Among the main factors in the development of coronary artery disease and strokes as the main causes of death in Russia is hypertension, which is characterized by increases in blood pressure above 140/80 mm Hg. Treatment of arterial hypertension is a long, often lifelong process. In this situation, a competent approach to the choice of antihypertensive therapy is required, which is characterized by significant antihypertensive efficacy, a positive effect on organs exposed to the harmful effects of high blood pressure, minimal side effects and convenient methods of application. According to current recommendations, one of the main groups of drugs used in the treatment of arterial hypertension are angiotensin receptor 2 blockers as a single drug or in combination with other drugs.

Show all

Mechanism of action and pharmacological effects

Angiotensin II receptor blockers (sartans) are a class of antihypertensive drugs, the mechanism of action of which is based on inhibition of the activity of the renin-angiotensin-aldosterone system (RAAS) - the main hormonal regulator of blood pressure (BP) and blood volume in the body.

ARBs inhibit (inhibit) angiotensin receptors of the first type, through which the negative effects of angiotensin II are carried out, namely:

increased blood pressure due to vasoconstriction;
increased reuptake of Na + ions in the kidney tubules;
increased production of aldosterone, adrenaline and renin - the main vasoconstrictor hormones;
stimulation of structural changes in the vascular wall and heart muscle;
activation of the activity of the sympathetic (excitatory) nervous system.

Excessive activity of angiotensin 2 receptors leads to the appearance of harmful, often life-threatening changes in internal organs (Table 1).

Activity of type 1 receptors of angiotensin 2 in relation to internal organs:

ARBs, selectively acting on type 1 receptors, reduce vascular tone, improve diastolic function of the myocardium, stimulate a decrease in cardiac muscle hypertrophy, and reduce the secretion of hormones aldosterone, norepinephrine, and endothelin. ARBs are similar in properties to another class of antihypertensive drugs, angiotensin-converting enzyme inhibitors (ACE inhibitors), both of which significantly improve kidney function. It is recommended to switch from angiotensin II blockers to ACE inhibitors if the former cause a cough.

Metabolic effects and classification

Angiotensin receptor blockers, especially Losartan, have a uricosuric (promoting the excretion of uric acid in the urine) effect. This property provides additional benefits of combination therapy with thiazide diuretics. Most ARB drugs are capable of increasing insulin sensitivity in peripheral tissues. This effect is due to sympatholytic action, improved endothelial function and expansion of peripheral vessels.

ARBs have also been shown to act on specific PPRAγ receptors, which directly increase insulin sensitivity at the cell level and stimulate anti-inflammatory response, reduce triglyceride and free fatty acid levels. Modern research has demonstrated the possibility of preventing the development of type 2 diabetes mellitus when taking ARBs.

ARB classification:

Clinical pharmacology

All drugs are highly active in the blood, have good bioavailability and have a long-lasting effect when taken orally, so it is recommended to take them once a day. ARBs are preferentially excreted by the liver and to a lesser extent by the kidneys, which makes it possible to use them carefully in renal failure. Because ARBs are similar in activity to ACE inhibitors, angiotensin II blockers should not be prescribed for stenosis of both renal arteries. Eprosartan and Telmisartan are relatively contraindicated in diseases of the liver and bile ducts, since more than 90% of their concentration is eliminated by the liver. The clinical pharmacology of the master drug list is presented in Table 3.

Pharmacokinetic parameters of angiotensin II receptor antagonists:

ARBs affect neurohumoral interactions in the body, including the main regulatory systems: the RAAS and the sympathoadrenal system (SAS), which are responsible for an increase in blood pressure, the emergence and progression of cardiovascular pathologies.

Indications and contraindications

The main indications for the appointment of angiotensin receptor blockers:

arterial hypertension;
chronic heart failure (CHF functional classes II – IV according to the classification of the New York Heart Association NYHA in drug combinations, if it is impossible to use or ineffective ACE inhibitors) in complex treatment;
an increase in the percentage of patients who have had acute myocardial infarction complicated by left ventricular failure and / or systolic left ventricular dysfunction, with stable hemodynamics;
reducing the likelihood of developing acute disorders of cerebral circulation (strokes) in patients with arterial hypertension and left ventricular hypertrophy;
nephroprotective function in patients with type 2 diabetes mellitus associated with proteinuria in order to reduce it, regress renal pathology, reduce the risk of progression of chronic renal failure to the terminal stage (prevention of hemodialysis, the likelihood of an increase in serum creatinine concentration).

Contraindications to ARB use: individual intolerance, bilateral stenosis of renal arteries or stenosis of an artery of a single kidney, pregnancy, lactation.

Side effects

Research has shown that ARBs have the lowest reported side effects. Unlike a similar class of antihypertensive drugs, ACE inhibitors, angiotensin II receptor blockers are significantly less likely to cause coughing. With increasing dosages and in combination with taking diuretics, hypersensitivity reactions, orthostatic hypotension may develop.

In the case of ARB administration in patients with chronic renal failure or undiagnosed renal artery stenosis, hyperkalemia, an increase in creatinine and blood urea may develop, which requires a decrease in the dosage of the drug. Numerous studies have not revealed data on an increased risk of developing cancer with long-term use of angiotensin receptor blockers.

Pharmacological interactions

Angiotensin II receptor blockers can enter into pharmacodynamic interactions, changing the manifestation of the hypotensive effect, increasing the concentration of potassium in the blood serum when combined with potassium-sparing diuretics and potassium-sparing drugs. Pharmacokinetic interactions are also possible with Warfarin and Digoxin (Table 4).

Drug interactions with angiotensin II receptor blockers:

Interacting drug	Angiotensin II receptor antagonists	Interaction result
Alcohol	Losartan, Valsartan, Eprosartan
Antihypertensive drugs, diuretics	Everything	Strengthening the hypotensive effect
Non-steroidal anti-inflammatory drugs, estrogens, sympathomimetics	Everything	Weakening of the hypotensive effect
Potassium-sparing diuretics, potassium-containing drugs	Everything	Hyperkalemia
Warfarin	Valsartan, Telmesartan	Decrease in maximum blood concentration, increase in prothrombin time
Digoxin	Telmisartan	Increase in maximum blood concentration

List of drugs and their trade names

Currently, in a market economy, there are a significant number of brands of drugs containing the same active ingredient. To select a suitable drug, a specialist consultation is imperative.

A list of the most appointed ARBs and their trade names:

Active substance	Trade names (manufacturing company)	Features of the drug
Valsartan	Valz (Actavis Group hf.), Valsakor (KRKA), Valsartan-NW (North Star), Diovan (Novartis Pharma)	It is used in patients after an acute disturbance of coronary blood flow (myocardial infarction). It should be used carefully if it is necessary to drive vehicles, since it is possible to impair concentration of attention
Irbesartan	Aprovel (Sanofi Clear ESNS), Irsar (Kanonpharma production CJSC)	Not recommended for use in patients with primary hyperaldosteronism, in the case of high stages of chronic renal failure, in patients who have recently undergone a kidney transplant
Candesartan	Angiakand (Kanonfarma production CJSC), Ordiss (Teva), Xarten (VERTEX CJSC)	Dizziness and increased fatigue may occur during treatment. This should be taken into account before starting work with equipment or driving.
Losartan	Lorista (Krka-Rus), Vazotenz (CNViTi PHARMA LIMITED), Lozap (Zentiva a.s)	Most often prescribed. Has an additional uricosuric effect. May be recommended in the complex therapy of gout
Telmisartan	Telsartan (Dr. Reddy "s), Mikardis (Boehringer Ingelheim Pharma)	Reliably prevents the development of acute disorders of cerebral circulation and acute disorders of coronary blood flow (myocardial infarction), has a pronounced nephroprotective effect

Before starting the use of such medicines, it is imperative to consult a doctor.

Catad_tema Heart failure - articles

Advances in drug therapy for chronic heart failure. Part II

»» No. 1 "2000

LITERATURE REVIEWS Sidorenko B.A., Preobrazhensky D.V.
Medical Center of the Administrative Department 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 80s, randomized studies were conducted to assess the efficacy and safety of drugs belonging to the classes of aldosterone receptor blockers, antiarrhythmic drugs, AT1-angiotensin receptor blockers, vasodilators and non-glycoside inotropic drugs in patients with CHF.

Aldosterone receptor blockers

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

Until recently, the blocker of aldosterone receptors spironolokton (aldactone, veroshpiron, spironol) in CHF was used only as a potassium-sparing agent for the correction of 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 overwhelming majority of cases in patients with CHF receiving ACE inhibitors, there is no reason to fear the development of hypokalemia, and therefore to prescribe potassium-sparing diuretics.

CHF is characterized by increased 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 overactive renin-angiogenesis system (RAS), but also with a decrease in its inactivation in the liver. In turn, impaired aldosterone inactivation may result from both a decrease in hepatic blood flow and impairment of its uptake by hepatocytes. It is known that impaired degradation of aldosterone in the liver can in itself 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 it was found that aldosterone plays an important role in the pathogenesis of CHF. Aldosterone not only regulates water and electrolyte homeostasis, promoting sodium retention and enhancing the excretion of potassium and magnesium by the kidneys. Long-term hyperaldosteronism has been shown to induce 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 assumed that increased concentrations of aldosterone in blood plasma 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 weaken the undesirable effects of hyperaldosteronemia, the use of specific aldosterone antagonists is required, among which the most famous 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 aldosterone synthetase activity and thus decrease aldosterone synthesis. In addition, it inhibits the activity of 5alpha-reductase. As a result, the formation of the alpha isomer of aldosterone decreases, which has a greater mineralocorticoid activity than its beta isomer.

Recently, an experiment has shown that spironolactone prevents aldosterone-induced cardiovascular remodeling. 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 RALES Mortality Trial was undertaken.

The aim of this study was to evaluate the effect of low doses of spironolactone on mortality in patients with CHF III-IV FC and with left ventricular ejection fraction 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 received placebo.

In August 1998, the RALES Mortality Trial was suspended early after a significantly lower mortality rate was found in the spironolactone-treated group than in the control group. Mortality from all causes in the group of patients treated with spironolactone was 27% lower than among patients receiving placebo (95% confidence interval, 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 decompensated heart failure - by about 36%. The total number of deaths and hospitalizations with the addition of spironolactone decreased by about 22% (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, in the RALES Mortality Trial it was shown that the use of the aldosterone receptor blocker spironolactone can significantly improve the survival rate of patients with severe CHF.

Eplerenone is a more selective aldosterone (mineralocorticoid) receptor blocker 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, in fact, is the only antiarrhythmic drug that can be used for long-term therapy of ventricular rhythm disturbances, and therefore for the prevention of sudden death in patients with CHF. The use of dofetilide, a new antiarrhythmic drug belonging to the III class 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 GESICA study 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 sudden death (by 27%) and deaths from progressive heart failure (by 23%). Amiodarone was especially effective in women (reduction in mortality by 48%) and in patients with unstable ventricular tachycardia (reduction in mortality by 34%).

Somewhat different data regarding the effectiveness of amiodarone in patients with CHF were obtained in a placebo-controlled, randomized CHF-STAT study. In this study, amiodarone did not significantly affect the prognosis of life in patients with CHF II-IV FC. At the same time, the dependence of the effectiveness of long-term therapy with amiodarone on the etiology of CHF was noted. Thus, there was a clear tendency to improve survival in the treatment of amiodarone in patients 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, amiodarone significantly reduces mortality in patients with CHF - 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, in the GESICA study, patients with CHF of non-ischemic etiology predominated (about 60%), in whom, according to the CHF-STAT study, amiodarone appears to increase survival. In the GESICA study, amiodarone significantly improved survival only in women (a 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, there were only 1% of women among patients.

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., primarily, in patients with dilated cardiomyopathy. Amiodarone appears to be particularly effective in women, as well as in patients with baseline tachycardia (heart rate> 90 beats per minute) and episodes of unstable ventricular tachycardia as measured by 24-hour ECG monitoring.

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

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

Therefore, along with beta-blockers, amiodarone and dofetilide can be used to improve the prognosis in patients with postinfarction systolic left ventricular 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 inhibiting RAS activity, since they act at a lower level - at the level of cellular receptors; (2) their action is more selective, since they suppress the activity of RAS only, 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 RAS activity compared to ACE inhibitors, and, moreover, are distinguished by 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 valzargan, zolarzartan, irbesartan, candesartan, were completed. , losartan, tazosartan, telmisartan and eprosartan.

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

In the multicenter ELITE study, mortality in the group of patients with CHF II-IV FC and with left ventricular ejection fraction of no more than 40% treated with losartan was approximately two times lower (on average by 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 may serve as indirect evidence of the high efficacy, safety and excellent tolerability of losartan in patients with CHF caused by left ventricular systolic dysfunction. Nevertheless, the results of these studies do not allow recommending the widespread use of any AT1-angiotensin receptor blockers for the treatment of cholesterol instead of ACE inhibitors. The fact is that the randomized controlled trial RESOLVD failed to find 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 a higher mortality rate was found in the groups of patients treated with candesartan (6.1%) and the combination of candesartan and enalapril (8.7%), compared with patients treated with enalapril (3.7% ). 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, were not so encouraging. In the ELITE-II study (as opposed to the ELITE-I study), the total number of deaths and hospitalizations due to CHF decompensation in the group of patients treated with losartan was insignificantly less than in the group receiving captopril (by 6%; p = 0, 21)

Thus, there is currently no indisputable evidence of a beneficial effect of AT1-angiotensin receptor blockers on mortality and (or) the need for hospitalization (as 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 painful cough.

Calcium antagonists

Calcium antagonists as potent arterial vasodilators may be useful in reducing post-left ventricular load 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. The hopes that nifedipine would be useful in the treatment of CHF did not come true. The addition of nifedipine to standard CHF therapy increased the likelihood of decompensation. The use of dihydropyridine calcium antagonists with a higher vasoselectivity than nifedipine, amlodipine and felodipine, as well as mibefradil, turned out to be more promising in the treatment of patients with CHF.

The efficacy and safety of amlodipine was evaluated in a multicenter, randomized, placebo-controlled study PRAISE, which involved 1153 patients with CHF III-IV FC and left ventricular ejection fraction less than 30%. Overall mortality was insignificantly lower (on average by 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, on average by 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. There was no significant effect of felodipine on either mortality or the frequency of hospitalizations, although it prevented the deterioration of patients' exercise tolerance and the quality of life of patients.

In a randomized placebo-controlled study MACH-I, mortality in the group of patients with CHF 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 the differences were not reached a statistically significant value. At the same time, a significant increase in mortality was noted 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 CHF III-IV FC, receiving "triple" combination therapy. Neither felodipine nor mibefradil improves the survival rate of patients with CHF.

Other vasodilators

Along with ACE inhibitors, AT1-angiotensin receptor blockers and calcium antagonists, other drugs with a vasodilating effect are being tried to reduce the post-load on the left ventricle in patients with CHF.

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

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

Analysis of the effectiveness of enalapril in various subgroups showed that it significantly improves survival compared with combined therapy in patients with CHF I-II FC, with normal heart sizes (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 insignificant 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 of 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 the impaired contractile function of the left ventricle in patients with CHF. In addition, they can reduce the post-load on the left ventricle, as they have a 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. Agonists of DA-dopaminergic receptors (ibopamine, fenoldopam, etc.); and

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

In the 80s-90s, several dozen randomized placebo-controlled studies were performed, in which the efficacy and safety of long-term therapy with non-glycoside inotropic drugs with different mechanisms of action were studied in patients with CHF III-IV FC. In all studies, mortality in the groups of patients receiving these drugs was higher than in the control groups. Some of the studies were 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 trials of non-haicoside inotropic drugs in humans until there is convincing evidence in experimental studies that these drugs can prolong life. 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 a 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 they reduce the need for hospitalization due to decompensation of CHF and control the ventricular rate in tachysystolic atrial fibrillation.

Other groups of drugs can also be useful in certain situations, but they should only be used in addition to the "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.B., Sidorenko B.A., Iosava I.K., Sololeva Yu.V. Physiology and pharmacology of the renin-angiotensin system. // Cardiology, 1997; 11: 91-95.
12. Sidorenko BA, Preobrazhensky DV Lozartan - 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 JK 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.

1998 marked the 100th anniversary of the discovery of renin by the Swedish physiologist R. Tigerstedt. Almost 50 years later, in 1934, Goldblatt and co-authors, using a model of renin-dependent hypertension, first proved the key role of this hormone in the regulation of blood pressure levels. 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 (teprotid, saralazin, 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 perspectives in the treatment of hypertension, heart failure, 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 established that angiotensin is presented in the circulating blood in two forms: in the form of decapeptide and 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 influence 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 mediated by several other biologically active substances. The most important of these is angiotensin (1-7), which is formed mainly from angiotensin I, and (to a lesser extent) from angiotensin II. Heptapeptide (1-7) has a vasodilating and antiproliferative effect. It has no effect on the secretion of aldosterone, in contrast to angiotensin II.

Under the influence of proteinases, several more active metabolites are formed from angiotensin II - angiotensin III, or angiotensin (2-8) and angiotensin IV, or angiotensin (3-8). Processes that increase blood pressure are associated with angiotensin III - 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 the renin and angiotensin II genes ... The importance 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 nature of the renin-angiotensin system, the systemic link is assigned a 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 reactions occurring within seconds, in accordance with their physiological role of supporting 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 at the tissue level are more important than fast responses at the systemic link of the renin-angiotensin system.

In addition to the ACE-dependent conversion of angiotensin I into angiotensin II, alternative pathways of its formation have been established. It was found that the accumulation of angiotensin II continues, despite the almost complete blockade of ACE with the help of 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 capable of not only converting angiotensin I to angiotensin II, but also cleaving angiotensin II directly from angiotensinogen without the involvement of renin. In organs and tissues, the leading place is occupied by the pathways of angiotensin II formation independent of ACE. 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 mediated through its interaction with specific cellular receptors. Currently, several types and subtypes of angiotensin receptors have been identified: AT1, AT2, AT3 and AT4. In humans, only AT1, - and AT2 receptors are found. The first type of receptor is divided into two subtypes - AT1A and AT1B. Previously, it was believed that AT1A and AT2B subtypes are present only in animals, but now they are identified in humans. The functions of these isoforms are not completely clear. AT1A receptors prevail in vascular smooth muscle cells, heart, lungs, ovaries and hypothalamus. The predominance of AT1A receptors in vascular smooth muscles indicates their role in the processes of vasoconstriction. 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 mainly 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 cardiac conduction system.

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 represented much more widely than in adults and are predominant in them. Soon 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 represented in fetal tissues and their concentration sharply decreases in the first weeks after birth indicates their role in 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. Apparently, they 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 the concentration of aldosterone in the blood, an increase in afterload due to vasoconstriction. The direct effect of angiotensin II on the heart consists in an inotropic effect, as well as in 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 increased 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 in the myocardium.

Vessels

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

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

The vasoconstrictive 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.

Kidney

The renal effects of angiotensin II play an essential role in blood pressure regulation. Activation of AT1 receptors in the kidneys promotes sodium retention and therefore fluid retention in the body. This process is realized by increasing the synthesis of aldosterone and the direct action of angiotensin II on the proximal descending tubule of the nephron.

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

The local formation of angiotensin II has a decisive influence on the regulation of renal function. It directly acts on the renal tubules, increasing the reabsorption of Na +, contributes to the contraction of mesangial cells, which reduces the total surface area of the glomeruli.

Nervous system

The effects due to 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 an increase in sympathetic neurotransmission and inhibition of the reuptake of norepinephrine in 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 receptor level have been undertaken for a long time. In 1972, the peptide angiotensin II antagonist saralazin was synthesized, but it did not find therapeutic use due to its short half-life, partial agonist 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 a non-peptide angiotensin II antagonist losartan, which became the prototype of a new group of antihypertensive drugs. It has been used in the clinic since 1994.

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

The 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. Having a 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 in comparison with 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 undesirable side reactions 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, therefore, 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 through which angiotensin II antagonists reduce vascular resistance are as follows:

suppression of vasoconstriction and hypertrophy of the vascular wall caused by angiotensin II
decrease in Na + reabsorption due to the direct action of angiotensin II on the renal tubules and through a decrease in the release of aldosterone
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 production of nitric oxide by endothelium due to activation of AT2 receptors and bradykinin receptors by increased levels 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 6-8 weeks of treatment. Most drugs have a dose-dependent decrease in blood pressure. They do not disrupt his normal daily rhythm. Available clinical observations indicate that long-term administration of angiotensin receptor blockers (for 2 years or more) does not develop resistance to their action. Cancellation of treatment does not lead to a "rebound" increase in blood pressure. AT1 receptor blockers do not lower blood pressure if it is within the normal range.

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 when using 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 action of drugs due to inhibition of the activity of the tissue link of the renin-angiotensin system at the level of brain structures.

Particularly important is the blockade of the activity of this system directly in the myocardium and the vascular wall, which contributes to the regression of myocardial and vascular wall hypertrophy. 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 enhances the 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 suppresses collagen synthesis by fibroblasts.

The effect of AT1 receptor blockers on the processes of hypertrophy and myocardial 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 the 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 damage to the vessels of the heart.

Effects on the kidneys

The kidney is a target organ in hypertension, the function of which is significantly influenced by AT1 receptor blockers. The 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 rate of glomerular filtration does not change or increases.

AT1 receptor blockers, promoting dilatation of efferent renal arterioles and a decrease in intraglomerular pressure, as well as suppressing the renal effects of angiotensin II (increased sodium reabsorption, impaired mesangial cell function, activation of glomerular sclerosis processes), prevent the progression of renal failure. Due to a selective decrease in the tone of efferent arterioles and, consequently, a decrease in intraglomerular pressure, the 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.

The blockade of AT, -receptors has a moderate natriuretic effect by directly suppressing sodium reabsorption in the proximal tubule, as well as by inhibiting the synthesis and release of aldosterone. A decrease in aldosterone-mediated 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 sodium chloride. Its mechanism is not yet completely clear.

Nervous system

Blockers of AT, -receptors slow down neurotransmission, inhibiting peripheral sympathetic activity by blocking presynaptic adrenergic receptors. With experimental intracerebral administration of drugs, central sympathetic responses are suppressed at the level of the paraventricular nuclei. As a result of the action on the central nervous system, the release of vasopressin decreases, and 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 tolerance comparable to placebo. Side effects when using them are much less common than when using them. Unlike the latter, the use of angiotensin II antagonists is not accompanied by the accumulation of bradykinin and the appearance of a cough caused by this. Angioneurotic edema 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, impairment of renal function is possible. In patients with CRF, there is a risk of developing hyperkalemia due to inhibition of the release of aldosterone during treatment.

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

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

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

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 benzylimidazole, has no agonistic activity towards 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 undergoes metabolism with the formation of 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 lack of agonist activity.

The oral bioavailability of losartan is only 33%. Its excretion is carried out with bile (65%) and urine (35%). Impaired renal function insignificantly 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 more than 50 mg per day does not give an additional antihypertensive effect, while others observed a more significant decrease in blood pressure when the dose was increased to 100 mg / day. A further increase in the dose does not lead to an increase in the effectiveness of the drug.

Great hopes were pinned on 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 reduced the risk of death by 46% 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 contingent (722) patients, a larger study ELITE II (1992) was undertaken, 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. In terms of chemical structure, it belongs to imidazole derivatives. It has a high affinity for AT1 receptors, 10 times higher than losartan in selectivity.

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.

In numerous studies, it has been 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, since they prevent the effects of angiotensin II of any origin.

Several studies have studied 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 being conducted to study the renoprotective effect of irbesartan in patients with diabetic nephropathy and hypertension. One of them, IDNT, studies the comparative efficacy of irbesartan and amlodipine in patients with hypertension and diabetic nephropathy.

Telmisartan

Telmisartan has an inhibitory effect on AT1 receptors, 6 times higher 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. An increase in 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. An increase in the dose of more than 80 mg per day does not give an additional decrease in blood pressure.

Valsartan

A persistent decrease in SBP and DBP occurs after 2-4 weeks of regular use, like other AT1 receptor blockers. An increase in the effect is observed after 8 weeks. Daily monitoring of blood pressure indicates that valsartan does not violate the normal circadian rhythm, and the T / P index is, according to various sources, 60-68%. Effectiveness is independent of gender, age and race. Valsartan is not inferior in antihypertensive efficacy to amlodipine, hydrochlorothiazide and lisinopril, surpassing them in tolerance.

In the VALUE study, which was launched 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 make it possible to decide whether they, like relatively new drugs, have advantages in influencing risk. the development of complications in patients with hypertension compared with diuretics, etc.

Angiotensin receptor blockers (ARA) are a new class of drugs that regulate and normalize blood pressure. They are not inferior in effectiveness to drugs with a similar spectrum of action, but unlike them, they have one indisputable plus - they practically have no side effects.

The most common groups of medicines are:

sartans;
angiotensin receptor antagonists;
angiotensin receptor blockers.

Research on these drugs, at the moment, is still only in the initial stage and will continue for at least another 4 years. There are some contraindications to the use of angiotensin 2 receptor blockers.

The use of drugs is unacceptable during pregnancy and during lactation, with hyperkalemia, as well as in patients with severe renal failure and bilateral renal artery stenosis. Do not use these drugs for children.

Classification of drugs

According to their chemical constituents, angiotensin receptor blockers can be divided into 4 groups:

Telmisartan. Non-biphenyl derivative of tetrazole.
Eprosartan. Non-biphenyl nettetrazole.
Valsartan. Non-cyclic compound.
Losartan, Candesartan, Irbesartan. This group belongs to biphenyl derivatives of tetrazole.

Attempts to achieve blockade of the renin-angiotensin system at the receptor level have been undertaken for a long time. In 1972, the peptide angiotensin II antagonist saralazin was synthesized, but it did not find therapeutic use due to its short half-life, partial agonist 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 a non-peptide angiotensin II antagonist losartan, which became the prototype of a new group of antihypertensive drugs. It has been used in the clinic since 1994.

Indications for the use of AT1 receptor blockers and side effects

The use of angiotensin 2 receptor blockers is recommended for patients with the following pathologies:

Arterial hypertension. Hypertension is the main indication for the use of sartans. Angiotensin receptor antagonists are well tolerated by patients and can be compared to placebo. Virtually do not cause uncontrolled hypotension. Also, these drugs, unlike beta-blockers, do not affect metabolic processes and sexual function, there is no arrhythmogenic effect. In comparison with angiotensin-converting enzyme inhibitors, ARBs practically do not cause cough and angioedema, do not increase the concentration of potassium in the blood. Angiotensin receptor blockers rarely induce drug tolerance in patients. The maximum and lasting effect of taking the drug is observed after two to four weeks.
Kidney damage (nephropathy). This pathology is a complication of hypertension and / or diabetes mellitus. The improvement in prognosis is influenced by a decrease in the excreted protein in the urine, which slows down the development of renal failure. Recent studies have shown that ARA reduces proteinuria (excretion of protein in the urine) by protecting the kidneys, but these results are not yet fully proven.
Heart failure. The development of this pathology is due to the activity of the renin-angiotensin-aldosterone system. At the very beginning of the disease, it improves the activity of the heart, performing a compensatory function. In the course of the development of the disease, remodeling of the myocardium occurs, which ultimately leads to its dysfunction. Treatment with angiotensin receptor blockers in heart failure is due to the fact that they are able to selectively suppress the activity of the renin-angiotensin-aldosterone system.

In addition, among the indications for the use of angiotensin receptor blockers are the following diseases:

myocardial infarction;
diabetic nephropathy;
metabolic syndrome;
atrial fibrillation;

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 tolerance comparable to placebo. Side effects with their use are observed much less frequently than with the use of ACE inhibitors. Unlike the latter, the use of angiotensin II antagonists is not accompanied by the accumulation of bradykinin and the appearance of a cough caused by this. Angioneurotic edema is also much less common.

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

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

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

Losartan

It is the first non-peptide blocker of AT1-receptors, which became the prototype of this class of antihypertensive drugs. It is a derivative of benzylimidazole, has no agonistic activity towards 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 undergoes metabolism with the formation of 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 main biological effects of losartan are due to this metabolite. Like losartan, it is characterized by high selectivity for AT1 receptors and lack of agonist activity.

Great hopes were pinned on the use of losartan in patients with chronic heart failure. It was based on the data of the ELITE study (1997), in which losartan therapy (50 mg / day) for 48 weeks reduced the risk of death by 46% in patients with chronic heart failure compared with captopril administered at 50 mg 3 times a day.

Since this study was conducted in a relatively small contingent (722) patients, a larger study ELITE II (1992) was undertaken, including 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

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, an increase in the dose to achieve the target level of DBP ((amp) lt; 90 mm Hg) was required in 53% of patients receiving irbesartan and in 61% of patients receiving losartan. The additional appointment of hydrochlorothiazide more significantly increased the antihypertensive effect of irbesartan than losartan.

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.

Several studies have studied 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.

Telmisartan has an inhibitory effect on AT1 receptors, 6 times higher 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.

Valsartan

A persistent decrease in SBP and DBP occurs after 2-4 weeks of regular use, like other AT1 receptor blockers. An increase in the effect is observed after 8 weeks. Daily monitoring of blood pressure indicates that valsartan does not violate the normal circadian rhythm, and the T / P index is, according to various sources, 60-68%.

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 make it possible to decide whether they have advantages in influencing risk, as in relatively new drugs. the development of complications in patients with hypertension compared with diuretics and beta-blockers.

Additional effects

Sartans have the following additional clinical effects:

arrhythmic effect;
protection of cells of the nervous system;
metabolic effects.

Side effects of taking blockers

Angiotensin 2 receptor blockers are well tolerated by the patient's body. In principle, these drugs do not have specific side effects, unlike other groups of drugs with a similar effect, but they can cause allergic reactions, like any other drug.

Among the few side effects, the following can be noted:

dizziness;
headache;
insomnia;
abdominal pain;
nausea;
vomit;
constipation.

In rare cases, the patient may observe such disorders:

painful sensations in the muscles;
joint pain;
increased body temperature;
manifestation of ARVI symptoms (runny nose, cough, sore throat).

Sometimes there are side effects from the genitourinary and cardiovascular systems.

Application features

As a rule, drugs that block angiotensin receptors are produced in the form of tablets, which can be drunk regardless of food intake. The maximum stable concentration of the drug is achieved after two weeks of regular administration. The period of elimination from the body is at least 9 hours.

Angiotensin 2 blockers may differ in their spectrum of action.

The course of treatment for hypertension is 3 weeks or more, depending on individual characteristics.

In addition, this drug lowers the concentration of uric acid in the blood and flushes sodium water out of the body. The dosage is adjusted by the attending physician based on the following indicators:

Combination treatment, which includes the use of this drug with diuretics, involves the use of no more than 25 mg. per day.
If side effects occur, such as headache, dizziness, lowering blood pressure, the dosage of the drug must be reduced.
In patients with hepatic and renal insufficiency, the drug is prescribed with caution and in small doses.

The drug acts only on AT-1 receptors, blocking them. The effect of a single dose is achieved after 2 hours. It is prescribed only by the attending physician, since there is a risk that the drug can harm.

Caution should be exercised when using the drug in patients who have the following pathologies:

Obstruction of the biliary tract. The drug is excreted from the body with bile, therefore, the use of valsartan is not recommended for patients who have disturbances in the work of this organ.
Renovascular hypertension. In patients with this diagnosis, monitoring of serum urea and creatinine levels is necessary.
Imbalance of water-salt metabolism. In this case, correction of this violation is mandatory.

Important! When using Valsartan, the patient may experience symptoms such as cough, swelling, diarrhea, insomnia, decreased sexual function. While taking the drug, there is a risk of developing various viral infections.

The drug should be taken with caution during work that requires maximum concentration of attention.

The effect of taking this drug is achieved after 3 hours. After completing the course of taking Ibersartan, blood pressure systematically returns to its original value.

Ibersartan does not prevent the development of atherosclerosis, unlike most angiotensin receptor antagonists, since it does not affect lipid metabolism.

Important! The drug assumes a daily intake at the same time. If you miss an appointment, doubling the dose is strongly discouraged.

Adverse reactions when taking Ibersartan:

headache;
nausea;
dizziness;
weakness.

In the treatment of hypertension, it has a mild and persistent effect throughout the day. When you stop taking, no sudden pressure surges are observed. Eprosartan is prescribed even for diabetes mellitus, as it does not affect blood sugar levels. The drug can also be taken by patients with renal impairment.

Eprosartan has the following side effects:

cough;
runny nose;
dizziness;
headache;
diarrhea;
chest pain;
dyspnea.

Adverse reactions are usually short-lived and do not require dose adjustment or complete discontinuation of the drug.

The drug is not prescribed for pregnant women, during breastfeeding and children. Do not prescribe Eprosartan to patients with renal artery stenosis, as well as with primary hyperaldosteronism.

The most powerful drug among the sartans. Displaces angiotensin 2 from the connection with AT-1 receptors. It can be prescribed to patients with impaired renal function, while the dosage does not change. However, in some cases, it can cause hypotension even in small doses.

Telmisartan is contraindicated in patients with the following disorders:

primary aldosteronism;
severe violations of liver and kidney function.

Do not prescribe the drug during pregnancy and lactation, as well as children and adolescents.

Among the side effects of Telmisartan use are:

dyspepsia;
diarrhea;
angioedema;
back pain;
muscle pain;
the development of infectious diseases.

Telmisartan belongs to a group of drugs that act by accumulation. The maximum effect of the application can be achieved after a month of regular intake of the drug. Therefore, it is important not to adjust the dosage yourself in the first weeks of admission.

Despite the fact that drugs that block angiotensin receptors have a minimum of contraindications and side effects, they should be taken with caution due to the fact that these drugs are still under study. The correct dose for the treatment of high blood pressure in a patient can be prescribed exclusively by the attending physician, since self-medication can lead to undesirable consequences.

Treatment of hypertension with angiotensin II receptor blockers

Originally, sartans were developed as medicines for hypertension. Numerous studies have shown that they lower blood pressure in about the same power as other major classes of hypertension pills. Angiotensin II receptor blockers, when taken once a day, evenly lower blood pressure for 24 hours.

Read about the treatment of diseases associated with hypertension:

Cardiac ischemia
Myocardial infarction
Heart failure
Diabetes

The effectiveness of blood pressure lowering with drugs from this group depends on the initial activity of the renin-angiotensin system. They act most strongly on patients with high renin activity in the blood plasma. You can check it by taking a blood test. All angiotensin II receptor blockers have a long-term blood pressure lowering effect that lasts for 24 hours.

Available clinical observations indicate that with prolonged use of angiotensin receptor blockers (for two years or more), there is no addiction to their action. Cancellation of treatment does not lead to a "rebound" increase in blood pressure. Angiotensin II receptor blockers do not lower blood pressure levels if they are within the normal range.

Angiotensin receptor antagonists not only lower blood pressure, but also improve renal function in diabetic nephropathy, cause regression of left ventricular hypertrophy, and improve indicators in heart failure. In recent years, there has been a debate in the literature regarding the ability of these tablets to increase the risk of fatal myocardial infarction.

If patients are prescribed only one drug from the sartan group, then the effectiveness will be 56-70%, and if combined with other drugs, most often with diuretics dichlothiazide (hydrochlothiazide, hypothiazide) or indapamide, then the effectiveness increases to 80-85%. We point out that thiazide diuretics not only enhance, but also lengthen the effect of angiotensin II receptor blockers to lower blood pressure.

Angiotensin receptor antagonists registered and used in Russia (April 2010)

A drug	Tradename	Manufacturer	Dosage of tablets, mg
Losartan	Kozaar	Merck	50, 100
Losartan hypothiazide	Gizaar		50 12,5
Losartan hypothiazide	Gizaar forte		100 12,5
Losartan	Lorista	KRKA	12,5, 25, 50, 100
Losartan hypothiazide	Lorista N		50 12,5
Losartan hypothiazide	Lorista ND		100 12,5
Losartan	Lozap	Zentiva	12,5, 50
Losartan hypothiazide	Lozap plus	Zentiva	50 12,5
Losartan	Presartan	IPKA	25, 50
Losartan	Vasotenz	Actavis	50, 100
Valsartan	Diovan	Novartis	40, 80, 160, 320
Valsartan hypothiazide	Co-Diovan		80 12,5, 160 12,5,
Amlodipine valsartan	Exforge		5(10) 80(160)
Amlodipine valsartan hydrochlorothiazide	Co-Exforge		5 160 12,5, 10 160 12,5
Valsartan	Valsacor	KRKA	40, 80, 160
Candesartan	Atacand	AstraZeneca	8, 16, 32
Candesartan hypothiazide	Atacand plus	AstraZeneca	16 12,5
Eprosartan	Teveten	Solvay Pharmaceuticals	400, 600
Eprosartan hypothiazide	Teveten plus	Solvay Pharmaceuticals	600 12,5
Irbersartan	Aprovel	Sanofi	150, 300
Irbesartan hypothiazide	Coaprovel	Sanofi	150 12,5, 300 12,5
Mikardis	Boehringer ingelheim	40, 80
Telmisarnat hypothiazide	Boehringer ingelheim	Mikardis plus	40 12,5, 80 12,5

Sartans differ in their chemical structure and their effect on the patient's body. Depending on the presence of an active metabolite, they are divided into prodrugs (losartan, candesartan) and active substances (valsartan, irbesartan, telmisartan, eprosartan).

	Influence of food	Excretion from the body by the kidneys / liver,%	Dosage, mg per tablet	Starting dose, mg	Maintenance dose, mg
Valsartan	40-50%	30/70	80-160	80	80-160
Irbesartan	No	25/75	75, 150, 300	75-150	150-300
Candesartan	No	60/40	4, 8, 16, 32	16	8-16
Losartan	minimally	35/65	25, 50, 100	25-50	50-100
	No	1/99	40, 80	40	40-80
Eprosartan	No	30/70	200, 300, 400	60	600-800

heart failure;
postponed myocardial infarction;
diabetic nephropathy;
proteinuria / microalbuminuria;
hypertrophy of the left ventricle of the heart;
atrial fibrillation;
metabolic syndrome;
intolerance to ACE inhibitors.

The difference between sartans and ACE inhibitors lies in the fact that when they are used in the blood, the level of proteins associated with inflammatory reactions does not increase. This avoids unwanted side reactions such as cough and angioedema.

In the 2000s, serious studies were completed, which confirmed that angiotensin receptor antagonists have a powerful effect on protecting internal organs from damage due to hypertension. Accordingly, patients have an improved cardiovascular prognosis. In patients who have a high risk of heart attack and stroke, the likelihood of a cardiovascular accident is reduced.

From 2001 to 2008, the indications for the use of angiotensin II receptor blockers in the European clinical guidelines for the treatment of hypertension were constantly expanding. Dry cough and intolerance to ACE inhibitors have long been not the only indication for their appointment. The LIFE, SCOPE, and VALUE studies support the use of sartans for cardiovascular disease, while the IDNT and RENAAL studies support renal problems.

Combination of sartans with diuretics

Angiotensin II receptor blockers are often prescribed with diuretics, especially dichlothiazide (hydrochlorothiazide). It is officially recognized that this combination is good at lowering pressure, and it is advisable to use it. Sartans in combination with diuretics act evenly and for a long time. The target blood pressure level can be achieved in 80-90% of patients.

Examples of tablets containing fixed combinations of sartans with diuretics:

Atacand plus - candesartan 16 mg; hydrochlorothiazide 12.5 mg;
Co-diovan - valsartan 80 mg; hydrochlorothiazide 12.5 mg;
Lorista N / ND - losartan 50/100 mg hydrochlorothiazide 12.5 mg;
Mikardis plus - telmisartan 80 mg hydrochlorothiazide 12.5 mg;
Teveten plus - eprosartan 600 mg hydrochlorothiazide 12.5 mg.

Practice shows that all these drugs effectively lower blood pressure, and also protect the internal organs of patients, reducing the likelihood of heart attack, stroke and kidney failure. Moreover, side effects develop very rarely. However, it should be borne in mind that the effect of taking the pills increases slowly, gradually.

In 2000, the results of the CARLOS study (Candesartan / HCTZ versus Losartan / HCTZ) were published. It involved 160 patients with grade 2-3 hypertension. 81 of them took candesartant dichlothiazide, 79 - losartan dichlothiazide. As a result, the combination with candesartan was found to lower blood pressure more and last longer.

How angiotensin II receptor blockers act on the heart muscle

A decrease in blood pressure with the use of angiotensin II receptor blockers is not accompanied by an increase in heart rate. Of particular importance is the blockade of the activity of the renin-angiotensin-aldosterone system directly in the myocardium and the vascular wall, which contributes to the regression of hypertrophy of the heart and blood vessels.

The effect of angiotensin II receptor blockers on the processes of hypertrophy and myocardial remodeling is of therapeutic importance in the treatment of ischemic and hypertensive cardiomyopathy, as well as cardiosclerosis in patients with coronary heart disease. Angiotensin II receptor blockers also neutralize the participation of angiotensin II in the processes of atherogenesis, reducing atherosclerotic damage to the vessels of the heart.

Indications for the use of angiotensin II receptor blockers (2009)

Index	Losartan	Valsartan	Candesartan	Irbesartan	Olmesartan	Eprosartan
Arterial hypertension
Patients with hypertension and hypertrophy of the left ventricular myocardium
Nephropathy (kidney damage) in patients with type 2 diabetes
Chronic heart failure
Patients who have had myocardial infarction

How these pills work on the kidneys

The kidney is a target organ in hypertension, the function of which is significantly influenced by angiotensin II receptor blockers. They usually decrease urinary protein excretion (proteinuria) in people with hypertensive and diabetic nephropathy (kidney damage). However, it must be remembered that in patients with unilateral renal artery stenosis, these drugs can cause an increase in plasma creatinine levels and acute renal failure.

Angiotensin II receptor blockers have a moderate natriuretic effect (forcing the body to get rid of salt in the urine) by suppressing the reabsorption of sodium in the proximal tubule, as well as by inhibiting the synthesis and release of aldosterone. A decrease in aldosterone-mediated reabsorption of sodium into the bloodstream in the distal tubule contributes to some diuretic effect.

Medicines for hypertension from another group - ACE inhibitors - have a proven property of protecting the kidneys and inhibiting the development of renal failure in patients. However, with the accumulation of experience in application, the problems associated with their purpose became obvious. In 5-25% of patients, a dry cough develops, which can be so painful as to require discontinuation of the medication. Occasionally angioedema occurs.

Also, nephrologists attach particular importance to specific renal complications, which sometimes develop while taking ACE inhibitors. This is a sharp drop in the glomerular filtration rate, which is accompanied by an increase in the level of creatinine and potassium in the blood. The risk of such complications is increased for patients who have been diagnosed with atherosclerosis of the renal arteries, congestive heart failure, hypotension, and decreased blood volume (hypovolemia).

Why choose angiotensin II receptor blockers

As you know, for the treatment of hypertension, there are 5 main classes of drugs that reduce blood pressure in approximately the same way. Read more in the article "Medicines for hypertension: what they are". Since the power of drugs differs slightly, the doctor chooses a drug depending on how it affects the metabolism, how well it reduces the risk of heart attack, stroke, renal failure and other complications of hypertension.

Angiotensin II receptor blockers have a uniquely low incidence of side effects comparable to placebo. Their "relatives" - ACE inhibitors - are characterized by such undesirable effects as dry cough, and even angioedema. When sartans are prescribed, the risk of these problems is minimal. We also mention that the ability to reduce the concentration of uric acid in the blood favorably distinguishes losartan from other sartans.

Subgroup preparations 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 possess pressor activity, is hydrolyzed, forming angiotensin I, a biologically inactive decapeptide that is easily subject to further transformations. Under the action of angiotensin-converting enzyme (ACE), 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, and 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 sodium and water reabsorption, 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 presumably involved in the regulation of hemostasis.

It is known that in addition to the RAAS of systemic blood flow, the activation of which leads to short-term effects (including such as vasoconstriction, increased blood pressure, secretion of aldosterone), there are local (tissue) RAAS in various organs and tissues, incl. in the heart, kidneys, brain, blood vessels. The increased activity of tissue RAAS determines the 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 lesions of the cerebral vessels, kidney damage, etc.

It has now been shown that in humans, in addition to the ACE-dependent pathway for 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 different organs and tissues, either ACE-dependent or alternative pathways of angiotensin II formation prevail. Thus, cardiac serine protease, its DNA and mRNA were found in the tissue of the human myocardium. Moreover, the largest amount of this enzyme is contained in the myocardium of the left ventricle, where the chymase pathway accounts for more than 80%. Chemase-dependent formation of angiotensin II prevails in the myocardial interstitium, adventitia and vascular media, while ACE-dependent - 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 have been identified and most fully studied - the AT 1 and AT 2 subtypes.

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

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

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

Enhanced 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, the stimulation of these receptors is accompanied by the damaging effect of angiotensin II on the cardiovascular system, including the development of myocardial hypertrophy, thickening of the arterial walls, etc.

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

A large number of AT 2 receptors are found in fetal tissues (including 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 was disrupted, suggest their participation in the processes of growth and maturation, including cell proliferation and differentiation, the 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, atresized 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 vessels), myocardial infarction, and heart failure. It is assumed 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 the effects caused by the excitation of AT 1 receptors and are relatively weak. 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 type II angiotensin II receptors (AT 2) in humans and their relationship with cardiovascular homeostasis are currently not fully understood.

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

Other angiotensin receptors and their role in humans and animals are poorly understood.

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

AT 3 receptors with an affinity for angiotensin II are found on the membranes of neurons, their function is unknown. AT 4 receptors are found on endothelial cells. By interacting with these receptors, angiotensin IV stimulates the release of 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 possesses tropism for AT 4 -receptors.

Long-term studies of the RAAS not only revealed the importance of this system in the regulation of homeostasis, in the development of cardiovascular pathology, the effect on 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 links of the RAAS.

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

The first blocker of angiotensin II receptors, introduced into therapeutic practice in 1971, was saralazin, a peptide compound similar in structure to angiotensin II. Saralazin blocked the pressor effect of angiotensin II and lowered the tone of peripheral vessels, decreased the content of aldosterone in the plasma, and lowered blood pressure. However, by the mid-70s, the experience of using saralazine showed that it has the properties of a partial agonist and in some cases gives a poorly predictable 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 use.

In the early 90s, the first non-peptide selective antagonist of AT 1 -receptors, effective when taken orally, losartan, was synthesized, which has received practical application as an antihypertensive agent.

Currently, in the world medical practice, several synthetic non-peptide selective AT 1 -blockers are used or are undergoing clinical trials - valsartan, irbesartan, candesartan, losartan, telmisartan, eprosartan, olmesartan medoxomil, azilsartan medoxomil, zolarsartan Russia).

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

According to their chemical structure, non-peptide AT 1 receptor blockers can be divided into 3 main groups:

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

Biphenyl non-tetrazole compounds - telmisartan;

Non-phenyl non-tetrazole 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. 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).

By 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 reversibly bind 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 the binding sites), while valsartan, irbesartan , candesartan, telmisartan, and the active metabolite of losartan EXP-3174 act as noncompetitive antagonists and bind irreversibly to receptors.

The pharmacological action of the agents of this group 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 AT 1 receptor antagonists. It has been shown that their affinity for AT 1 exceeds that for AT 2 receptors by a factor of 1000: for losartan and eprosartan by more than 1 thousand times, telmisartan - more than 3 thousand, irbesartan - 8.5 thousand, the active metabolite of losartan EXP-3174 and candesartan - 10 thousand times, olmesartan - 12.5 thousand times, valsartan - 20 thousand times.

The 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 on vascular smooth muscle cells, mesangial cells, fibroblasts, a decrease in cardiomyocyte hypertrophy, etc.

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

In 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, the formation of angiotensin- (1-7) occurs. 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 vasodilating and natriuretic effects. The effects of angiotensin- (1-7) are mediated through the 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 associated with endothelial modulation and effects on nitric oxide (NO) production. The experimental data obtained 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 blockade of AT 1 receptors, the adverse effect of angiotensin II (and angiotensin III, which has an affinity for angiotensin II receptors) on the cardiovascular system is inhibited and, presumably, its protective effect is manifested (by stimulating AT 2 receptors), and the action also develops angiotensin- (1-7) by stimulation of 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 the presynaptic AT 1 receptors of sympathetic neurons in the central nervous system, they inhibit the release of norepinephrine and reduce the stimulation of vascular smooth muscle adrenergic receptors, which leads to vasodilation. Experimental studies show that this additional mechanism of vasodilatory action is more characteristic of eprosartan. The 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 several 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 features of the pharmacokinetics of the drugs of this group make their use by patients convenient. 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 (with mild arterial hypertension) or in combination with other antihypertensive drugs (with moderate and severe forms).

Currently, according to the recommendations of the WHO / IOG (International Society for Hypertension), the 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) (telicardis + hydrochlorothiazide), Micardis Plus ...

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

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

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

The data obtained in experiments on animals indicate that agents that have a direct effect on the RAAS can cause damage to the fetus, the death of the fetus and the newborn. Especially dangerous is the effect on the fetus in the II and III trimesters of pregnancy, because development of hypotension, hypoplasia of the skull, anuria, renal failure and death in the fetus is possible. There are no direct indications of the development of such defects when taking AT 1 receptor blockers, however, the drugs of this group should not be used during pregnancy, and if pregnancy is detected during the treatment period, they should be discontinued.

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

You should refrain from using these drugs in pediatric practice, since the safety and efficacy of their use in children have not been determined.

There are a number of limitations for therapy with AT 1 antagonists of angiotensin receptors. Caution should be exercised in patients with reduced BCC and / or hyponatremia (during treatment with diuretics, restriction of salt intake with diet, diarrhea, vomiting), as well as in patients on hemodialysis, because development of symptomatic hypotension is possible. 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 solitary kidney. excessive inhibition of the RAAS in these cases increases the risk of severe hypotension and renal failure. It should be used with caution in aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy. In the presence of impaired renal function, monitoring of serum potassium and creatinine levels is necessary. Not recommended for patients with primary hyperaldosteronism, because in this case, drugs that inhibit the RAAS are ineffective. There are no sufficient data on the use in patients with severe liver disease (for example, with cirrhosis).

Hitherto reported side effects of angiotensin II receptor antagonists are usually mild, transient, and rarely warrant discontinuation of therapy. The overall incidence 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 directly affect the metabolism of bradykinin, substance P, other peptides and, as a result, do not cause dry cough, which often occurs during treatment with ACE inhibitors.

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

The results of multicenter placebo-controlled studies show high efficacy and good tolerance of AT 1 -receptor antagonists of angiotensin II. However, so far their use is limited by the lack of data on the long-term effects of their use. According to WHO / MTF experts, their use for the treatment of arterial hypertension is advisable in case of intolerance to ACE inhibitors, in particular, in case of indication 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 effect on mortality, duration and quality of life of patients and compared with antihypertensive and other drugs in the treatment of arterial hypertension, chronic heart failure, atherosclerosis, etc.

Drugs

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

Active substance	Trade names
Information is absent