BARs are insufficiently studied but effective antihypertensive drugs. Angiotensin II receptor antagonists

Angiotensin II receptor antagonists: new prospects for clinical use

I. G. Bereznyakov
Kharkov Medical Academy of Postgraduate Education

Angiotensin II receptor antagonists (ARA II) were introduced into clinical practice in the early 90s of the last century. Already in 1997 in the USA they were included in the list of main antihypertensive drugs. After 2 years, the World Health Organization (WHO) and the International Society for the Study of Hypertension (ISH) joined the opinion of American experts. The list of indications for the use of ARA II continues to expand. In 2001, the FDA (US Food and Drug Administration) approved the use of losartan to slow the onset of end-stage chronic renal failure, and valsartan in patients with chronic heart failure (in case of intolerance to angiotensin-converting enzyme inhibitors). 4 drugs of this group are registered in Ukraine, and this, apparently, is not the limit. Thus, there is every reason to take a closer look at them.

Renin-angiotensin system (RAS)

The RAS takes an active part in the regulation of blood pressure (BP). The key element of this system is angiotensin II (A II), which is formed from inactive angiotensin I or even angiotensinogen under the action of various enzymes (scheme). The main effects of A II are aimed at increasing blood pressure. It has a direct vasoconstrictor effect, stimulates the activity of the sympathetic-adrenal system, increases the sensitivity of vascular smooth muscle cells to circulating catecholamines, stimulates the production of aldosterone (the most powerful mineralocorticoid), and promotes the retention of sodium ions in the body. The discovery of angiotensin-converting enzyme (ACE), under the influence of which A II is formed in the blood plasma from inactive angiotensin I, made it possible to identify a new target for pharmacological action. This is how ACE inhibitors appeared, which marked significant progress in the treatment of not only arterial hypertension, but also chronic heart failure, diabetic and non-diabetic nephropathy and many other diseases. The use of ACE inhibitors, however, did not allow achieving a complete blockade of A II formation in the body. It soon became clear that it is formed not only in the blood under the influence of ACE, but also in tissues, under the influence of other enzymes. In the course of studying the effects of A II, it was possible to establish that in organs and tissues it binds to specific receptors, and all the main pressor (increasing blood pressure) effects are realized through binding to type 1 receptors (AT1).

Currently, 3 more types of receptors have been described, but their functions remain to be studied. In particular, stimulation of type 2 receptors (AT2) causes a number of effects that are opposite to those that develop when stimulating type 1 receptors. Thus, the creation of drugs that block AT1 receptors represents an attractive alternative to ACE inhibitors, since it makes it possible to suppress the adverse effects of A II, regardless of whether it is formed in the blood or in tissues. Additional possibilities open up with simultaneous stimulation of AT2 receptors. In addition, ACE inhibitors prolong the circulation of bradykinin in the blood, which is associated with some side effects when using these drugs, in particular dry cough. Specific blockade of AT1 receptors does not affect the metabolism of bradykinin in the body, which makes it possible to predict better tolerability of such drugs. The foregoing served as a theoretical basis for the development and implementation of specific ARA II into clinical practice.

ARA II: comparative characteristics

Based on their chemical structure, the following ARA II are distinguished:

• biphenyltetrazoles (losartan, irbesartan, candesartan);
• non-biphenyl tetrazoles (telmisartan, eprosartan);
• non-hetorocyclic compounds (valsartan).

Losartan (cozaar) and candesartan are prodrugs (that is, they are converted to active compounds directly in the human body). During the metabolism of both drugs, substances with pharmacological activity are formed. Unlike losartan and candesartan, valsartan (Diovan) initially has pharmacological activity and does not have active metabolites. In addition, valsartan is a non-competitive (insurmountable) A II antagonist and has the highest affinity for AT1 receptors. This means that high concentrations of A II are not able to displace valsartan from binding sites with AT1 receptors, and stimulation of unblocked AT2 receptors by circulating A II can cause additional positive effects.

Use of ARA II for arterial hypertension

Epidemiological studies indicate that arterial hypertension (AH) is registered in 15–30% of the adult population of the planet. There are some geographic differences in the prevalence of this disease. Thus, in some African countries, elevated blood pressure levels are detected in 6% of the adult population, while in Scandinavian countries this figure is 5–6 times higher. In 2000, 7,645,306 patients with hypertension were registered in Ukraine, which is about 18.8% of the adult population. At the same time, the prevalence of hypertension in Ukraine increased by 40% compared to 1997 and by 18% compared to 1999.

In the recommendations of the WHO Expert Committee and the International Institute of Hygiene (1999) on the diagnosis and treatment of hypertension, 6 classes of antihypertensive drugs were listed as first-line drugs: diuretics, β-blockers, calcium antagonists, ACE inhibitors, α-blockers and ARB II. It was assumed that they all have an equal ability to reduce blood pressure and prevent the occurrence of cardiovascular complications of hypertension. Clinical studies completed at that time showed that neither calcium antagonists nor ACE inhibitors are inferior to diuretics and β-blockers (but are not superior to them) in their ability to reduce the risk of death from cardiovascular causes and the occurrence of severe cardiovascular diseases in patients with hypertension. vascular diseases (such as myocardial infarction and stroke). Diuretics and β-blockers were chosen as comparators because their benefits in hypertension have been convincingly demonstrated in large, well-designed clinical trials.

In 2000, the first doubts arose about the “equality” of all six classes of main antihypertensive drugs. The large-scale ALLHAT study (its name translates as a study of antihypertensive and lipid-lowering treatment to prevent heart attacks) included 42 thousand patients with hypertension at high risk of cardiovascular diseases. The primary objective of this study was to determine whether calcium antagonists (amlodipine), ACE inhibitors (lisinopril), and α1-blockers (doxazosin) reduce cardiovascular morbidity and mortality compared with a diuretic (chlorthalidone). In 2000, the study was stopped early in the group of patients receiving doxazosin. At that time, 9067 patients were under observation in this group. When comparing the results of treatment, hypertension in patients receiving doxazosin and in patients receiving chlorthalidone (15,268 people), equal antihypertensive effectiveness of both drugs was established. In particular, systolic blood pressure decreased to 137 and 134 mmHg, respectively. Art. (the differences are not statistically significant). However, in the group of patients receiving doxazosin, cardiovascular morbidity and mortality were 25% higher (p< 0,0001), а риск возникновения инсульта - на 19% выше (p = 0,04), чем у больных, получавших хлорталидон. Был сделан вывод, что α1-адреноблокаторы, в частности доксазозин, уступают диуретикам по способности предупреждать сердечно-сосудистые осложнения АГ и, следовательно, не должны рассматриваться в качестве средств 1-го ряда в лечении этого заболевания.

In March of this year, the results of the LIFE (Losartan Intervention For Endpoint reduction in hypertension study) study were published, which, apparently, will cause a serious revision of modern ideas about the role of various classes of antihypertensive drugs in the treatment of hypertension. This study was the first to show that ARB II (losartan) is superior to β-blockers (atenolol) in its ability to prevent cardiovascular morbidity and mortality in patients with hypertension. To date, there is no evidence of this kind for any class of antihypertensive drugs.

The LIFE study included 9193 hypertensive patients aged 55–80 years with sitting BP 160–200/95–115 mmHg. Art. A mandatory condition for inclusion was the presence of signs of left ventricular hypertrophy on the ECG, i.e. all patients were at increased risk of adverse outcomes. Losartan was prescribed at a dose of 50–100 mg/day. and, if necessary, combined with hydrochlorothiazide at 12.5–25 mg/day. The comparison drug, atenolol, was also used at 50–100 mg/day. If necessary, hydrochlorothiazide was added to it at a dose of 12.5–25 mg/day. All drugs were prescribed once a day. The follow-up duration was on average 4.8 ± 0.9 years.

The aim of the study was to compare cardiovascular morbidity and mortality (death from cardiovascular causes + myocardial infarction + stroke) in groups of patients receiving losartan and atenolol.

In the group of patients receiving losartan, a significant reduction in cardiovascular morbidity and mortality was found compared with the group of patients receiving atenolol. This reduction was achieved mainly due to a decrease in the number of strokes. In addition, the incidence of newly diagnosed diabetes mellitus in the losartan group was 25% lower, and the tolerability of losartan was significantly better than atenolol.

If the results obtained are confirmed in other comparative studies of ARA II with antihypertensive drugs of other classes, the strategy and tactics of treating hypertension will be radically revised. One such study in particular is VALUE, which compared valsartan with amlodipine in 15,320 high-risk hypertensive patients. Completion of this study is expected in 2004.

Another advantage of APA II is its beneficial effect on sexual function. To date, it has been convincingly proven that the prevalence of sexual problems in men with untreated hypertension is significantly higher than in men with normal blood pressure values. Moreover, the risk of sexual dysfunction increases during treatment with diuretics, central sympatholytics (methyldopa, clonidine) and beta-blockers (especially non-selective ones). Comparative studies of valsartan and losartan with β-blockers showed that ARA II do not cause deterioration in sexual function, unlike comparison drugs, and the differences reach statistical significance. Moreover, valsartan is no different from placebo in its ability to influence sexual function.

Use of ARA II in diabetes mellitus

Diabetes mellitus can rightfully be considered a cardiovascular disease. The presence of type II diabetes mellitus increases the risk of coronary artery disease by 2–3 times in men and 4–5 times in women. Diabetes mellitus increases the risk of adverse outcomes (death, myocardial infarction, readmission within 1 year) in acute coronary syndrome by almost 5 times. The risk of death in diabetic patients who have not had a myocardial infarction is no different from that in patients who have had a myocardial infarction but do not have diabetes. The share of macrovascular complications (primarily myocardial infarction and stroke) in the structure of mortality in patients with type II diabetes mellitus reaches 65%.

One of the severe and steadily progressing complications of diabetes mellitus is diabetic nephropathy. Studies conducted in past years have convincingly demonstrated the ability of ACE inhibitors to slow down the onset of end-stage chronic renal failure in patients with diabetic nephropathy. In 2001, the results of the RENAAL study were published, which included 1513 patients with type II diabetes mellitus aged 31–70 years who had albuminuria (urinary loss of more than 300 mg/day of protein) and impaired renal function. 751 people received losartan 50–100 mg/day, 762 patients received placebo. The average follow-up duration was 3.5 years. During this time, the incidence of end-stage chronic renal failure in the active treatment group was 28% lower. Apparently, the ability to slow down the onset of end-stage chronic renal failure is a property inherent in all ARA II, since results close to those achieved in RENAAL were also obtained in the studies MARVAL (with valsartan), IDNT (with irbesartan) and others.

Use of ARA II in chronic heart failure

Chronic heart failure (CHF) is a very serious clinical problem, primarily due to its extremely poor prognosis. Thus, mortality within 5 years in the presence of CHF is 26–75%, and 34% of patients with CHF die due to a stroke or myocardial infarction.

Studies of ARA II in CHF performed before last year were relatively unsuccessful. In particular, the ELITE II study, designed to prove the superiority of losartan over the ACE inhibitor captopril, failed to confirm this hypothesis. The RESOLVD study, which compared candesartan with enalapril, was also stopped early due to higher mortality in the groups of patients receiving candesartan and especially the combination of this drug with enalapril.

In this regard, the Val-HeFT study deserves special attention, which included 5010 patients with CHF functional class II–IV according to the New York Heart Association classification. All patients received modern and effective therapy for CHF (ACE inhibitors - more than 90% of patients, β-blockers - about a third). The addition of valsartan to this therapy compared with placebo led to a decrease in the number of hospitalizations due to worsening CHF, an improvement in the quality of life and objective symptoms (shortness of breath, wheezing in the lungs, etc.). A particularly significant effect was achieved in those patients who received either an ACE inhibitor, a β-blocker, or did not take any of these drugs. At the same time, the addition of valsartan to patients taking both an ACE inhibitor and a β-blocker led to a worsening of the disease. The results obtained allowed the FDA to approve the use of valsartan in patients with CHF who are not receiving ACE inhibitors (for example, due to side effects - cough, angioedema, etc.).

Conclusion

The evidence accumulated to date suggests that angiotensin II receptor antagonists are not only a safe alternative to ACE inhibitors in the treatment of arterial hypertension. ARA II can be successfully used instead of ACE inhibitors (or together with them) in the treatment of chronic heart failure (valsartan), to slow down the onset of end-stage chronic renal failure (losartan), and in hypertension they are perhaps the most effective class of antihypertensive drugs for reducing cardiovascular morbidity and mortality.

Literature

1. Sirenko Yu. M. Arterial hypertension 2002.- Kiev: Morion, 2002
2. Dahlхf B. et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002; 359:995-1003.
3. Fogari R., Zoppi A., Poletti L., Marasi G., Mugellini A., Corradi L. Sexual activity in hypertensive men treated with valsartan or carvedilol: a crossover study. Am. J. Hypertens. 2001; 14(1):27–31
4. American Diabetes Association. Diabetes 1996 Vital Statistics. Chicago: Am. Diab. Ass., 1996, 29.
5. Cohn J.N., Tognoni G. A randomized trial of angiotensin-receptor blocker valsartan in chronic heart failure. N.Engl. J. Med. 2001; 345(23):1667–75.

Currently, two types of receptors for angiotensin II, which perform different functions, are the most well studied - angiotensin receptors-1 and -2.

Angiotensin receptors-1 are localized in the vascular wall, adrenal glands, and liver.

Angiotensin receptor-1 mediated effects :
• Vasoconstriction.
• Stimulation of aldosterone synthesis and secretion.
• Tubular reabsorption of sodium.
• Decreased renal blood flow.
• Proliferation of smooth muscle cells.
• Hypertrophy of the heart muscle.
• Increased release of norepinephrine.
• Stimulation of vasopressin release.
• Inhibition of renin formation.

Angiotensin receptors-2 are present in the central nervous system, vascular endothelium, adrenal glands, reproductive organs (ovaries, uterus). The number of angiotensin receptors-2 in tissues is not constant: their number increases sharply with tissue damage and activation of reparative processes.

Angiotensin receptor-2 mediated effects :
• Vasodilation.
• Natriuretic action.
• Release of NO and prostacyclin.
• Antiproliferative effect.
• Stimulation of apoptosis.

Angiotensin II receptor antagonists are characterized by a high degree of selectivity for angiotensin receptors-1 (the ratio of selectivity indicators for angiotensin receptors-1 and -2 is 10,000-30,000: 1). Drugs in this group block angiotensin-1 receptors.

As a result, with the use of angiotensin II receptor antagonists, angiotensin II levels increase and stimulation of angiotensin-2 receptors is observed.

By chemical structure Angiotensin II receptor antagonists can be divided into 4 groups:

• Biphenyl tetrazole derivatives (losartan, candesartan, irbesartan).
• Non-biphenyl tetrazole derivatives (telmisartan).
• Non-biphenyl non-tetrazoles (eprosartan).
• Non-heterocyclic derivatives (valsartan).

Most drugs in this group (for example, irbesartan, candesartan, losartan, telmisartan) are non-competitive angiotensin II receptor antagonists. Eprosartan is the only competitive antagonist whose effect is overcome by high levels of angiotensin II in the blood.

Angiotensin II receptor antagonists have hypotensive, antiproliferative and natriuretic effects .

Mechanism hypotensive effect Angiotensin II receptor antagonists are to eliminate vasoconstriction caused by angiotensin II, reduce the tone of the sympathetic-adrenal system, and increase sodium excretion. Almost all drugs in this group exhibit a hypotensive effect when taken once a day and allow you to control blood pressure for 24 hours.

Thus, the onset of the hypotensive effect of valsartan is observed within 2 hours, maximum 4–6 hours after oral administration. After taking the drug, the antihypertensive effect persists for more than 24 hours. The maximum therapeutic effect develops after 2–4 weeks. from the start of treatment and persists with long-term therapy.

The onset of the antihypertensive effect of candesartan after taking the first dose develops within 2 hours. During ongoing therapy with the drug at a fixed dose, the maximum reduction in blood pressure is usually achieved within 4 weeks and is maintained further during treatment.

When taking telmisartan, the maximum hypotensive effect is usually achieved 4-8 weeks after the start of treatment.

Pharmacologically, angiotensin II receptor antagonists differ in their degree of affinity for angiotensin receptors, which affects their duration of action. So, for losartan this indicator is approximately 12 hours, for valsartan – about 24 hours, for telmisartan – more than 24 hours.

Antiproliferative effect Angiotensin II receptor antagonists determine the organoprotective (cardio- and renoprotective) effects of these drugs.

The cardioprotective effect is realized by regression of myocardial hypertrophy and hyperplasia of the vascular wall muscles, as well as by improving the functional state of the vascular endothelium.

The renoprotective effect exerted on the kidneys by drugs of this group is close to that of ACE inhibitors, but some differences are noted. Thus, angiotensin II receptor antagonists, in contrast to ACE inhibitors, have a less pronounced effect on the tone of efferent arterioles, increase renal blood flow and do not affect the glomerular filtration rate.

To the main differences in pharmacodynamics Angiotensin II receptor antagonists and ACE inhibitors include:

• When prescribing angiotensin II receptor antagonists, a more pronounced elimination of the biological effects of angiotensin II in tissues is observed than when using ACE inhibitors.
• The stimulating effect of angiotensin II on angiotensin-2 receptors enhances the vasodilating and antiproliferative effects of angiotensin II receptor antagonists.
• Angiotensin II receptor antagonists have a milder effect on renal hemodynamics than with the use of ACE inhibitors.
• When prescribing angiotensin II receptor antagonists, there are no undesirable effects associated with activation of the kinin system.

The renoprotective effect of drugs in this group is also manifested by a decrease in microalbuminuria in patients with arterial hypertension and diabetic nephropathy.

The renoprotective effects of angiotensin II receptor antagonists are observed when they are used in doses lower than those that produce a hypotensive effect. This may have additional clinical significance in patients with severe chronic renal failure or heart failure.

Natriuretic action Angiotensin II receptor antagonists are associated with blockade of angiotensin-1 receptors, which regulate sodium reabsorption in the distal tubules of the kidneys. Therefore, with the use of drugs in this group, sodium excretion in urine increases.

Following a diet low in sodium salt potentiates the renal and neurohumoral effects of angiotensin II receptor antagonists: the level of aldosterone decreases more significantly, the content of renin in plasma increases, and stimulation of natriuresis is observed against the background of an unchanged glomerular filtration rate. With increased intake of table salt into the body, these effects weaken.

The pharmacokinetic parameters of angiotensin II receptor antagonists are mediated by the lipophilicity of these drugs. Losartan is the most hydrophilic, and telmisartan is the most lipophilic among the drugs in this group.

Depending on the lipophilicity, the volume of distribution of angiotensin II receptor antagonists changes. Telmisartan has the highest rate.

Angiotensin II receptor antagonists differ in their pharmacokinetic characteristics: bioavailability, half-life, metabolism.

Valsartan, losartan, eprosartan are characterized by low and variable bioavailability (10-35%). The latest generation of angiotensin II receptor antagonists (candesartan, telmisartan) have higher bioavailability (50-80%).

After oral administration of angiotensin II receptor antagonist drugs, the maximum concentrations of these drugs in the blood are achieved after 2 hours. With long-term regular use, a steady-state, or equilibrium, concentration is established after 5-7 days.

Angiotensin II receptor antagonists are characterized by a high degree of binding to plasma proteins (more than 90%), mainly albumin, partially with α 1-acid glycoprotein, γ-globulin and lipoproteins. However, strong binding to proteins does not affect the plasma clearance and volume of distribution of drugs in this group.

Angiotensin II receptor antagonists have a long half-life - from 9 to 24 hours. Due to these features, the frequency of administration of drugs in this group is 1 time / day.

Drugs in this group undergo partial (less than 20%) metabolism in the liver under the action of glucuronyl transferase or the liver microsomal system involving cytochrome P450. The latter is involved in the metabolism of losartan, irbesartan and candesartan.

The route of elimination of angiotensin II receptor antagonists is predominantly extrarenal - more than 70% of the dose. Less than 30% of the dose is excreted by the kidneys.

Pharmacokinetic parameters of angiotensin II receptor antagonists

A drug	Bioavailability (%)	Plasma protein binding (%)	Maximum concentration (h)	Half-life (h)	Distribution volume (l)	Excretion (%)
						Hepatic	Renal
Valsartan	23	94-97	2-4	6-7	17	70	30
Irbesartan	60-80	96	1,5-2	11-15	53-93	More than 75	20
Candesartan	42	Over 99	4	9	10	68	33
Losartan	33	99	1-2	2 (6-7)	34 (12)	65	35
Telmisartan	42-58	More than 98	0,5-1	24	500	More than 98	Less than 1
Eprosartan	13	98	1-2	5-9	13	70	30

In patients with severe hepatic impairment, an increase in the bioavailability, maximum concentration and area under the concentration-time curve (AUC) of losartan, valsartan and telmisartan may be observed.

Subgroup drugs excluded. Turn on

Description

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

The RAAS plays an important role in the regulation of blood pressure, the pathogenesis of arterial hypertension and chronic heart failure (CHF), as well as a number of other diseases. Angiotensins (from angio- vascular and tensio- tension) - peptides formed in the body from angiotensinogen, which is a glycoprotein (alpha 2 globulin) of blood plasma synthesized in the liver. Under the influence of renin (an enzyme formed in the juxtaglomerular apparatus of the kidneys), the angiotensinogen polypeptide, which does not have pressor activity, is hydrolyzed, forming angiotensin I, a biologically inactive decapeptide that is easily subject to further transformations. Under the influence 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 peripheral vascular resistance, 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 and has positive inotropic activity. Angiotensin IV is presumably involved in the regulation of hemostasis.

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

It has now been shown that in humans, in addition to the ACE-dependent pathway 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 high specificity for angiotensin I. In different organs and tissues, either ACE-dependent or alternative pathways of angiotensin II formation predominate. Thus, cardiac serine protease, its DNA and mRNA were found in human myocardial tissue. 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 formation occurs in the blood plasma.

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

It is believed that 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—subtypes AT 1 and AT 2.

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

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

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

Increased sodium reabsorption in the proximal renal tubules,

Secretion of aldosterone by the adrenal cortex

Secretion of vasopressin, endothelin-1,

Renin release

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

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

In arterial hypertension against the background of excessive activation of the RAAS, the AT 1 receptor-mediated effects of angiotensin II directly or indirectly contribute to an increase in blood pressure. In addition, 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 arterial walls, etc.

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

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

AT 2 receptors are found in the heart, blood vessels, adrenal glands, kidneys, some areas of the brain, reproductive organs, incl. in the uterus, atretic ovarian follicles, and also in skin wounds. It has been shown that the number of AT 2 receptors can increase with tissue damage (including blood vessels), myocardial infarction, and heart failure. It is 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 stimulation of AT 1 receptors and are relatively weakly expressed. Stimulation of AT 2 receptors is accompanied by vasodilation, inhibition of cell growth, incl. suppression of cell proliferation (endothelial and smooth muscle cells of the vascular wall, fibroblasts, etc.), inhibition of cardiomyocyte hypertrophy.

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

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

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

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

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

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

The first angiotensin II receptor blocker introduced into therapeutic practice in 1971 was saralazine, a peptide compound similar in structure to angiotensin II. Saralazin blocked the pressor effect of angiotensin II and decreased the tone of peripheral vessels, reduced the content of aldosterone in plasma, and lowered blood pressure. However, by the mid-70s, experience with the use of saralazine showed that it has partial agonist properties 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 high levels of renin, while against the background of low levels of angiotensin II or with rapid injection, blood pressure increased. Due to the presence of agonistic properties, as well as due to the complexity of synthesis and the need for parenteral administration, saralazine has not received wide practical use.

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

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

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

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

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

Biphenyl non-tetrazole compounds - telmisartan;

Non-biphenyl non-tetrazole compounds - eprosartan.

Based on the presence of pharmacological activity, AT 1 receptor blockers are divided into active dosage forms and prodrugs. Thus, 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. Losartan and tazosartan have active metabolites. For example, the active metabolite of losartan, EXP-3174, has a stronger and longer-lasting effect than losartan (the pharmacological activity of EXP-3174 is 10-40 times greater than losartan).

According to the mechanism of binding to receptors, AT 1 receptor blockers (as well as their active metabolites) are divided into competitive and non-competitive angiotensin II antagonists. Thus, losartan and eprosartan 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 blood volume, they can be displaced from binding sites), while valsartan, irbesartan , candesartan, telmisartan, as well as the active metabolite of losartan EXP−3174 act as non-competitive antagonists and bind irreversibly to receptors.

The pharmacological effect of drugs in 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 receptors exceeds that for AT 2 receptors by thousands of times: for losartan and eprosartan 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, olmesartan - 12.5 thousand, valsartan - 20 thousand times.

Blockade of AT 1 receptors prevents the development of the effects of angiotensin II mediated by these receptors, which prevents the adverse effects of angiotensin II on vascular tone and is accompanied by a decrease in high 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 the cells of the juxtaglomerular apparatus of the kidneys are involved in the process of regulating the release of renin (according to the principle of negative feedback). Blockade of AT 1 receptors causes a compensatory increase in renin activity, an increase in the production of angiotensin I, angiotensin II, etc.

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

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

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

Thus, 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 effects of angiotensin II (and angiotensin III, which has an affinity for angiotensin II receptors) on the cardiovascular system are inhibited and, presumably, its protective effect is manifested (by stimulating AT 2 receptors), and the effect also develops angiotensin-(1-7) by stimulating AT x receptors. All these effects contribute to vasodilation and weakening of the proliferative effect of angiotensin II on vascular and cardiac cells.

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

All AT 1 receptor blockers act gradually, the antihypertensive effect develops smoothly, within 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 pharmacokinetic features of this group of drugs make their use convenient for patients. These medicines can be taken with or without food. A single dose is enough to provide a good hypotensive effect throughout the day. They are equally effective in patients of different sexes and ages, including patients over 65 years of age.

Clinical studies show that all angiotensin receptor blockers have a high antihypertensive and pronounced organoprotective effect and are well tolerated. 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. Monotherapy is possible (for mild arterial hypertension) or in combination with other antihypertensive drugs (for moderate and severe forms).

Currently, according to WHO/ISH (International Society of Hypertension) recommendations, preference is given to combination therapy. The most rational option for angiotensin II receptor antagonists is their combination with thiazide diuretics. The addition of a diuretic in low doses (for example, 12.5 mg hydrochlorothiazide) can increase the effectiveness of therapy, as confirmed by the results of randomized multicenter studies. Drugs have been created that include this combination - Gizaar (losartan + hydrochlorothiazide), Co-diovan (valsartan + hydrochlorothiazide), Coaprovel (irbesartan + hydrochlorothiazide), Atacand Plus (candesartan + hydrochlorothiazide), Micardis Plus (telmisartan + hydrochlorothiazide), etc. .

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

The results of experimental as well as 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, patients showed a tendency to decrease the size of the left ventricle in systole and diastole, and an increase in myocardial contractility. Regression of LVH was noted with long-term use of valsartan and eprosartan in patients with arterial hypertension. Some AT 1 receptor blockers have been shown to improve renal function, incl. in diabetic nephropathy, as well as indicators of central hemodynamics in CHF. So far, clinical observations regarding the effect of these drugs on target organs are few, but research in this area is actively continuing.

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

Data obtained from animal experiments indicate that drugs that have a direct effect on the RAAS can cause damage to the fetus, death of the fetus and newborn. The effect on the fetus is especially dangerous in the second and third trimesters of pregnancy, because the development of hypotension, cranial hypoplasia, 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, drugs of this group should not be used during pregnancy, and if pregnancy is detected during treatment, their use should be stopped.

There is no information about the ability of AT 1 receptor blockers to penetrate into women's breast milk. However, in experiments on animals it was established 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 nursing women, and if therapy is necessary for the mother, breastfeeding is stopped.

The use of these drugs in pediatric practice should be avoided since the safety and effectiveness of their use in children have not been determined.

There are a number of limitations for therapy with AT 1 angiotensin receptor antagonists. Caution should be exercised in patients with reduced blood volume and/or hyponatremia (during treatment with diuretics, limiting salt intake with diet, diarrhea, vomiting), as well as in patients on hemodialysis, because Symptomatic hypotension may develop. An assessment of the risk/benefit ratio is necessary in patients with renovascular hypertension caused by bilateral renal artery stenosis or renal artery stenosis of a single kidney, because excessive inhibition of the RAAS in these cases increases the risk of severe hypotension and renal failure. Use 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. It is not recommended for use in patients with primary hyperaldosteronism, because in this case, drugs that inhibit the RAAS are ineffective. There is insufficient data on use in patients with severe liver disease (eg, cirrhosis).

Side effects with angiotensin II receptor antagonists that have been reported so far are usually mild, transient, and rarely warrant discontinuation of therapy. The total incidence of side effects is comparable to placebo, which is confirmed 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, and other peptides and, as a result, do not cause a dry cough, which often appears during treatment with ACE inhibitors.

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

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

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

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