximately two times lower (by an average of 46%) than in the group of patients treated with the ACE inhibitor captopril. The total number of deaths and (or) hospitalizations due to heart failure significantly decreased under the influence of losartan treatment, on average, by 32%.

The data obtained during the ELITE study can serve as indirect evidence of the high efficacy, safety and excellent tolerability of losartan in patients with CHF due to left ventricular systolic dysfunction. However, the results of these studies do not allow us to recommend the widespread use of any AT1-angiotensin receptor blockers for the treatment of cholesterol instead of ACE inhibitors. The fact is that in the randomized controlled trial RESOLVD, it was not possible to detect any advantages of another AT1-angiotensin receptor blocker (candesartan) over the ACE inhibitor enalapril in patients with left ventricular systolic dysfunction. The RESOLVD study was terminated early after higher mortality was found in the candesartan (6.1%) and candesartan/enalapril combination (8.7%) groups compared with enalapril-treated patients (3.7%). ) . Not so encouraging were the results of the ELITE-II study, which compared the effects of long-term therapy with losartan and captopril on the survival of patients with CHF. In the ELITE-II study (unlike the ELITE-I study), the total number of deaths and hospitalizations due to CHF decompensation in the group of patients treated with losartan was significantly less than in the group receiving captopril (by 6%; p = 0, 21)

Thus, at present, there is no indisputable evidence of a beneficial effect of AT1-angiotensin receptor blockers on mortality and (or) the need for hospitalization (compared to ACE inhibitors) in patients with CHF. Therefore, AT1-angiotensin receptor blockers are recommended for the treatment of CHF only in those few cases when ACE inhibitors cannot be used due to the development of angioedema or a painful cough.

calcium antagonists

Calcium antagonists, as potent arterial vasodilators, may be useful in reducing left ventricular afterload in patients with CHF. Unfortunately, all calcium antagonists have a negative inotropic effect, which is most pronounced in such cardioselective drugs as verapamil and dilgiazem. For this reason, verapamil and dilgiazem are not suitable for long-term therapy in patients with left ventricular systolic dysfunction.

Theoretically, in CHF, vasoselective L-type calcium antagonists from the group of dihydropyridine derivatives, as well as the T-type calcium antagonist mibefradil, are the safest. Hopes that nifedipine would be useful in the treatment of CHF did not materialize. The addition of nifedipine to standard CHF therapy increased the likelihood of decompensation. More promising was the use in the treatment of patients with CHF dihydropyridine calcium antagonists with higher vasoselectivity than nifedipine - amlodipine and felodipine, as well as mibefradil.

The efficacy and safety of amlodipine were evaluated in the PRAISE multicenter, randomized, placebo-controlled study, which involved 1153 patients with CHF III-IV FC and a left ventricular ejection fraction of less than 30%. Overall mortality was not significantly lower (by an average of 16%) in the group of patients treated with amlodipine than in the control group. When analyzing the effectiveness of amlodipine depending on the etiology of CHF, it was found that in patients with dilated cardiomyopathy, the addition of amlodipine leads to a decrease in mortality by an average of 46% (95% confidence interval from 21 to 63%; p<0,001). Интересно, что терапия амлодипином сопровождалась значительным снижением риска внезапной смерти у больных с ХСН, обусловленной дилатационной кардиомиопатией (на 44%; р=0,05).

Long-term effects of felodipine in 450 patients with CHF II-III FC and left ventricular ejection fraction less than 45% were studied in a multicenter placebo-controlled study V-HeFT III. No significant effect of felodipine on mortality or hospitalization was found, although it prevented the deterioration of patients' exercise tolerance and the quality of life of patients.

In a randomized placebo-controlled study of MACH-I, mortality in patients with HF II-IV FC and left ventricular ejection fraction less than 35%, treated with the T-type calcium antagonist mibefradil, was 12% higher than in the control group, but there were no differences. reached a statistically significant value. However, there was a significant increase in mortality when prescribing mibefradil to women, patients with atrial fibrillation and patients receiving antiarrhythmic drugs that can cause the development of ventricular tachycardia of the "pirouette" type (torsades de pointes).

Thus, to date, amlodipine is the only calcium antagonist known to improve survival in patients with dilated cardiomyopathy with FC III-IV FC receiving "triple" combination therapy. Neither felodipine nor mibefradil improves the survival of patients with CHF.

Other vasodilators

Along with ACE inhibitors, AT1-angiotensin receptor blockers and calcium antagonists, other drugs with a vasodilatory effect are being tried to reduce left ventricular afterload in patients with CHF.

In 1991, the results of the randomized study V-HeFT (Vasodilator-Heart Failure Trial) II were published, in which the efficacy of the ACE inhibitor enalapril and the combination of hydralazine and isosorbide dinitrate in 804 patients with CHF treated with digoxin and diuretics was compared in a double-blind manner.

Follow-up of patients lasted from 6 months to 5.7 years (average 2.5 years). During follow-up, overall mortality was slightly lower among patients treated with enalapril compared with patients treated with the combination of hydralazine and isosorbide dinitrate (32.8% vs. 38.2%; p = 0.08).

Analysis of the effectiveness of enalapril in various subgroups showed that it significantly improves survival compared with combination therapy in patients with CHF I-II FC, with normal heart size (cardiothoracic index less than 0.50) and with high levels of renin and norepinephrine in blood plasma. On the other hand, the combination of hydralazine (up to 300 mg / day) and isosorbide dinitrate (up to 160 mg / day) was not inferior to enalapril in terms of effectiveness in patients with CHF III-IV FC and with slight activation of the sympathetic-adrenal or renin-angiotensin systems.

The data of the V-HeFT II study on the beneficial effect of the combination of hydralazine and isosorbide dinitrate on the survival of patients with CHF coincide with the results of the placebo-controlled study V-HeFT I (1986), which for the first time showed that in the first three years after the start of therapy, this combination reduces mortality in patients with CHF, on average, by 36% (p<0,05).

Therefore, in some patients with CHF, the combination of hydralazine and isosorbide dinitrate can be used as an alternative to ACE inhibitors, especially in cases where ACE inhibitors are contraindicated or cause serious side effects.

Non-glycoside inotropic drugs

Non-glycoside inotropic drugs have a more pronounced cardiotonic effect than cardiac glycosides, and therefore at one time they were considered more promising for improving impaired contractile function of the left ventricle in patients with CHF. In addition, they may reduce left ventricular afterload due to their vasodilating effect. Hence, by the way, another name for non-glycoside inotropic drugs is inodilators.

Non-glycoside inotropic drugs intended for oral administration are divided into the following groups, depending on the mechanism of action:

1. Beta-adrenergic receptor agonists (xamoterol, pirbuterol, prenalterol, etc.);

2. Phosphodiesterase III inhibitors (amrinone, milrinone, enoximone, etc.)

3. DA-dopaminergic receptor agonists (ibopamine, fenoldopam, etc.); and

4. Drugs with a complex or unknown mechanism of positive inotropic action (vesnarinone, levosimendan, pimobendan, flosequinan, forskolin, etc.).

In the 1980s and 1990s, several dozens of randomized placebo-controlled trials were performed, in which the efficacy and safety of long-term therapy with non-glycoside inotropic drugs with different mechanisms of action was studied in patients with FC III-IV FC. In all studies, mortality in groups of patients treated with these drugs was higher than in control groups. Some of the studies were prematurely suspended for this reason.

Given that non-glycoside inotropic drugs can increase mortality, they are not suitable for long-term therapy in patients with CHF. In an editorial in the Lancet, J. Niebauer and A. Coats even recommend a moratorium on human trials of non-gaicoside inotropic drugs until convincing evidence is obtained from experimental studies of the ability of these drugs to prolong life expectancy. Currently, it is not recommended to use non-glycoside inotropic drugs for a long time, even in the treatment of patients with severe CHF. Only in patients with refractory symptoms of CHF is it allowed to prescribe non-glycoside inotropic drugs in the form of continuous intravenous infusion for several days.

Thus, based on the results of randomized controlled trials, it is recommended to use four groups of drugs for long-term therapy of patients with CHF: ACE inhibitors, thiazide or loop diuretics, cardiac glycosides and beta-blockers. The clinical efficacy and safety of these drugs is now beyond doubt. ACE inhibitors and beta-blockers, along with symptomatic improvement, can reduce the need for hospitalization and improve survival. Thiazide or loop diuretics are the only group of drugs that can eliminate fluid retention in patients with CHF. Cardiac glycosides do not improve survival, but reduce the need for hospitalization due to CHF decompensation and control the ventricular rate in tachysystolic atrial fibrillation.

Other groups of drugs may also be useful in certain situations, but they should only be used in addition to "basic" drugs or in cases where any of the "basic" drugs is contraindicated or causes serious side effects.

LITERATURE

1. Sidorenko B.A., Preobrazhensky D.V. Treatment and prevention of chronic heart failure. // Moscow, 1997.
2. Weber K.T., Brilla C.G. Pathological hypertrophy and cardiac interstitium: fibrosis and renin-angiotensin-aldosterone system. // Circulation, 1991; 83:1849-1865.
3. Weber K.T., Brilla C.G., Camphell S.E. et al. Pathological hypertrophy with fibrosis: the structural basis for myocardial failure. // Blood Pressure, 1992, 1: 75-85.
4. Weber K.N., Villarreal D. Heart failure: A salt-sensitive disorder. // Columbia Missuri (USA), 1997.
5. Richardson M., Cockbum N., Cleland J.G.F. Update of recent clinical trials in heart failure and myocardial infarction. // Europ. J. Heart failure, 1999; 1(1):109-115.
6. Packer M., Cohn J.N. (eds) Consensus recommendations for the management of chronic heart failure. //Amer. J. Cardiol., 1999; 83(2A): IA-38A.
7. Doval H.C., Nul D.R., Doval H.C, Grancelli H.O. et al. Randomized trial of low-dose aittiodarone in severe congestive heart failure. // Lancet, 1994; 344 (8921): 493-498.
8. Singh S.N., Fletcher R.D., Fisher S.G. et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. // New Engl. J. Med., 1995; 333(2): 77-82.
9. Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after myocardial infarction and in congestive heart failure: Meta-analysis of individual data from 6500 patients in randomized trial. //Lancet, 1997; 350: 1417-1427.
10. Kober L. The DIAMOND Study Group. A clinical trial of dofetilide in patients with Acute Myocardial infarction and left ventricular dysfunction: the DIAMOND MI study. // Europ. Heart J., 1998; 19 (suppl.): 90 (abstract No. P639).
11. Preobrazhensky D.V., Sidorenko B.A., Iosava I.K., Sololeva Yu.V. Physiology and pharmacology of the renin-angiotensin system. // Cardiology, 1997; 11:91-95.
12. Sidorenko B. A., Preobrazhensky D. V. Losartan - an AT1-angiotensin receptor blocker: a new direction in the treatment of chronic heart failure. // Cardiology, 1997; 11:84-87.
13. Pitt B., Segal R., Martinez F.A. et al. Randomized trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). // Lancet, 1997; 349 (9054): 747-452.
14. Willenheimer R., Dahlia B., Rydberg E., Erhardt L. AT1-receptor blockers in hypertension and heart failure: clinical experience and future directions. // Europ. Heart J., 1999, 20 (14): 997-1008.
15. Parker M., O "Connor Ch.M., Ghali J.K. et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. // New Engl. J. Med., 1996; 335 (15): 1107 -1114.
16. Cohn J.N., Ziesche S., Smith R. et al. Effect of calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril V-He-FT III. // Circulation, 1997; 96:856-863.
17. Cohn J.N., Johnson G, Ziesche S. et al A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. // New Engl. J. Med., 1991; 325:303-310.
18. Niebauer J. Coats and A.J.S. Treating chronic heart failure: time to take stock. // Lancet, 1997; 349 (9057): 966-967.

For citation: Podzolkov V.I., Osadchiy K.K. AT1-angiotensin receptor blockers in the treatment of arterial hypertension: focus on valsartan // BC. 2009. No. 8. S. 552

The choice of a drug for the treatment of arterial hypertension (AH) remains a challenge. Currently, doctors have at least 7 groups of antihypertensive drugs at their disposal, 5 of which are, according to modern international and domestic recommendations, first-line drugs. On the one hand, the presence of many drugs provides the doctor with ample opportunities for individual selection of the necessary treatment in each individual case, and on the other hand, it creates the problem of choosing a specific drug. This choice must be made taking into account many factors, including both the characteristics of the patient and the course of his illness, and the properties of the drug.
In recent years, the requirements for drugs for the treatment of hypertension have changed significantly. Although the reduction of blood pressure (BP) in itself remains the most important task of antihypertensive therapy, the presence of a drug alone in the antihypertensive effect today cannot be considered sufficient. A modern drug for the treatment of hypertension must meet a set of requirements. First, it is antihypertensive efficacy. Today, it is understood as not only a decrease in blood pressure as such, but also the ability of the drug to have a stable antihypertensive effect, that is, the possibility of long-term retention of target blood pressure values ​​during treatment. At the same time, it is desirable that the drug has a positive effect on the daily blood pressure profile and be effective in special groups of patients: in the elderly, in patients with diabetes mellitus (DM), with isolated systolic AH (ISAH), etc. Secondly, this is the ability of the drug to have a positive effect on the state of target organs (heart, kidneys, blood vessels), that is, organoprotective properties. These properties are assessed mainly by the ability of drugs to influence such markers as left ventricular myocardial mass (LVML), microalbuminuria (MAU), intima/media complex thickness, etc. Thirdly, a modern antihypertensive drug should demonstrate an effect on endpoints. in randomized clinical trials (RCTs). Preferably, these should be "hard" endpoints, such as cardiovascular, and ideally, total mortality. Fourth, a modern antihypertensive drug must be safe. By this we mean not only a favorable profile of unwanted side effects and general tolerability of treatment, but also the absence of a negative effect on various organs and body systems in the long term. Today, it is especially important that an antihypertensive drug does not contribute to the development of de novo DM, that is, does not have the so-called "pro-diabetogenic" effect, is metabolically neutral, does not contribute to the progression of atherosclerosis, and does not impair sexual function. And, finally, a modern antihypertensive drug should be convenient to use, preferably once a day, which helps to increase patient adherence to treatment.
Of the 5 major classes of antihypertensive drugs available, angiotensin II AT1 receptor blockers (ARBs) are the most recent. But at the same time, in their short history, they have proven to meet all the requirements, unlike some classes, about which the debate continues.
The pharmacodynamic effects of ARBs are related to their ability to block the renin-angiotensin-aldosterone system (RAAS) at the level of angiotensin receptor type 1 (AT1). It is through the activation of these receptors, according to modern concepts, that the pathological effect of high concentrations of the main RAAS effector angiotensin II in cardiovascular diseases is realized (Fig. 1).
The first class of drugs that block the RAAS, introduced into clinical practice, was the class of angiotensin-converting enzyme inhibitors (ACE inhibitors). These drugs have proven themselves in the treatment of hypertension, coronary heart disease (CHD), chronic heart failure (CHF) and chronic kidney disease. However, as is known, in addition to the classical ACE-dependent pathways for the formation of angiotensin II, there are alternative ones associated with the effect on angiotensinogen and angiotensin I of chymases, cathepsin G, and kallikrein-like enzymes. Therefore, ACE inhibition cannot completely block the formation of angiotensin II, especially in tissues where alternative pathways for its formation are most active. This is of great importance, because it is the activity of tissue RAAS that plays the leading role in the development of target organ damage in AH. On the other hand, a decrease in the formation of angiotensin II under the action of ACE inhibitors leads to a decrease in the stimulation of AT2 receptors, which probably have a certain counterregulatory effect on the effects of AT1 receptors (Fig. 1). On the contrary, direct blockade of AT1 receptors with ARBs provides stimulation of AT2 receptors with a constant concentration of angiotensin II and, moreover, does not affect the processes of bradykinin degradation. As a result, the incidence of cough, the main side effect of ACE inhibitors, is sharply reduced.
The first synthetic ARB, created back in 1971 (by the way, earlier than the first ACE inhibitor), was the peptide saralazine. However, it had the properties of a partial agonist and could only be used for parenteral administration. For the first time, non-peptide ARBs were synthesized based on imidazoline derivatives in the mid-1980s and were the prototypes for the modern generation of these drugs. These substances had the advantages of sufficient absorption from the gastrointestinal tract, bioavailability, lack of partial agonist activity, and selectivity in blockade of angiotensin type 1 receptors. ARBs were introduced into clinical practice in 1994, when the first drug of this group, losartan, was registered for the treatment of hypertension. Later, valsartan, irbesartan, candesartan, telmisartan and eprosartan were created. The main pharmacokinetic properties of modern ARBs are presented in Table 1.
In current guidelines for the treatment of hypertension, ARBs are considered first-line drugs suitable for initial treatment of uncomplicated hypertension. In addition, the additional effects of ARBs identified in the course of clinical trials made it possible to form a number of additional indications for the use of these drugs in hypertensive patients with target organ damage, in various clinical situations and in the presence of concomitant conditions (Table 2), which was reflected in national guidelines for the treatment of hypertension.
The most important feature of ARBs is their unique tolerability profile. The results of many RCTs consistently show that the frequency of side effects when using drugs in this group, even at high dosages, is extremely low and comparable to placebo. For a long time, this served as the basis for considering ARBs as a kind of replacement for ACE inhibitors in case of intolerance to the latter. However, in recent years, a large evidence base has been accumulated, indicating that both in terms of the main pharmacodynamic effects and in terms of effects on endpoints, ARBs are not inferior to other classes of antihypertensive drugs.
A large meta-analysis was published in 2008 comparing the efficacy of ARBs and ACE inhibitors in hypertension. Results from 61 direct comparison studies of ARBs and ACE inhibitors were analyzed, including 47 RCTs. As a result, almost the same ability of ARBs and ACE inhibitors to reduce blood pressure in hypertensive patients was shown. Thirty-seven RCTs showed no difference in antihypertensive efficacy between ARBs and ACE inhibitors, 8 RCTs showed higher efficacy of ARBs, and 2 studies showed higher efficacy of ACE inhibitors. At the same time, it was noted that the frequency of discontinuation of therapy is much higher with the use of ACE inhibitors, while ARBs were better tolerated by patients and therefore ensured greater adherence to treatment. ARBs and ACE inhibitors did not differ significantly in the frequency of side effects such as headache and dizziness, but cough was observed 3 times less often with ARBs, and in cohort studies its total frequency did not exceed 0.6%. In this meta-analysis, there were no significant differences between ACE inhibitors and ARBs in terms of the effect on the main endpoints (myocardial infarction, stroke, CHF), as well as on quality of life, lipid levels, LVH, etc.
Another recent meta-analysis of 46 RCTs involving 13,451 hypertensive patients evaluated the antihypertensive efficacy of 9 different ARBs. All ARBs have been shown to have a similar BP-lowering ability, comparable to that of ACE inhibitors. At the same time, from 60 to 70% of the maximum antihypertensive effect was achieved using 1/8-1/4 of the maximum recommended dose of ARB, and the use of 1/2 of the maximum dose provided 80% of the effect.
One commonly used ARB is valsartan. It is rapidly absorbed from the gastrointestinal tract, the maximum plasma concentration is reached 2-4 hours after ingestion; at the same time, the antihypertensive effect of the drug is manifested. A long half-life (about 9 hours), as well as a strong connection with AT1 receptors, provides a 24-hour maintenance of the effect, which allows you to take the drug once a day. This year, Valsacor (pharmaceutical company Krka) appeared on the Russian pharmaceutical market, tablets 40 mg, 80 mg and 160 mg of valsartan.
The antihypertensive efficacy of valsartan has been confirmed in a number of RCTs, including comparison with other antihypertensive drugs. In particular, in two studies, valsartan at a dose of 80 mg / day. not inferior in effectiveness to 20 mg of enalapril. At the same time, the frequency of coughing against the background of valsartan was almost 6 times lower than against the background of enalapril.
Larger data were obtained in the course of an open, multicenter, randomized Val-MARC trial to evaluate the effect of lowering blood pressure on the concentration of C-reactive protein in 1668 patients with stage 2 AH. . The use of valsartan at a dose of 160-320 mg provided a decrease in systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 18 and 9 mm Hg. respectively. Interestingly, the antihypertensive effect of valsartan appears starting at very low doses (20-40 mg/day) and increases as the dose is increased. At the same time, the decrease in blood pressure while taking valsartan at a dosage of 80-320 mg occurs while maintaining a normal daily rhythm. Later, these data were confirmed by a pooled analysis of the results of 9 studies, including 803 patients with stage 1 hypertension, which showed both an increase in the antihypertensive effect and the frequency of achieving target blood pressure with an increase in the dose of valsartan from 80 to 160 mg / day. . The shown efficacy in a wide dose range makes valsartan convenient for use in hypertensive patients with varying degrees of increased blood pressure and in combination therapy, when low doses of the drug can be useful.
Interesting data came from a small trial of valsartan using ambulatory 24-hour BP monitoring. In 90 patients with hypertension 1-2 tbsp. an equal decrease in the average daily values ​​of SBP and DBP was noted both with morning and evening single doses of 160 mg of the drug. Thus, the time of taking valsartan does not affect the stability of its antihypertensive effect. These data are essential, as they allow the doctor to use the drug more flexibly, take into account the individual characteristics of the patient in conditions of polymorbidity and inevitable polypharmacy. Ultimately, this may increase adherence to therapy, which is a sine qua non for effective treatment of hypertension.
When comparing the antihypertensive efficacy of valsartan and enalapril in elderly patients, the degree of blood pressure reduction was the same. The efficacy of valsartan in ISAH was studied in the Val-Syst study in comparison with amlodipine. It was shown that both drugs effectively reduced SBP, however, against the background of valsartan, the frequency of adverse events was one and a half times lower. Thus, taking valsartan in some cases can be an alternative to conventional treatment of hypertension in elderly patients.
It is important to note that ARBs have pronounced organoprotective properties. Thus, a meta-analysis that included 3767 patients from 146 treatment groups and 346 patients from 17 placebo groups, standardized for duration of treatment and DBP, showed that ARBs provide the greatest reduction in left ventricular mass index (LVML) (-13%), superior to calcium antagonists (-11%), ACE inhibitors (-10%), diuretics (-8%) and β -adrenergic blockers (-6%).
The ability of valsartan to reduce the severity of LVH in hypertensive patients has been demonstrated in several studies. In particular, in a comparative study with amlodipine, it was noted that with the same decrease in blood pressure, the LVML index in the valsartan group significantly decreased by 16%, and in the amlodipine group - only by 1.2%, and not significantly.
Important results have been obtained in the Val-PREST and VALVACE studies. It has been shown that valsartan therapy reduces the risk of restenosis and reoperations in patients undergoing transluminal balloon angioplasty of the coronary arteries. Cardioprotective properties are also evidenced by the ability of valsartan, proven in the VALUE and Val-HeFT studies, to reduce the risk of developing new cases of atrial fibrillation in patients with hypertension and CHF.
The advantages of ARBs include their proven nephroprotective effect, the most important component of which is the antiproteinuric effect. A recently published meta-analysis assessed the effect of ARBs versus placebo or other antihypertensive drugs, and the combination of ARBs and ACE inhibitors on proteinuria in chronic kidney disease. We analyzed data from 49 studies (total 6181 patients), including 72 comparisons with a follow-up period of 1 to 4 months. and 38 comparisons with a follow-up period of 5 to 12 months. The results of a meta-analysis showed that ARBs are more effective than placebo and calcium antagonists in reducing proteinuria both for 1-4 months and 5-12 months. Interestingly, the combination of ARBs and ACE inhibitors was more effective in reducing proteinuria than either of the drug groups alone.
The nephroprotective properties of valsartan in patients with hypertension against the background of type 2 diabetes were studied in the MARVAL multicenter randomized comparative study. As a result, with the same decrease in blood pressure in both groups, the level of albumin excretion (AE) in the valsartan group decreased by 44%, and in the amlodipine group - only by 8%, the difference between the groups was significant. The proportion of patients who reached the level of normoalbuminuria while taking valsartan (29.9%) was significantly higher than that while taking amlodipine (14.5%). At the same time, the decrease in UEA in the valsartan group began already from the first weeks of treatment and at low doses (80 mg/day). On the contrary, in the amlodipine group, UEA increased in the first 8 weeks, and its decrease began only after doubling the dose of the drug (up to 10 mg / day), that is, against the background of an increase in the antihypertensive effect. In addition, valsartan had an effect on UEA not only in hypertensive patients, but also in patients with initially normal blood pressure. These data suggested that valsartan is able to reduce the degree of albuminuria, regardless of the ability to reduce blood pressure.
Later, the antiproteinuric efficacy of valsartan in hypertension and type 2 diabetes was confirmed in the Japanese open single-center comparative study SMART. It was shown that with the same antihypertensive efficacy, the ratio of albumin / creatinine (UAC) in the urine in the valsartan treatment group significantly decreased by 32%, and in the amlodipine treatment group it increased by 18%. The proportion of patients with MAU remission or regression was significantly higher in the valsartan group compared to amlodipine. And in this study, while taking valsartan, there was a continuous progressive decrease in the total blood volume. In the amlodipine group, a decrease in blood pressure was detected only in patients who reached the target values ​​of blood pressure. If the target blood pressure was not achieved in the amlodipine group, the total blood pressure increased by 40%. Thus, the assumption that valsartan reduces MAU, regardless of the reduction in blood pressure, was again confirmed.
Interesting data on the effect of different dosages of valsartan on the level of proteinuria in patients with hypertension and type 2 diabetes were obtained in the DROP study. Patients were randomized into 3 groups, in which valsartan was prescribed in one of the dosages - 160, 320 or 640 mg per day. As a result, a significant decrease in UEA was noted when using the drug at a dose of 160 mg by 36%, and at doses of 320 and 640 mg - by 44 and 48%, respectively. Proportion of patients who achieved normal AER values ​​(<20 мкг/мин.), составила 12,4% в группе, получавшей 160 мг валсартана, 19,2% - на дозе 320 мг и 24,3% - на дозе 640 мг. При оценке влияния разных доз валсартана на уровень АД выявилась аналогичная картина: снижение САД/ДАД на дозах 160 и 320 мг достигало 13,7/8 мм рт.ст. и 14,7/8 мм рт.ст. соответственно, а на дозе 640 мг - 17,4/10 мм рт.ст., что достоверно превзошло эффект меньших доз по влиянию на ДАД и эффект 160 мг по влиянию на САД. Важно, что доля пациентов, достигших целевых значений АД (<130 и 80 мм рт.ст.) составила для доз 160, 320 и 640 мг - 30, 32 и 47% соответственно. Таким образом, в исследовании DROP не только подтверждена антигипертензивная эффективность валсартана и его способность существенно уменьшать протеинурию у больных АГ и СД 2 типа, но и была показана эффективность и безопасность применения препарата в высокой дозе - 640 мг/сут. Этот факт имеет большое значение, учитывая трудности достижения целевых значений АД и обеспечения нефропротекции у больных АГ на фоне СД 2 типа.
The effect of valsartan on endpoints was convincingly demonstrated in the Investigator-led Jikei Heart Study. This RCT included 3081 patients with hypertension and/or CAD and/or CHF. Randomized into 2 groups, they received valsartan (40–160 mg/day) or conventional treatment (not including ARBs) in addition to standard therapy. The study was prematurely terminated for ethical reasons, since after 3.1 years of follow-up, significant benefits of valsartan were noted. During therapy with valsartan, there was a significant reduction in the risk of cardiovascular mortality and morbidity by 39%. In addition, there was a 40% reduction in the risk of primary or recurrent stroke, a 65% reduction in the risk of hospitalization for angina pectoris, a 47% reduction in the risk of hospitalization for heart failure, and an 81% reduction in the risk of a dissecting aortic aneurysm.
An important positive property of ARBs is their ability to reduce the risk of developing new cases of diabetes in hypertensive patients, surpassing other classes of antihypertensive drugs in this respect. This effect has been demonstrated in selected RCTs, in particular for valsartan in the VALUE study and in clinical practice. A large meta-analysis of 22 RCTs involving 143,153 hypertensive patients who did not have DM at the time of entry into the studies showed that ARBs reduced the risk of de novo DM by almost 2-fold, outperforming all other classes of antihypertensive drugs, including ACE inhibitors. This property of ARBs seems to be very significant, since the steady increase in the number of patients with type 2 diabetes throughout the world is a major medical and social problem.
ARBs have a favorable metabolic profile. It has been shown, for example, that valsartan improves the sensitivity of peripheral tissues to glucose in patients with hypertension. Therefore, ARBs are recommended for use in hypertensive patients with metabolic syndrome.
Among the advantages of ARBs, it is necessary to note the positive impact on such an important aspect of the quality of life as sexual function in men and women with hypertension. This has been convincingly demonstrated for valsartan. This may be one of the most significant factors explaining the longest patient adherence to prescribed ARB treatment.
Thus, AT1-angiotensin receptor blockers have a pronounced antihypertensive effect, a complex of organoprotective properties, and a proven effect on the most important endpoints. The excellent tolerability and safety profile in patients with metabolic syndrome and diabetes mellitus, as well as high rates of adherence to ARB treatment, allow us to recommend a wider use of this group of drugs, in particular valsartan, in the treatment of arterial hypertension.

Literature
1. 2003 European Society of Hypertension - European Society of Cardiology guidelines for the management of arterial hypertension. Guidelines Committee. J Hypertens 2003;21(6):1011-53.
2. Mancia G, De Backer G, Dominiczak A et al. Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25:1105-87.
3. Prevention, diagnosis and treatment of arterial hypertension. Recommendations of the Russian Medical Society for Arterial Hypertension and the All-Russian Scientific Society of Cardiology. 2008
4. Pals D.T., Massucci F.D., Sipos F., Dennig Jr G.S.A specific compepitive antagonist of the vascular action of angiotensin II. Cirs Res. 1971; 29:664-12.
5. Kang P.M., Landau A.J., Eberhardt R.T., Frishman W.H. Angiotensin II receptor antagonists: A new approach to blockade of the renin-angiotensin system. Am heart J. 1994; 127:1388-401.
6. Matchar DB, McCrory DC, Orlando LA, et al. Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension. Ann Intern Med. 2008 Jan 1;148(1):16-29.
7. Heran BS, Wong MM, Heran IK, Wright JM. Blood pressure lowering efficacy of angiotensin receptor blockers for primary hypertension. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD003822.
8 Holwerda et al. J Hypertens 1996;14(9):1147-1151.
9 Mallion et al. Blood Press Monit 1997;2(4):179-184.
10 Ridker et al. Hypertension 2006;48(1):73-79.
11 Neutel et al. Clin Ther 1997;19(3):447-458.
12 Weir et al. J Clin Hypertens 2006;8(5;suppl A):A102 (P-232).
13. Hermida et al. Hypertension 2003;42:283-290.
14 Fogari et al. Eur J Clin Pharmacol 2004 Feb;59(12):863-8.
15. Malacco et al. Clin Ther 2003;25:2765-2780.
16. Malacco E et al. Am J Hypertens. 2003;16:126A.
17. Klingbeil AU, Schneider M, Martus P, Messerli FH, Schmieder RE. A meta-analysis of the effects of treatment on left ventricular mass in essential hypertension. Am J Med. 2003 Jul;115(1):41-6.
18. Mutlu H, Ozhan H, Okcun B et al. The Efficacy of Valsartan in Essential Hypertension and its Effects on Left Ventricular Hypertrophy. Blood Pressure 2002; 11:53-5.
19. Thurmann PA, Kenedi P, Schmidt A et al. Influence of the angiotensin II antagonist valsartan on left ventricular hypertrophy in patients with essential hypertension. Circulation 1998; 98:2037-42.
20 Yasunari et al. JACC 2004;43:2116-212.
21. Peters S, Gotting B, Trummel M et al. Valsartan for prevention of restenosis after stenting of type B2/C lesions: the VAL-PREST trial. J Invasive Cardiol 2001; 13:93-7.
22. Peters S, Trummel M, Meyners W et al. Valsartan versus ACE inhibition after bare metal stent implantation-results of the VALVACE trial. Int J Cardiol 2005; 98:331-5.
23. Schmieder R, Hua T. Reduced Incidence of New Onset Atrial Fibrillation with Angiotensin II Receptor Blockade: The VALUE-Trial. J Hypertens 2006; 24 (Suppl.): S3.
24 Maggioni AP, Latini R, Carson PE et al. Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: results from the Valsartan Heart Failure Trial (Val-HeFT). Am Heart J 2005; 149:548-57.
25. Kunz R, Friedrich C, Wolbers M, Mann JF. Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med. 2008 Jan 1;148(1):30-48.
26. Viberti G et al. circulation. 2002;106:672-678.
27. The Shiga Microalbuminuria Reduction Trial (SMART) Group. Reduction of Microalbuminuria in Patients with Type 2 Diabetes. Diabetes Care; 2007:30.6:1581-1583.
28 Hollenberg et al. American Heart Association 2006 (abstract).
29 Mochizuki S, Dahlof B, Shimizu M et al. Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study. Lancet 2007; 369:1431-9.
30. Kjeldsen SE, Julius S, Mancia G et al. Effects of valsartan compared to amlodipine on preventing type 2 diabetes in high-risk hypertensive patients: the VALUE trial. J Hypertens 2006; 24:1405-12.
31. Weycker D, Edelsberg J, Vincze G et al. Risk of diabetes in a real-world setting among patients initiating antihypertensive therapy with valsartan or amlodipine. J Hum Hypertens 2007; 21:374-80.
32. W. J. Elliott, P. M. Meyer. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet 2007;369:201-07.
33. Top C, Cingozbay BY, Terekeci H et al. The effects of valsartan on insulin sensitivity in patients with primary hypertension. J Int Med Res 2002; 30:15-20.
34. Diagnosis and treatment of metabolic syndrome. Russian recommendations. Moscow, 2007. Cardiovascular therapy and prevention 2007; appendix 2: 3-26.
35 Fogari R, Preti P, Derosa G et al. Effect of antihypertensive treatment with valsartan or atenolol on sexual activity and plasma testosterone in hypertensive men. Eur J Clin Pharmacol 2002; 58:177-80.
36 Fogari R, Zoppi A, Poletti L et al. Sexual activity in hypertensive men treated with valsartan or carvedilol: a crossover study. Am J Hypertens 2001; 14:27-31.
37 Fogari R, Preti P, Zoppi A et al. Effect of valsartan and atenolol on sexual behavior in hypertensive postmenopausal women. Am J Hypertens 2004; 17:77-81.
38. Bloom BS. Continuation of initial antihypertensive medication after 1 year of therapy. Clin Ther 1998; 20:671-81.

1998 marked the 100th anniversary of the discovery of renin by the Swedish physiologist R. Tigerstedt. Almost 50 years later, in 1934, Goldblatt et al., using a model of renin-dependent hypertension, proved for the first time the key role of this hormone in the regulation of blood pressure. The synthesis of angiotensin II by Brown-Menendez (1939) and Page (1940) was another step towards the assessment of the physiological role of the renin-angiotensin system. The development of the first inhibitors of the renin-angiotensin system in the 70s (teprotide, saralazine, and then captopril, enalapril, etc.) made it possible for the first time to influence the functions of this system. The next development was the creation of compounds that selectively block angiotensin II receptors. Their selective blockade is a fundamentally new approach to eliminating the negative effects of activation of the renin-angiotensin system. The creation of these drugs has opened up new prospects in the treatment of hypertension, heart failure, and diabetic nephropathy.

In accordance with classical concepts, the main effector hormone of the renin-angiotensin system, angiotensin II, is formed in the systemic circulation as a result of a cascade of biochemical reactions. In 1954, L. Skeggs and a group of specialists from Cleveland found that angiotensin is present in the circulating blood in two forms: in the form of a decapeptide and an octapeptide, later called angiotensin I and angiotensin II.

Angiotensin I is formed as a result of its cleavage from angiotensinogen produced by liver cells. The reaction is carried out under the action of renin. Subsequently, this inactive decaptide is exposed to ACE and, in the process of chemical transformation, is converted into the active octapeptide angiotensin II, which is a powerful vasoconstrictor factor.

In addition to angiotensin II, the physiological effects of the renin-angiotensin system are carried out by several more biologically active substances. The most important of them is angiotensin(1-7), which is formed mainly from angiotensin I, and also (to a lesser extent) from angiotensin II. Heptapeptide(1-7) has a vasodilatory and antiproliferative effect. It, unlike angiotensin II, does not affect the secretion of aldosterone.

Under the influence of proteinases from angiotensin II, several more active metabolites are formed - angiotensin III, or angiotensin (2-8) and angiotensin IV, or angiotensin (3-8). Angiotensin III is associated with processes that increase blood pressure - stimulation of angiotensin receptors and the formation of aldosterone.

Studies of the last two decades have shown that angiotensin II is formed not only in the systemic circulation, but also in various tissues, where all components of the renin-angiotensin system (angiotensinogen, renin, ACE, angiotensin receptors) are found, and the expression of renin and angiotensin II genes is also revealed. . The significance of the tissue system is due to its leading role in the pathogenetic mechanisms of the formation of diseases of the cardiovascular system at the organ level.

In accordance with the concept of the two-component renin-angiotensin system, the system link is assigned the leading role in its short-term physiological effects. The tissue link of the renin-angiotensin system provides a long-term effect on the function and structure of organs. Vasoconstriction and release of aldosterone in response to angiotensin stimulation are immediate responses occurring within seconds, in accordance with their physiological role, which is to maintain circulation after blood loss, dehydration or orthostatic changes. Other effects - myocardial hypertrophy, heart failure - develop over a long period. For the pathogenesis of chronic diseases of the cardiovascular system, slow responses carried out at the tissue level are more important than fast responses implemented by the systemic link of the renin-angiotensin system.

In addition to the ACE-dependent conversion of angiotensin I to angiotensin II, alternative pathways for its formation have been established. Angiotensin II accumulation has been found to continue despite near-complete ACE blockade with its inhibitor, enalapril. Subsequently, it was found that at the level of the tissue link of the renin-angiotensin system, the formation of angiotensin II occurs without the participation of ACE. The conversion of angiotensin I to angiotensin II is carried out with the participation of other enzymes - tonin, chymases and cathepsin. These specific proteinases are able not only to convert angiotensin I to angiotensin II, but also to cleave angiotensin II directly from angiotensinogen without the participation of renin. In organs and tissues, the leading place is occupied by ACE-independent pathways for the formation of angiotensin II. So, in the human myocardium, about 80% of it is formed without the participation of ACE.

Angiotensin II receptors

The main effects of angiotensin II are carried out through its interaction with specific cellular receptors. Currently, several types and subtypes of angiotensin receptors have been identified: AT1, AT2, AT3 and AT4. Only AT1 and AT2 receptors have been found in humans. The first type of receptors is divided into two subtypes - AT1A and AT1B. The AT1A and AT2B subtypes were previously thought to exist only in animals, but they have now been identified in humans as well. The functions of these isoforms are not entirely clear. AT1A receptors predominate in vascular smooth muscle cells, the heart, lungs, ovaries, and the hypothalamus. The predominance of AT1A receptors in vascular smooth muscle indicates their role in vasoconstriction processes. Due to the fact that AT1B receptors prevail in the adrenal glands, uterus, anterior pituitary gland, it can be assumed that they are involved in the processes of hormonal regulation. The presence of AT1C, a subtype of receptors in rodents, is assumed, but their exact localization has not been established.

It is known that all cardiovascular and extracardiac effects of angiotensin II are mediated predominantly through AT1 receptors.

They are found in the tissues of the heart, liver, brain, kidneys, adrenal glands, uterus, endothelial and smooth muscle cells, fibroblasts, macrophages, peripheral sympathetic nerves, in the conduction system of the heart.

Much less is known about AT2 receptors than about AT1 receptors. The AT2 receptor was first cloned in 1993, and its localization on the X chromosome was established. In the adult body, AT2 receptors are present in high concentrations in the adrenal medulla, in the uterus and ovaries, they are also found in the vascular endothelium, heart, and various areas of the brain. In embryonic tissues, AT2 receptors are much more widely represented than in adults and are predominant in them. Shortly after birth, the AT2 receptor is "turned off" and activated in certain pathological conditions, such as myocardial ischemia, heart failure, and vascular damage. The fact that AT2 receptors are most widely present in fetal tissues and their concentration sharply decreases in the first weeks after birth indicates their role in the processes associated with cell growth, differentiation, and development.

It is believed that AT2 receptors mediate apoptosis - programmed cell death, which is a natural consequence of the processes of its differentiation and development. Due to this, stimulation of AT2 receptors has an antiproliferative effect.

AT2 receptors are considered a physiological counterbalance to AT1 receptors. They appear to control overgrowth mediated through AT1 receptors or other growth factors and also counterbalance the vasoconstrictor effect of AT1 receptor stimulation.

It is believed that the main mechanism of vasodilation upon stimulation of AT2 receptors is the formation of nitric oxide (NO) by the vascular endothelium.

Effects of Angiotensin II

Heart

The effect of angiotensin II on the heart is carried out both directly and indirectly - through an increase in sympathetic activity and aldosterone concentration in the blood, an increase in afterload due to vasoconstriction. The direct effect of angiotensin II on the heart is an inotropic effect, as well as an increase in the growth of cardiomyocytes and fibroblasts, which contributes to myocardial hypertrophy.

Angiotensin II is involved in the progression of heart failure, causing such adverse effects as an increase in pre- and afterload on the myocardium as a result of venoconstriction and narrowing of arterioles, followed by an increase in venous return of blood to the heart and an increase in systemic vascular resistance; aldosterone-dependent fluid retention in the body, leading to an increase in circulating blood volume; activation of the sympathetic-adrenal system and stimulation of proliferation and fibroelastosis processes in the myocardium.

Vessels

Interacting with AT, vascular receptors, angiotensin II has a vasoconstrictor effect, leading to an increase in blood pressure.

Angiotensin II-induced hypertrophy and hyperplasia of smooth muscle cells, hyperproduction of collagen by the vascular wall, stimulation of endothelin synthesis, and inactivation of NO-induced vascular relaxation also contribute to an increase in OPSS.

Vasoconstrictor effects of angiotensin II in different parts of the vascular bed are not the same. The most pronounced vasoconstriction due to its effect on AT receptors is observed in the vessels of the peritoneum, kidneys and skin. A less significant vasoconstrictor effect is manifested in the vessels of the brain, lungs, heart and skeletal muscles.

kidneys

The renal effects of angiotensin II play a significant role in the regulation of blood pressure levels. Activation of AT1 receptors in the kidneys contributes to the retention of sodium and, consequently, fluid in the body. This process is realized through an increase in the synthesis of aldosterone and the direct action of angiotensin II on the proximal section of the descending tubule of the nephron.

The renal vessels, especially the efferent arterioles, are extremely sensitive to angiotensin II. By increasing the resistance of the afferent renal vessels, angiotensin II causes a decrease in renal plasma flow and a decrease in the glomerular filtration rate, and a narrowing of the efferent arterioles contributes to an increase in glomerular pressure and the appearance of proteinuria.

Local formation of angiotensin II has a decisive influence on the regulation of kidney function. It acts directly on the renal tubules to increase Na+ reabsorption, promote mesangial cell contraction, which reduces the total glomerular surface area.

Nervous system

The effects caused by the influence of angiotensin II on the central nervous system are manifested by central and peripheral reactions. The effect of angiotensin on the central structures causes an increase in blood pressure, stimulates the release of vasopressin and adrenocorticotropic hormone. Activation of angiotensin receptors in the peripheral parts of the nervous system leads to increased sympathetic neurotransmission and inhibition of norepinephrine reuptake in the nerve endings.

Other vital effects of angiotensin II are the stimulation of the synthesis and release of aldosterone in the glomerular zone of the adrenal glands, participation in the processes of inflammation, atherogenesis, and regeneration. All these reactions play an important role in the pathogenesis of diseases of the cardiovascular system.

Angiotensin II receptor blocking drugs

Attempts to achieve blockade of the renin-angiotensin system at the level of receptors have been made for a long time. In 1972, the peptide angiotensin II antagonist saralazine was synthesized, but it did not find therapeutic use due to the short half-life, partial agonistic activity, and the need for intravenous administration. The basis for the creation of the first non-peptide blocker of angiotensin receptors was the research of Japanese scientists, who in 1982 obtained data on the ability of imidazole derivatives to block AT1 receptors. In 1988, a group of researchers led by R. Timmermans synthesized the non-peptide angiotensin II antagonist losartan, which became the prototype of a new group of antihypertensive drugs. Used in the clinic since 1994.

Subsequently, a number of AT1 receptor blockers were synthesized, but only a few drugs have found clinical use at present. They differ in bioavailability, absorption rate, tissue distribution, elimination rate, presence or absence of active metabolites.

Main effects of AT1 receptor blockers

The effects of angiotensin II antagonists are due to their ability to bind to specific receptors of the latter. With high specificity and preventing the action of angiotensin II at the tissue level, these drugs provide a more complete blockade of the renin-angiotensin system compared to ACE inhibitors. The advantage of AT1 receptor blockers over ACE inhibitors is also the absence of an increase in the level of kinins during their use. This avoids such unwanted side effects due to the accumulation of bradykinin, such as cough and angioedema.

Blockade of AT1 receptors by angiotensin II antagonists leads to the suppression of its main physiological effects:

• vasoconstriction
• aldosterone synthesis
• release of catecholamines from the adrenal glands and presynaptic membranes
• release of vasopressin
• slowing down the process of hypertrophy and proliferation in the vascular wall and myocardium

Hemodynamic effects

The main hemodynamic effect of AT1 receptor blockers is vasodilation and, consequently, a decrease in blood pressure.

The antihypertensive efficacy of drugs depends on the initial activity of the renin-angiotensin system: in patients with high renin activity, they act more strongly.

The mechanisms by which angiotensin II antagonists reduce vascular resistance are as follows:

• suppression of vasoconstriction and hypertrophy of the vascular wall caused by angiotensin II
• decreased Na+ reabsorption due to the direct action of angiotensin II on the renal tubules and through decreased aldosterone release
• elimination of sympathetic stimulation due to angiotensin II
• regulation of baroreceptor reflexes by inhibiting the structures of the renin-angiotensin system in the brain tissue
• an increase in the content of angiotensin which stimulates the synthesis of vasodilator prostaglandins
• decreased release of vasopressin
• modulating effect on vascular endothelium
• increased nitric oxide formation by the endothelium due to the activation of AT2 receptors and bradykinin receptors by an increased level of circulating angiotensin II

All AT1 receptor blockers have a long-term antihypertensive effect that lasts for 24 hours. It manifests itself after 2-4 weeks of therapy and reaches a maximum by the 6-8th week of treatment. Most drugs have a dose-dependent decrease in blood pressure. They do not disturb its normal daily rhythm. The available clinical observations indicate that with long-term administration of angiotensin receptor blockers (for 2 years or more), resistance to their action does not develop. Cancellation of treatment does not lead to a "rebound" increase in blood pressure. AT1 receptor blockers do not reduce blood pressure if it is within normal limits.

When compared with antihypertensive drugs of other classes, it was noted that AT1 receptor blockers, having a similar antihypertensive effect, cause fewer side effects and are better tolerated by patients.

Action on the myocardium

A decrease in blood pressure levels with the use of AT1 receptor blockers is not accompanied by an increase in heart rate. This may be due to both a decrease in peripheral sympathetic activity and the central effect of drugs due to inhibition of the activity of the tissue link of the renin-angiotensin system at the level of brain structures.

Of particular importance is the blockade of the activity of this system directly in the myocardium and vascular wall, which contributes to the regression of myocardial hypertrophy and the vascular wall. AT1 receptor blockers not only inhibit growth factors, the action of which is mediated through the activation of AT1 receptors, but also act on AT2 receptors. Suppression of AT1 receptors contributes to increased stimulation of AT2 receptors due to an increase in the content of angiotensin II in the blood plasma. Stimulation of AT2 receptors slows down the growth and hyperplasia of vascular smooth muscles and endothelial cells, and also inhibits collagen synthesis by fibroblasts.

The effect of AT1 receptor blockers on the processes of myocardial hypertrophy and remodeling is of therapeutic importance in the treatment of ischemic and hypertensive cardiomyopathy, as well as cardiosclerosis in patients with coronary artery disease. Experimental studies have shown that drugs of this class increase coronary reserve. This is due to the fact that fluctuations in coronary blood flow depend on the tone of the coronary vessels, diastolic perfusion pressure, end-diastolic pressure in the LV factors modulated by angiotensin II antagonists. AT1 receptor blockers also neutralize the participation of angiotensin II in the processes of atherogenesis, reducing atherosclerotic lesions of the heart vessels.

Action on the kidneys

The kidneys are a target organ in hypertension, the function of which is significantly affected by AT1 receptor blockers. Blockade of AT1 receptors in the kidneys contributes to a decrease in the tone of efferent arterioles and an increase in renal plasma flow. In this case, the glomerular filtration rate does not change or increases.

Blockers of AT1 receptors, contributing to the dilatation of efferent renal arterioles and a decrease in intraglomerular pressure, as well as suppressing the renal effects of angiotensin II (increased sodium reabsorption, dysfunction of mesangial cells, activation of glomerular sclerosis), prevent the progression of renal failure. By selectively reducing the tone of efferent arterioles and, consequently, reducing intraglomerular pressure, drugs reduce proteinuria in patients with hypertensive and diabetic nephropathy.

However, it must be remembered that in patients with unilateral renal artery stenosis, AT1 receptor blockers can cause an increase in plasma creatinine levels and acute renal failure.

Blockade of AT receptors has a moderate natriuretic effect through direct suppression of sodium reabsorption in the proximal tubule, as well as due to inhibition of the synthesis and release of aldosterone. The decrease in aldosterone-induced sodium reabsorption in the distal tubule contributes to some diuretic effect.

Losartan, the only AT1 receptor blocker, has a dose-dependent uricosuric effect. This effect does not depend on the activity of the renin-angiotensin system and the use of table salt. Its mechanism is not completely clear yet.

Nervous system

Blockers of AT, receptors slow down neurotransmission by inhibiting peripheral sympathetic activity through the blockade of presynaptic adrenergic receptors. With experimental intracerebral administration of drugs, central sympathetic responses are suppressed at the level of paraventricular nuclei. As a result of the action on the central nervous system, the release of vasopressin decreases, the feeling of thirst decreases.

Indications for the use of AT1 receptor blockers and side effects

Currently, the only indication for the use of AT1 receptor blockers is hypertension. The feasibility of their use in patients with LVH, chronic heart failure, diabetic nephropathy is being clarified in the course of clinical trials.

A distinctive feature of the new class of antihypertensive drugs is good tolerability comparable to placebo. Side effects with their use are observed much less frequently than when used. Unlike the latter, the use of angiotensin II antagonists is not accompanied by the accumulation of bradykinin and the appearance of the resulting cough. Angioedema is also much less common.

Like ACE inhibitors, these drugs can cause a fairly rapid decrease in blood pressure in renin-dependent forms of hypertension. In patients with bilateral narrowing of the renal arteries of the kidneys, deterioration in renal function is possible. In patients with chronic renal failure, there is a risk of developing hyperkalemia due to inhibition of aldosterone release during treatment.

The use of AT1 receptor blockers during pregnancy is contraindicated due to the possibility of fetal developmental disorders and death.

Despite the above undesirable effects, AT1 receptor blockers are the most well-tolerated group of antihypertensive drugs with the lowest incidence of adverse reactions.

AT1 receptor antagonists are well combined with almost all groups of antihypertensive drugs. Their combination with is especially effective.

Losartan

It is the first non-peptide AT1 receptor blocker, which became the prototype of this class of antihypertensive drugs. It is a derivative of benzimidazole, does not have agonist activity for AT1 receptors, which blocks 30,000 times more actively than AT2 receptors. The half-life of losartan is short - 1.5-2.5 hours. During the first passage through the liver, losartan is metabolized to form the active metabolite EPX3174, which is 15-30 times more active than losartan and has a longer half-life - from 6 to 9 hours. the biological effects of losartan are due to this metabolite. Like losartan, it is characterized by high selectivity for AT1 receptors and the absence of agonistic activity.

The oral bioavailability of losartan is only 33%. Its excretion is carried out with bile (65%) and urine (35%). Impaired renal function slightly affects the pharmacokinetics of the drug, while with liver dysfunction, the clearance of both active agents decreases, and their concentration in the blood increases.

Some authors believe that increasing the dose of the drug to more than 50 mg per day does not provide an additional antihypertensive effect, while others have observed a more significant decrease in blood pressure when the dose is increased to 100 mg / day. Further increase in dose does not increase the effectiveness of the drug.

Great hopes were associated with the use of losartan in patients with chronic heart failure. The basis was the data of the ELITE study (1997), in which losartan therapy (50 mg / day) for 48 weeks contributed to a 46% reduction in the risk of death in patients with chronic heart failure compared with captopril, administered 50 mg 3 times a day. Since this study was conducted on a relatively small cohort (722) patients, a larger study was undertaken ELITE II (1992), which included 3152 patients. The aim was to study the effect of losartan on the prognosis of patients with chronic heart failure. However, the results of this study did not confirm the optimistic prognosis - the mortality of patients treated with captopril and losartan was almost the same.

Irbesartan

Irbesartan is a highly specific AT1 receptor blocker. According to its chemical structure, it belongs to imidazole derivatives. It has a high affinity for AT1 receptors, being 10 times more selective than losartan.

When comparing the antihypertensive effect of irbesartan at a dose of 150–300 mg/day and losartan at a dose of 50–100 mg/day, it was noted that 24 hours after administration, irbesartan reduced DBP more significantly than losartan. After 4 weeks of therapy, increase the dose to achieve the target level of DBP (<90 мм рт. ст.) потребовалось у 53% больных, получавших ирбесартан, и у 61% пациентов, получавших лосартан. Дополнительное назначение гидрохлоротиазида более значительно усилило антигипертензивный эффект ирбесартана, чем лосартана.

Numerous studies have established that blockade of the activity of the renin-angiotensin system has a protective effect on the kidneys in patients with hypertension, diabetic nephropathy and proteinuria. This effect is based on the inactivating effect of drugs on the intrarenal and systemic effects of angiotensin II. Along with a systemic decrease in blood pressure, which in itself has a protective effect, neutralization of the effects of angiotensin II at the organ level helps to reduce the resistance of efferent arterioles. This leads to a decrease in intraglomerular pressure with a subsequent decrease in proteinuria. It can be expected that the renoprotective effect of AT1 receptor blockers may be more significant than the effect of ACE inhibitors. AT1 receptor blockers selectively act at the level of the AT1 receptor, more completely block the renin-angiotensin system in the kidney tissue, as they prevent the effects of angiotensin II of any origin.

Several studies have investigated the renoprotective effect of irbesartan in patients with hypertension and type II diabetes mellitus with proteinuria. The drug reduced proteinuria and slowed down the processes of glomerulosclerosis.

Currently, clinical studies are underway to study the renoprotective effect of irbesartan in patients with diabetic nephropathy and hypertension. One of them, IDNT, examines the comparative efficacy of irbesartan and amlodipine in hypertensive patients with diabetic nephropathy.

Telmisartan

Telmisartan has an inhibitory effect on AT1 receptors, 6 times greater than that of losartan. It is a lipophilic drug, due to which it penetrates well into tissues.

Comparison of the antihypertensive efficacy of telmisartan with other modern drugs shows that it is not inferior to any of them.

The effect of telmisartan is dose dependent. Increasing the daily dose from 20 mg to 80 mg is accompanied by a twofold increase in the effect on SBP, as well as a more significant decrease in DBP. Increasing the dose of more than 80 mg per day does not give an additional reduction in blood pressure.

Valsartan

A persistent decrease in SBP and DBP occurs after 2-4 weeks of regular intake, as well as other AT1 receptor blockers. Strengthening of the effect is observed after 8 weeks. Daily monitoring of blood pressure indicates that valsartan does not disturb the normal circadian rhythm, and the T / R index is, according to various sources, 60-68%. Efficiency does not depend on gender, age and race. Valsartan is not inferior in antihypertensive efficacy to amlodipine, hydrochlorothiazide and lisinopril, surpassing them in tolerability.

In the VALUE study, which began in 1999 and includes 14,400 patients with hypertension from 31 countries, a comparative assessment of the effectiveness of the effect of valsartan and amlodipine on endpoints will allow us to decide whether they, like relatively new drugs, have a risk advantage. the development of complications in patients with hypertension compared with diuretics and.

Subgroup drugs excluded. Turn on

Description

Angiotensin II receptor antagonists, or AT 1 receptor blockers, are one of the new groups of antihypertensive drugs. It combines drugs that modulate the functioning of the renin-angiotensin-aldosterone system (RAAS) through interaction with angiotensin receptors.

RAAS plays an important role in the regulation of blood pressure, the pathogenesis of arterial hypertension and chronic heart failure (CHF), as well as a number of other diseases. Angiotensins (from angio- vascular and tensio- tension) - peptides formed in the body from angiotensinogen, which is a glycoprotein (alpha 2-globulin) of blood plasma, synthesized in the liver. Under the influence of renin (an enzyme formed in the juxtaglomerular apparatus of the kidneys), the angiotensinogen polypeptide, which does not have pressor activity, is hydrolyzed, forming angiotensin I, a biologically inactive decapeptide, which is easily subjected to further transformations. Under the action of an angiotensin-converting enzyme (ACE), which is formed in the lungs, angiotensin I is converted into an octapeptide - angiotensin II, which is a highly active endogenous pressor compound.

Angiotensin II is the main effector peptide of the RAAS. It has a strong vasoconstrictor effect, increases OPSS, causes a rapid increase in blood pressure. In addition, it stimulates the secretion of aldosterone, and in high concentrations it increases the secretion of antidiuretic hormone (increased reabsorption of sodium and water, hypervolemia) and causes sympathetic activation. All these effects contribute to the development of hypertension.

Angiotensin II is rapidly metabolized (half-life - 12 minutes) with the participation of aminopeptidase A with the formation of angiotensin III and then under the influence of aminopeptidase N - angiotensin IV, which have biological activity. Angiotensin III stimulates the production of aldosterone by the adrenal glands, has a positive inotropic activity. Angiotensin IV is thought to be involved in the regulation of hemostasis.

It is known that in addition to the RAAS of the systemic circulation, the activation of which leads to short-term effects (including such as vasoconstriction, increased blood pressure, aldosterone secretion), there are local (tissue) RAAS in various organs and tissues, incl. in the heart, kidneys, brain, blood vessels. Increased activity of tissue RAAS causes long-term effects of angiotensin II, which are manifested by structural and functional changes in target organs and lead to the development of such pathological processes as myocardial hypertrophy, myofibrosis, atherosclerotic damage to cerebral vessels, kidney damage, etc.

It has now been shown that in humans, in addition to the ACE-dependent pathway of converting angiotensin I to angiotensin II, there are alternative pathways involving chymases, cathepsin G, tonin, and other serine proteases. Chymases, or chymotrypsin-like proteases, are glycoproteins with a molecular weight of about 30,000. Chymases have a high specificity for angiotensin I. In various organs and tissues, either ACE-dependent or alternative pathways for the formation of angiotensin II predominate. Thus, cardiac serine protease, its DNA and mRNA were found in human myocardial tissue. The largest amount of this enzyme is found in the myocardium of the left ventricle, where the chymase pathway accounts for more than 80%. Chymase-dependent formation of angiotensin II prevails in the myocardial interstitium, adventitia, and vascular media, while ACE-dependent formation occurs in blood plasma.

Angiotensin II can also be formed directly from angiotensinogen by reactions catalyzed by tissue plasminogen activator, tonin, cathepsin G, etc.

It is believed that the activation of alternative pathways for the formation of angiotensin II plays an important role in the processes of cardiovascular remodeling.

The physiological effects of angiotensin II, like other biologically active angiotensins, are realized at the cellular level through specific angiotensin receptors.

To date, the existence of several subtypes of angiotensin receptors has been established: AT 1, AT 2, AT 3 and AT 4, etc.

In humans, two subtypes of membrane-bound, G-protein-coupled angiotensin II receptors, the AT 1 and AT 2 subtypes, have been identified and most thoroughly studied.

AT 1 receptors are localized in various organs and tissues, mainly in vascular smooth muscle, heart, liver, adrenal cortex, kidneys, lungs, and in some areas of the brain.

Most of the physiological effects of angiotensin II, including adverse ones, are mediated by AT 1 receptors:

Arterial vasoconstriction, incl. vasoconstriction of the arterioles of the renal glomeruli (especially the efferent ones), increased hydraulic pressure in the renal glomeruli,

Increased sodium reabsorption in the proximal renal tubules,

Secretion of aldosterone by the adrenal cortex

Secretion of vasopressin, endothelin-1,

renin release,

Increased release of norepinephrine from sympathetic nerve endings, activation of the sympathetic-adrenal system,

Proliferation of vascular smooth muscle cells, intimal hyperplasia, cardiomyocyte hypertrophy, stimulation of vascular and heart remodeling processes.

In arterial hypertension against the background of excessive activation of the RAAS, the effects of angiotensin II mediated by AT 1 receptors directly or indirectly contribute to an increase in blood pressure. In addition, stimulation of these receptors is accompanied by a damaging effect of angiotensin II on the cardiovascular system, including the development of myocardial hypertrophy, thickening of arterial walls, etc.

The effects of angiotensin II mediated by AT 2 receptors have only been discovered in recent years.

A large number of AT 2 receptors found in the tissues of the fetus (including in the brain). In the postnatal period, the number of AT 2 receptors in human tissues decreases. Experimental studies, in particular in mice in which the gene encoding AT 2 receptors has been destroyed, suggest their participation in the processes of growth and maturation, including cell proliferation and differentiation, development of embryonic tissues, and the formation of exploratory behavior.

AT 2 receptors are found in the heart, blood vessels, adrenal glands, kidneys, some areas of the brain, reproductive organs, incl. in the uterus, atrezirovannyh ovarian follicles, as well as in skin wounds. It has been shown that the number of AT 2 receptors can increase with tissue damage (including blood vessels), myocardial infarction, and heart failure. It is suggested that these receptors may be involved in the processes of tissue regeneration and programmed cell death (apoptosis).

Recent studies show that the cardiovascular effects of angiotensin II mediated by AT 2 receptors are opposite to those caused by excitation of AT 1 receptors and are relatively mild. Stimulation of AT 2 receptors is accompanied by vasodilation, inhibition of cell growth, incl. suppression of cell proliferation (endothelial and smooth muscle cells of the vascular wall, fibroblasts, etc.), inhibition of cardiomyocyte hypertrophy.

The physiological role of angiotensin II type II receptors (AT 2) in humans and their relationship with cardiovascular homeostasis is currently not fully understood.

Highly selective AT 2 receptor antagonists (CGP 42112A, PD 123177, PD 123319) have been synthesized, which are used in experimental studies of RAAS.

Other angiotensin receptors and their role in humans and animals have been little studied.

Subtypes of AT 1 receptors, AT 1a and AT 1b, differing in affinity for angiotensin II peptide agonists, were isolated from rat mesangial cell culture (these subtypes were not found in humans). The AT 1c receptor subtype has been isolated from the placenta of rats, the physiological role of which is not yet clear.

AT 3 receptors with affinity for angiotensin II are found on neuronal membranes, their function is unknown. AT 4 receptors are found on endothelial cells. Interacting with these receptors, angiotensin IV stimulates the release of a type 1 plasminogen activator inhibitor from the endothelium. AT 4 receptors are also found on the membranes of neurons, incl. in the hypothalamus, presumably in the brain, they mediate cognitive functions. In addition to angiotensin IV, angiotensin III also has a tropism for AT 4 receptors.

Long-term studies of the RAAS have not only revealed the importance of this system in the regulation of homeostasis, in the development of cardiovascular pathology, influencing the functions of target organs, among which the most important are the heart, blood vessels, kidneys and brain, but also led to the creation of drugs, purposefully acting on individual parts of the RAAS.

The scientific basis for the creation of drugs that act by blocking angiotensin receptors was the study of angiotensin II inhibitors. Experimental studies show that angiotensin II antagonists that can block its formation or action and thus reduce the activity of RAAS are angiotensinogen formation inhibitors, renin synthesis inhibitors, ACE formation or activity inhibitors, antibodies, angiotensin receptor antagonists, including synthetic non-peptide compounds, specifically blocking AT 1 receptors, etc.

The first angiotensin II receptor blocker introduced into therapeutic practice in 1971 was saralazine, a peptide compound similar in structure to angiotensin II. Saralazin blocked the pressor action of angiotensin II and lowered the tone of peripheral vessels, reduced the content of aldosterone in plasma, lowered blood pressure. However, by the mid-1970s, the experience of using saralazine showed that it has the properties of a partial agonist and in some cases gives an unpredictable effect (in the form of excessive hypotension or hypertension). At the same time, a good hypotensive effect was manifested in conditions associated with a high level of renin, while against the background of a low level of angiotensin II or with a rapid injection of blood pressure increased. Due to the presence of agonistic properties, as well as due to the complexity of the synthesis and the need for parenteral administration, saralazine has not received wide practical application.

In the early 1990s, the first non-peptide selective AT 1 receptor antagonist effective when taken orally, losartan, was synthesized, which received practical application as an antihypertensive agent.

Currently, several synthetic non-peptide selective AT 1 blockers are being used or undergoing clinical trials in world medical practice - valsartan, irbesartan, candesartan, losartan, telmisartan, eprosartan, olmesartan medoxomil, azilsartan medoxomil, zolarsartan, tazosartan (zolarsartan and tazosartan are not yet registered in Russia).

There are several classifications of angiotensin II receptor antagonists: by chemical structure, pharmacokinetic features, mechanism of binding to receptors, etc.

According to the chemical structure, non-peptide blockers of AT 1 receptors can be divided into 3 main groups:

Biphenyl derivatives of tetrazole: losartan, irbesartan, candesartan, valsartan, tazosartan;

Biphenyl netetrazole compounds - telmisartan;

Non-biphenyl netetrazole compounds - eprosartan.

By the presence of pharmacological activity, AT 1 receptor blockers are divided into active dosage forms and prodrugs. So, valsartan, irbesartan, telmisartan, eprosartan themselves have pharmacological activity, while candesartan cilexetil becomes active only after metabolic transformations in the liver.

In addition, AT 1 blockers differ depending on the presence or absence of active metabolites in them. Active metabolites are found in losartan and tazosartan. For example, the active metabolite of losartan, EXP-3174, has a stronger and longer-lasting effect than losartan (in terms of pharmacological activity, EXP-3174 exceeds losartan by 10-40 times).

According to the mechanism of binding to receptors, AT 1 receptor blockers (as well as their active metabolites) are divided into competitive and non-competitive angiotensin II antagonists. Thus, losartan and eprosartan bind reversibly to AT 1 receptors and are competitive antagonists (i.e., under certain conditions, for example, with an increase in the level of angiotensin II in response to a decrease in BCC, they can be displaced from binding sites), while valsartan, irbesartan , candesartan, telmisartan, and the active metabolite of losartan EXP-3174 act as non-competitive antagonists and bind irreversibly to the receptors.

The pharmacological action of this group of drugs is due to the elimination of the cardiovascular effects of angiotensin II, incl. vasopressor.

It is believed that the antihypertensive effect and other pharmacological effects of angiotensin II receptor antagonists are realized in several ways (one direct and several indirect).

The main mechanism of action of drugs in this group is associated with the blockade of AT 1 receptors. All of them are highly selective AT1 receptor antagonists. It has been shown that their affinity for AT 1 - exceeds that for AT 2 receptors thousands of times: for losartan and eprosartan more than 1 thousand times, for telmisartan - more than 3 thousand, for irbesartan - 8.5 thousand, for the active metabolite of losartan EXP-3174 and candesartan - 10 thousand times, olmesartan - 12.5 thousand times, valsartan - 20 thousand times.

Blockade of AT 1 receptors prevents the development of the effects of angiotensin II mediated by these receptors, which prevents the adverse effect of angiotensin II on vascular tone and is accompanied by a decrease in elevated blood pressure. Long-term use of these drugs leads to a weakening of the proliferative effects of angiotensin II in relation to vascular smooth muscle cells, mesangial cells, fibroblasts, a decrease in cardiomyocyte hypertrophy, etc.

It is known that AT 1 receptors in the cells of the juxtaglomerular apparatus of the kidneys are involved in the regulation of renin release (by the principle of negative feedback). Blockade of AT 1 receptors causes a compensatory increase in renin activity, an increase in the production of angiotensin I, angiotensin II, etc.

Under conditions of an increased content of angiotensin II against the background of blockade of AT 1 receptors, the protective properties of this peptide are manifested, which are realized through stimulation of AT 2 receptors and are expressed in vasodilation, slowing down of proliferative processes, etc.

In addition, against the background of an increased level of angiotensins I and II, angiotensin-(1-7) is formed. Angiotensin-(1-7) is formed from angiotensin I under the action of neutral endopeptidase and from angiotensin II under the action of prolyl endopeptidase and is another RAAS effector peptide that has vasodilatory and natriuretic effects. The effects of angiotensin-(1-7) are mediated through so-called, not yet identified, AT x receptors.

Recent studies of endothelial dysfunction in hypertension suggest that the cardiovascular effects of angiotensin receptor blockers may also be related to endothelial modulation and effects on nitric oxide (NO) production. The obtained experimental data and the results of individual clinical studies are rather contradictory. Perhaps, against the background of blockade of AT 1 receptors, endothelium-dependent synthesis and release of nitric oxide increase, which contributes to vasodilation, a decrease in platelet aggregation and a decrease in cell proliferation.

Thus, the specific blockade of AT 1 receptors allows for a pronounced antihypertensive and organoprotective effect. Against the background of the blockade of AT 1 receptors, the adverse effects of angiotensin II (and angiotensin III, which has affinity for angiotensin II receptors) on the cardiovascular system are inhibited and, presumably, its protective effect is manifested (by stimulating AT 2 receptors), and the action also develops. angiotensin-(1-7) by stimulating AT x receptors. All these effects contribute to vasodilation and weakening of the proliferative action of angiotensin II in relation to vascular and heart cells.

Antagonists of AT 1 receptors can penetrate the blood-brain barrier and inhibit the activity of mediator processes in the sympathetic nervous system. By blocking presynaptic AT 1 receptors of sympathetic neurons in the CNS, they inhibit the release of norepinephrine and reduce stimulation of adrenoceptors of vascular smooth muscle, which leads to vasodilation. Experimental studies show that this additional mechanism of vasodilatory action is more characteristic of eprosartan. Data on the effect of losartan, irbesartan, valsartan, etc. on the sympathetic nervous system (which manifested itself at doses exceeding therapeutic ones) are very contradictory.

All AT 1 receptor blockers act gradually, the antihypertensive effect develops smoothly, within a few hours after taking a single dose, and lasts up to 24 hours. With regular use, a pronounced therapeutic effect is usually achieved after 2-4 weeks (up to 6 weeks) of treatment.

The pharmacokinetic features of this group of drugs make it convenient for patients to use them. These medicines can be taken with or without food. A single dose is enough to provide a good hypotensive effect during the day. They are equally effective in patients of different sex and age, including patients over 65 years of age.

Clinical studies show that all angiotensin receptor blockers have a high antihypertensive and pronounced organoprotective effect, good tolerance. This allows them to be used, along with other antihypertensive drugs, for the treatment of patients with cardiovascular pathology.

The main indication for the clinical use of angiotensin II receptor blockers is the treatment of arterial hypertension of varying severity. Possible monotherapy (for mild arterial hypertension) or in combination with other antihypertensive drugs (for moderate and severe forms).

Currently, according to the recommendations of the WHO / IOH (International Society for Hypertension), preference is given to combination therapy. The most rational for angiotensin II receptor antagonists is their combination with thiazide diuretics. The addition of a low-dose diuretic (eg, 12.5 mg hydrochlorothiazide) can improve the effectiveness of therapy, as evidenced by the results of randomized multicenter trials. Preparations have been created that include this combination - Gizaar (losartan + hydrochlorothiazide), Co-diovan (valsartan + hydrochlorothiazide), Coaprovel (irbesartan + hydrochlorothiazide), Atakand Plus (candesartan + hydrochlorothiazide), Micardis Plus (telmisartan + hydrochlorothiazide), etc. .

A number of multicenter studies (ELITE, ELITE II, Val-HeFT, etc.) have shown the effectiveness of some AT 1 receptor antagonists in CHF. The results of these studies are mixed, but in general they indicate high efficacy and better (compared with ACE inhibitors) tolerability.

The results of experimental and clinical studies indicate that AT1-subtype receptor blockers not only prevent cardiovascular remodeling processes, but also cause regression of left ventricular hypertrophy (LVH). In particular, it was shown that during long-term therapy with losartan, patients showed a tendency to a decrease in the size of the left ventricle in systole and diastole, an increase in myocardial contractility. LVH regression has been noted with long-term use of valsartan and eprosartan in patients with arterial hypertension. Some AT 1 subtype receptor blockers have been found to improve renal function, incl. with diabetic nephropathy, as well as indicators of central hemodynamics in CHF. So far, clinical observations regarding the effect of these drugs on target organs are few, but research in this area is actively ongoing.

Contraindications to the use of angiotensin AT 1 receptor blockers are individual hypersensitivity, pregnancy, breastfeeding.

Animal data suggest that agents with a direct effect on the RAAS may cause fetal injury, fetal and neonatal death. Especially dangerous is the effect on the fetus in the II and III trimesters of pregnancy, because. possible development of hypotension, hypoplasia of the skull, anuria, renal failure and death in the fetus. There are no direct indications of the development of such defects when taking AT 1 receptor blockers, however, the funds of this group should not be used during pregnancy, and if pregnancy is detected during the treatment period, they must be stopped.

There is no information about the ability of AT 1 receptor blockers to penetrate into the breast milk of women. However, in experiments on animals, it has been established that they penetrate into the milk of lactating rats (in the milk of rats, significant concentrations are found not only of the substances themselves, but also of their active metabolites). In this regard, AT 1 receptor blockers are not used in lactating women, and if therapy is necessary for the mother, breastfeeding is stopped.

The use of these medicinal products in pediatric practice should be avoided as their safety and efficacy in children have not been determined.

For therapy with AT 1 angiotensin receptor antagonists, there are a number of limitations. Caution should be exercised in patients with reduced BCC and / or hyponatremia (during treatment with diuretics, limiting salt intake with diet, diarrhea, vomiting), as well as in patients on hemodialysis, tk. possible development of symptomatic hypotension. An assessment of the risk / benefit ratio is necessary in patients with renovascular hypertension due to bilateral renal artery stenosis or renal artery stenosis of a single kidney, because. excessive inhibition of the RAAS in these cases increases the risk of severe hypotension and renal failure. Caution should be used in aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy. Against the background of impaired renal function, it is necessary to monitor the levels of potassium and serum creatinine. Not recommended for patients with primary hyperaldosteronism, tk. in this case, drugs that inhibit the RAAS are ineffective. There are no sufficient data on the use in patients with severe liver disease (eg, cirrhosis).

Side effects reported so far with angiotensin II receptor antagonists are usually mild, transient, and rarely warrant discontinuation of therapy. The overall frequency of side effects is comparable to placebo, as evidenced by the results of placebo-controlled studies. The most common adverse effects are headache, dizziness, general weakness, etc. Angiotensin receptor antagonists do not have a direct effect on the metabolism of bradykinin, substance P, and other peptides and, as a result, do not cause dry cough, which often occurs during treatment with ACE inhibitors.

When taking drugs in this group, there is no effect of hypotension of the first dose, which occurs when taking ACE inhibitors, and sudden withdrawal is not accompanied by the development of rebound hypertension.

The results of multicenter placebo-controlled studies show high efficacy and good tolerability of angiotensin II AT 1 receptor antagonists. However, so far their use is limited by the lack of data on long-term effects of use. According to WHO / MOH experts, their use for the treatment of arterial hypertension is advisable in case of intolerance to ACE inhibitors, in particular, in the case of a history of cough caused by ACE inhibitors.

Currently, numerous clinical studies are ongoing, incl. and multicenter, devoted to the study of the efficacy and safety of the use of angiotensin II receptor antagonists, their impact on mortality, duration and quality of life of patients and comparison with antihypertensive and other drugs in the treatment of arterial hypertension, chronic heart failure, atherosclerosis, etc.

Preparations

Preparations - 4133 ; Trade names - 84 ; Active ingredients - 9

In the early 90s of the last century, drugs were synthesized that have a more selective and more specific effect on the effects of RAS activation. These are AT 1 -angiotensin receptor blockers that act as angiotensin II antagonists for AT 1 receptors, mediating the main cardiovascular and renal effects of RAAS activation.

It is known that with prolonged use of ACE inhibitors (as well as other antihypertensive drugs) there is an “escape” effect, which is expressed in a decrease in its effect on neurohormones (restoration of the synthesis of aldosterone and angiotensin), since the non-ACE-pathway of formation of AT II gradually begins to be activated. .

Another way to reduce the action of AT II is a selective blockade of AT I receptors, which also stimulates AT 2 receptors, while there is no effect on the kallikrein-kinin system (the potentiation of which determines part of the positive effects of ACE inhibitors. Thus, if ACE inhibitors perform non-selective blockade of the negative actions of AT II, ​​then AT II receptor blockers carry out a selective (complete) blockade of the action of AT II on AT 1 - receptors.

At present, two types of AT II receptors have been best studied, performing different functions of AT 1 and AT 2.

§ vasoconstriction;

§ stimulation of synthesis and secretion of aldosterone;

§ tubular reabsorption of Na +;

§ decrease in renal blood flow;

§ proliferation of smooth muscle cells;

§ hypertrophy of the heart muscle;

§ increased release of norepinephrine;

§ stimulation of the release of vasopressin;

§ inhibition of renin formation;

§ stimulation of thirst.

§ vasodilation;

§ natriuretic action;

§ release of NO and prostacyclin;

§ antiproliferative action;

§ stimulation of apoptosis;

§ differentiation and development of embryonic tissues.

AT 1 receptors are localized in the vascular wall, adrenal glands, and liver. Through the AT 1 receptors, the undesirable effects of AT II are realized. AT 2 receptors are also widely represented in the body: CNS, vascular endothelium, adrenal glands, reproductive organs.

ACE inhibitors, blocking the formation of AT II, ​​inhibit the effects of stimulation of both AT 1 and AT 2 receptors. At the same time, not only undesirable, but also physiological effects of AT II, ​​mediated through AT 2 receptors, are blocked, in particular, repair, regeneration, antiproliferative action and additional vasodilation. AT II receptor blockers are selective only for AT 1 receptors, thereby blocking the harmful effects of AT II.

According to the chemical structure, AT II receptor blockers belong to 4 groups:

§ biphenyl derivatives of tetrazole (losartan, candesartan, irbersartan);

§ non-biphenyl tetrazoles (telmisartan);

§ non-biphenyl netetrazoles (eprosartan);

§ non-heterocyclic derivatives (valsartan).

Some AT II receptor blockers are pharmacologically active (telmisartan, irbersartan, eprosartan); others are prodrugs (losartan, candesartan).

Pharmacologically, AT 1 receptor blockers differ in the way they bind to the receptors and the nature of the connection. Losartan is characterized by the lowest binding force to AT 1 receptors, its active metabolite binds 10 times stronger than losartan. The affinity of the new AT I receptor blockers is 10 times greater, which is characterized by a more pronounced clinical effect.

AT I receptor antagonists block the effects of AT II mediated through AT I - vascular and adrenal receptors, as well as arteriolar spasm, sodium and water retention, and myocardial vascular wall remodeling. In addition, these drugs interact with presynaptic receptors of noradrenergic neurons, which prevents the release of norepinephrine into the sympathetic cleft, and thereby prevents the vasoconstrictive effect of the sympathetic nervous system. As a result of the blockade of AT I receptors, they cause systemic vasodilation and a decrease in OPS without an increase in heart rate; natriuretic and diuretic effects. In addition, AT I receptor blockers have an antiproliferative effect, primarily in the cardiovascular system.

The mechanism of the hypotensive action of AT I receptor blockers is complex and consists of the elimination of vasoconstriction caused by AT II, ​​a decrease in the tone of the CAS, and a natriuretic effect. Almost all AT II receptor blockers show a hypotensive effect when taken 1 r / day and provide control of blood pressure for 24 hours.

The antiproliferative action of AT receptor blockers causes organoprotective effects: cardioprotective - due to reversal of myocardial hypertrophy and hyperplasia of the musculature of the vascular wall; improvement of vascular endothelial function.

The effects on the kidneys of AT receptor blockers are similar to those of ACE inhibitors, but there are some differences. AT I receptor blockers, unlike ACE inhibitors, have a less pronounced effect on the tone of the efferent arterioles, increase effective renal blood flow and do not significantly change the glomerular filtration rate. As a result, there is a decrease in intraglomerular pressure and filtration fraction, and a renoprotective effect is achieved. Compliance with a diet low in sodium chloride potentiates the renal and neurohumoral effects of AT I blockers.

In patients with hypertension and chronic renal failure, AT I receptor blockers maintain efficient renal blood flow and do not significantly alter the reduced glomerular filtration rate. The renoprotective effect of AT I receptor blockers is also manifested by a decrease in microalbuminuria in patients with hypertension and diabetic nephropathy.

Losartan stands out among AT I blockers with its unique ability to increase renal excretion of uric acid by inhibiting urate transport in the proximal renal tubules, i.e. has a uricosuric effect.

The most important differences between the pharmacodynamic effects of AT I receptor blockers and those of ACE inhibitors are:

§ more complete blocking of the adverse effects of AT II (tissue action);

§ increased influence of AT II on AT 2 receptors, which complements the vasodilating and antiproliferative effects;

§ milder effect on renal hemodynamics;

§ the absence of undesirable effects associated with the activation of the kinin system.

Pharmacokinetics

The pharmacokinetics of AT I receptor blockers is determined by lipophilicity. The lipophilicity of AT I receptor blockers characterizes not only stable pharmacokinetics, but also determines the degree of tissue distribution and effect on tissue RAPS. Losartan is the most hydrophilic drug, telmisartan is the most lipophilic.

Comparative pharmacokinetics of ATI receptor blockers are presented in Table 14.

Table 14

Comparative pharmacokinetics of AT I receptor blockers

The first ATI blockers are characterized by low and variable bioavailability (10-35%); new drugs are distinguished by improved stable bioavailability (50-80%). After oral administration, the maximum plasma concentration T max. reached after 2 hours; with prolonged regular use, the stationary concentration is established after 5-7 days. The volume of distribution of AT I receptor blockers varies according to their lipophilicity: telmisartan has the largest volume of distribution, which characterizes rapid membrane permeability and high tissue distribution.

All AT I receptor blockers are characterized by a long T ½ half-life - from 9 to 24 hours. Their pharmacodynamic T ½ exceeds the pharmacokinetic T ½, since the nature and strength of interaction with receptors also affect the duration of action. Due to these features, the frequency of taking AT I receptor blockers is 1 time per day. In patients with severe hepatic insufficiency, there may be an increase in bioavailability, the maximum concentration of losartan, valsartan and telmisartan, as well as a decrease in their biliary excretion. Therefore, they are contraindicated in patients with biliary obstruction or severe renal insufficiency.

In patients with mild or moderate renal insufficiency, correction of the dosing regimen of AT I receptor blockers is not required. Elderly patients may experience an increase in bioavailability, a doubling of the maximum plasma concentration, an increase in T ½. Doses in the elderly are not reduced, they are selected individually.

In the pivotal LIFE study in patients with hypertension and left ventricular hypertrophy, losartan-based antihypertensive therapy, compared with atenolol-based therapy, at the same degree of blood pressure reduction, reduced by 13% the incidence of the combined endpoint of stroke, myocardial infarction, and death from cardiovascular disease. - vascular causes. The main contributor to this result was the 25% reduction in first stroke in the losartan group compared to the atenolol group.

Controlled studies have shown that AT1 blockers such as valsartan, irbersartan, candesartan, losartan, telmisartan, and eprosartan cause significant regression of left ventricular hypertrophy in hypertensive patients. In terms of their ability to cause the regression of left ventricular hypertrophy, AT1 receptor blockers are comparable to ACE inhibitors and long-acting calcium antagonists, and also outperform beta-blockers (atenolol).

Data from a number of completed CALM, JDNT, RENAAL and ABCD-2V studies suggest that AT 1 receptor antagonists such as irbersartan, valsartan, candesartan and losartan can serve as an alternative to ACE inhibitors in the treatment of diabetic nephropathy in patients with type II diabetes mellitus.

At present, both the relationship between hypertension and the risk of dementia can be considered proven, as well as the need for a stable reduction in blood pressure to target values ​​for successful prevention. Both overt strokes and repeated minor cerebrovascular accidents without obvious focal symptoms are the leading causes of vascular dementia. A meta-analysis showed that AT 1 receptor antagonists were 24.4% superior to other classes of antihypertensive drugs in preventing primary stroke. The MOSES trial demonstrated a 25% advantage of eprosartan over the calcium antagonist nitrendipine in preventing recurrent strokes. The same study showed a protective effect of eprosartan against dementia.

At the same time, there is an obvious relationship between the presence of hypertension and the state of cognitive function in patients without a history of stroke or TIA, including young adults. The OSCAR study showed that treatment with eprosartan (teveten) in patients with arterial hypertension over 50 years of age for 6 months leads to an improvement in cognitive function against a background of a significant decrease in systolic blood pressure.

Given the high antihypertensive activity and good tolerability of these drugs, the WHO has included AT 1 receptor antagonists in the number of first-line drugs in the treatment of patients with hypertension.

Thus, given the unique spectrum of effects of AT 1 receptor antagonists and excellent tolerability, as well as the pathogenetically justified need for pharmacological correction of disorders in the renin-angiotensin system, the appointment of angiotensin II receptor antagonists is the key to successful treatment of hypertension in different categories of patients, regardless of gender, age. , race, and comorbidities and clinical conditions such as:

· diabetes;

metabolic syndrome;

kidney disease;

microalbuminuria;

Renal failure

a history of myocardial infarction;

atrial fibrillation (paroxysmal form / prevention);

history of stroke

systolic dysfunction of the left ventricle;

obstructive lung disease.

Side effects

It should be said that there is a very low frequency of side effects from the use of AT 1 receptor blockers. AT 1 receptor blockers do not affect the metabolism of kinins and therefore are much less common than

ACE inhibitors cause cough (1-4.6%). The incidence of angioedema, the appearance of a rash does not exceed 1%.

The effect of the "first dose" (postural hypotension) does not exceed 1%. Drugs do not cause clinically significant hyperkalemia (less than 1.5%), do not affect the metabolism of lipids and carbohydrates. Withdrawal syndrome in AT 1 receptor blockers was not noted.

Contraindications:

§ hypersensitivity to AT 1 receptor blockers;

§ arterial hypotension;

§ hyperkalemia;

§ dehydration;

§ stenosis of the renal arteries;

§ pregnancy and lactation;

§ childhood.

Interactions

In order to potentiate the hypotensive effect, the following combined forms of AT1 receptor blockers and hydrochlorothiazide are produced:

§ Losartan 50 mg + hydrochlorothiazide 12.5 mg ( Gizaar).

§ Irbersartan 150/300 mg + hydrochlorothiazide 12.5 mg ( Ko Aprovel).

§ Eprosartan 600 mg + hydrochlorothiazide 12.5 mg ( Teveten plus).

§ Telmisartan 80 mg + hydrochlorothiazide 12.5 mg ( Micardis plus).

Atacand plus).

§ Candesartan 16 mg + hydrochlorothiazide 12.5 mg ( Blopress).

§ Valsartan 80 mg + Hydrochlorothiazide 12.5 mg ( co-diovan).

In addition, the combination of alcohol and losartan, valsartan, eprosartan leads to an increase in the hypotensive effect. NSAIDs, estrogens, sympathomimetics weaken the hypotensive effect of AT1-receptor blockers. The use of potassium-sparing diuretics leads to the development of hyperkalemia. The joint appointment of valsartan, telmisartan and warfarin helps to reduce the maximum concentration of drugs in the blood and increase the prothrombin time.