Which is converted from its precursor serum globulin, synthesized by the liver. Angiotensin is extremely important for the hormonal renin-angiotensin system, a system that is responsible for blood volume and pressure in the human body.
The substance angiotensinogen belongs to the class of globulins, it consists of more than 400. Its production and release into the blood is carried out by the liver constantly. Angiotensin levels can increase under the influence of angiotensin II, thyroid hormone, estrogen, and plasma corticosteroids. When blood pressure decreases, this acts as a stimulating factor for the production of renin, releasing it into the blood. This process triggers the synthesis of angiotensin.
Angiotensin I and angiotensin II
Under influence renina The following substance is formed from angiotensinogen - angiotensin I. This substance does not have any biological activity; it the main role- to be a predecessor angiotensin II. The latter hormone is already active: it ensures the synthesis of aldosterone and constricts blood vessels. This system is a target for drugs that lower, as well as for many inhibitory agents that reduce the concentration of angiotensin II.
The role of angiotensin in the body
This substance is strong vasoconstrictor . This means that it also narrows the arteries, which in turn leads to an increase in blood pressure. This activity is ensured by chemical bonds that are formed when the hormone interacts with a special receptor. Also among the functions related to the cardiovascular system, one can highlight aggregation platelets, regulation of adhesion and prothrombotic effect. This hormone is responsible for those occurring in our body. It causes an increase in secretion in neurosecretory cells in such a part of the brain as hypothalamus, as well as the secretion of adrenocorticotropic hormone in pituitary gland. This leads to the rapid release of norepinephrine. Hormone aldosterone , secreted by the adrenal glands, is released into the blood precisely thanks to angiotensin. Plays an important role in maintaining electrolyte and water balance, renal hemodynamics. Sodium retention by this substance is ensured due to its ability to act on the proximal tubules. In general, it is able to catalyze the glomerular filtration reaction by increasing renal pressure and constricting renal efferent arterioles.
To determine the level of this hormone in the blood, a routine blood test is taken, like for any other hormones. Its excess may indicate increased concentration estrogen , be observed when using oral birth control pills and during, after binephrectomy, Itsenko-Cushing's disease may be a symptom of the disease. A reduced level of angiotensin is observed with glucocorticoid deficiency, for example, with liver diseases and Addison's disease.
Angiotensin is a hormone that, through several mechanisms, is responsible for increasing blood pressure. It is part of the so-called RAAS (renin-angiotensin-aldosterone system).
In people with high blood pressure, so-called periods of plasma renin activity can be observed, which manifests itself in the level of angiotensin I concentration.
The role of angiotensin in the body
Name RAAS comes from the first letters of its constituent compounds: renin, angiotensin and aldosterone. These compounds are inextricably linked and mutually influence each other's concentrations: renin stimulates the production of angiotensin, angiothesin increases the production of aldosterone, aldosterone and angiotensin inhibit the release of renin. Renin is an enzyme produced in the kidneys, within the so-called glomerular chambers.
Renin production is stimulated, for example, by hypovolemia (decreased circulating blood volume) and a decrease in the concentration of sodium ions in plasma. Renin released into the blood acts on angiotensinogen, that is, one of the blood plasma proteins produced mainly in the liver.
Renin breaks down angiotensinogen to angiotensin I, which is a precursor for angiotensin II. In the pulmonary bloodstream, an enzyme called angiotensin-converting enzyme converts angiotensin I to its biologically active form, angiotensin II.
Angiotensin II plays many roles in the body, including:
- stimulates the release of aldosterone from the adrenal cortex (this hormone, in turn, affects the water-electrolyte balance, which causes a retention of sodium and water ions in the body, increasing the release of potassium ions by the kidneys - this leads to an increase in the volume of circulating blood, that is, to an increase in volume, and, consequently, an increase in blood pressure).
- acts on receptors located in the wall of blood vessels, which leads to vascular contraction and increased blood pressure.
- also affects the central nervous system, increasing the production of vasopressin or antidiuretic hormone.
Blood levels of angiotensin I and angiotensin II
Determination of plasma renin activity is a test that is performed in patients with arterial hypertension. The study consists of obtaining from the patient venous blood after 6-8 hours of sleep at night on a diet containing 100-120 mmol of salt per day (this is the so-called study without activation of renin secretion).
A study with activation of renin secretion consists of analyzing the blood of patients after a three-day diet with limiting salt intake to 20 mmol per day.
Angiotensin II levels in blood samples are assessed using radioimmunoassay methods.
The standard test without activation of renin secretion in healthy people is about 1.5 ng/ml/hour, when researched after activation, the level increases 3-7 times.
An increase in angiotensin is observed:
- in persons with primary arterial hypertension(that is, hypertension that develops independently and whose cause cannot be identified), in these patients, measuring angotensin levels can help you select appropriate antihypertensive drugs;
- at malignant hypertension;
- renal ischemia, for example, during narrowing of the renal artery;
- in women taking oral contraceptives;
- renin-producing tumors.
Concerning norms of angiotensin I and angiotensin II levels in the blood, it is, respectively, 11-88 pg/ml and 12-36 pg/ml.
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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 rapid rise HELL. 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 fabrics, incl. in the heart, kidneys, brain, blood vessels. Increased activity of tissue RAAS causes long-term effects of angiotensin II, which are manifested by structural and functional changes in target organs and lead to the development of such pathological processes, 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 arterioles renal glomeruli(especially 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 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. AT 1c receptor subtype was isolated from rat placenta, physiological role which is not yet clear.
AT 3 receptors with affinity for angiotensin II are found on neuronal membranes; their function is unknown. AT 4 receptors are found on endothelial cells. 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 important this system in the regulation of homeostasis, in the development of cardiovascular pathology, 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 that specifically act 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 parenteral administration Saralasin has not received widespread 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 Angiotensin II receptor antagonists are implemented 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 These drugs lead 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 regulation of renin release (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.
In conditions high content 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 effect of angiotensin II (and angiotensin III, which has an affinity for angiotensin II receptors) on the cardiovascular system is inhibited and, presumably, its manifestation protective effect(by stimulating AT 2 receptors), and the effect of angiotensin-(1-7) also develops 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 the vasodilating effect 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 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 possible development of hypotension, cranial hypoplasia, anuria, renal failure and fetal death. 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 breast milk women. 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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Angiotensin is a peptide hormone that causes narrowing of blood vessels (vasoconstriction), an increase in blood pressure, and the release of aldosterone from the adrenal cortex into the bloodstream.
Angiotensin plays a significant role in the renin-angiotensin-aldosterone system, which is the main target of drugs that lower blood pressure.
The main mechanism of action of angiotensin 2 receptor antagonists is associated with the blockade of AT 1 receptors, which eliminates the adverse effects of angiotensin 2 on vascular tone and normalizes high blood pressure.
The level of angiotensin in the blood increases with renal hypertension and kidney tumors that produce renin, and decreases with dehydration, Conn's syndrome and kidney removal.
Angiotensin synthesis
The precursor of angiotensin is angiotensinogen, a protein of the globulin class, which belongs to serpins and is produced mainly by the liver.
The production of angiotensin 1 occurs under the influence of renin on angiotensinogen. Renin is a proteolytic enzyme that is one of the most significant renal factors involved in the regulation of blood pressure, although it itself does not have pressor properties. Angiotensin 1 also has no vasopressor activity and is rapidly converted to angiotensin 2, which is the most potent of all known pressor factors. The conversion of angiotensin 1 to angiotensin 2 occurs due to the removal of C-terminal residues under the influence of angiotensin-converting enzyme, which is present in all tissues of the body, but is most synthesized in the lungs. Subsequent cleavage of angiotensin 2 results in the formation of angiotensin 3 and angiotensin 4.
In addition, tonin, chymases, cathepsin G and other serine proteases have the ability to form angiotensin 2 from angiotensin 1, which is the so-called alternative pathway for the formation of angiotensin 2.
Renin-angiotensin-aldosterone system
The renin-angiotensin-aldosterone system is hormonal system, which provides regulation of blood pressure and the volume of blood circulating in the body.
Drugs that act by blocking angiotensin receptors have been developed through the study of angiotensin 2 inhibitors, which can block its formation or action and thus reduce the activity of the renin-angiotensin-aldosterone system.
The renin-angiotensin-aldosterone cascade begins with the synthesis of preprorenin by translation of renin mRNA in the juxtaglomerular cells of the afferent arterioles of the kidneys, where preprorenin, in turn, is formed from prorenin. A significant part of the latter is released into the bloodstream by exocytosis, but part of the prorenin is converted into renin in the secretory granules of juxtaglomerular cells, then also released into the bloodstream. For this reason, normally the volume of prorenin circulating in the blood is much higher than the concentration of active renin. Control of renin production is a determining factor in the activity of the renin-angiotensin-aldosterone system.
Renin regulates the synthesis of angiotensin 1, which has no biological activity and acts as a precursor to angiotensin 2, which serves as a strong vasoconstrictor. direct action. Under its influence, blood vessels narrow and a subsequent increase in blood pressure occurs. It also has a prothrombotic effect - it regulates platelet adhesion and aggregation. In addition, angiotensin 2 potentiates the release of norepinephrine, increases the production of adrenocorticotropic hormone and antidiuretic hormone, and can cause a feeling of thirst. By increasing pressure in the kidneys and narrowing the efferent arterioles, angiotensin 2 increases the rate of glomerular filtration.
Angiotensin 2 exerts its effect on body cells through different types of angiotensin receptors (AT receptors). Angiotensin 2 has the greatest affinity for AT 1 receptors, which are localized mainly in the smooth muscles of blood vessels, the heart, some areas of the brain, liver, kidneys, and adrenal cortex. The half-life of angiotensin 2 is 12 minutes. Angiotensin 3, formed from angiotensin 2, has 40% of its activity. The half-life of angiotensin 3 in the bloodstream is approximately 30 seconds, in body tissues - 15-30 minutes. Angiotensin 4 is a hexopeptide and is similar in its properties to angiotensin 3.
A prolonged increase in the concentration of angiotensin 2 leads to a decrease in cell sensitivity to insulin with a high risk of developing type 2 diabetes mellitus.
Angiotensin 2 and the extracellular level of potassium ions are among the most significant regulators of aldosterone, which is an important regulator of the balance of potassium and sodium in the body and plays a significant role in the control of fluid volume. It increases the reabsorption of water and sodium in the distal convoluted tubules, collecting ducts, salivary and sweat glands, and large intestine, causing the excretion of potassium and hydrogen ions. An increased concentration of aldosterone in the blood leads to sodium retention in the body and increased excretion of potassium in the urine, that is, to a decrease in the level of this microelement in the blood serum (hypokalemia).
Elevated angiotensin levels
With a prolonged increase in the concentration of angiotensin 2 in the blood and tissues, the formation of collagen fibers increases and hypertrophy of smooth muscle cells of blood vessels develops. As a result, the walls of blood vessels thicken, their internal diameter decreases, which leads to an increase in blood pressure. In addition, depletion and degeneration of cardiac muscle cells occurs, followed by their death and replacement with connective tissue, which causes the development of heart failure.
Prolonged spasm and hypertrophy of the muscular layer of blood vessels cause a deterioration in the blood supply to organs and tissues, primarily the brain, heart, kidneys, visual analyzer. Prolonged lack of blood supply to the kidneys leads to their degeneration, nephrosclerosis and the formation of renal failure. If there is insufficient blood supply to the brain, sleep disturbances occur, emotional disorders, decreased intelligence, memory, tinnitus, headache, dizziness, etc. Cardiac ischemia can be complicated by angina pectoris, myocardial infarction. Insufficient blood supply to the retina leads to a progressive decrease in visual acuity.
Renin regulates the synthesis of angiotensin 1, which has no biological activity and acts as a precursor of angiotensin 2, which serves as a strong direct-acting vasoconstrictor.
A prolonged increase in the concentration of angiotensin 2 leads to a decrease in cell sensitivity to insulin with a high risk of developing type 2 diabetes mellitus.
Angiotensin 2 blockers
Angiotensin 2 blockers (angiotensin 2 antagonists) are a group of medications that lower blood pressure.
Drugs that act by blocking angiotensin receptors have been developed through the study of angiotensin 2 inhibitors, which can block its formation or action and thus reduce the activity of the renin-angiotensin-aldosterone system. These substances include inhibitors of rhinin synthesis, inhibitors of angiotensinogen formation, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, etc.
Angiotensin 2 receptor blockers (antagonists) are a group of antihypertensive drugs that combine drugs that modulate the functioning of the renin-angiotensin-aldosterone system through interaction with angiotensin receptors.
The main mechanism of action of angiotensin 2 receptor antagonists is associated with the blockade of AT 1 receptors, which eliminates the adverse effects of angiotensin 2 on vascular tone and normalizes high blood pressure. Taking drugs from this group provides a long-lasting antihypertensive and organoprotective effect.
Clinical studies are currently ongoing to study the effectiveness and safety of angiotensin 2 receptor blockers.
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The main goals in the treatment of arterial hypertension are control over blood pressure levels, prevention of target organ damage and achieving maximum adherence to therapy. Currently, for the treatment of arterial hypertension as an initial means of lowering blood pressure, WHO and the International Society for the Study of Arterial Hypertension experts recommend six drug classes.
These are such well-known drugs as β-blockers, diuretics, calcium antagonists, ACE inhibitors, β-blockers. Also, in the new recommendations for the treatment of arterial hypertension, angiotensin II receptor blockers are included in this list for the first time. These drugs meet all the necessary requirements for the treatment of arterial hypertension.
The mechanism of action of angiotensin blockers is the competitive inhibition of angiotensin II receptors. Angiotensin II is the main hormone of the renin-angiotensin system; it causes vasoconstriction, salt and water retention in the body and promotes remodeling of the vascular wall and myocardium.
Thus, we can distinguish 2 main negative effect angiotensin II - hemodynamic and proliferative. The hemodynamic effect consists of systemic vasoconstriction and an increase in blood pressure, which also depends on the stimulating effect of angiotensin II on other pressor systems.
Resistance to blood flow increases mainly at the level of efferent arterioles of the renal glomeruli, resulting in an increase in hydraulic pressure in the glomerular capillaries. The permeability of glomerular capillaries also increases. The proliferative effect consists of hypertrophy and hyperplasia of cardiomyocytes, fibroblasts, endothelial and smooth muscle cells of arterioles, which is accompanied by a decrease in their lumen.
Hypertrophy and hyperplasia of mesangial cells occurs in the kidneys. Angiotensin II causes the release of norepinephrine from the endings of postganglionic sympathetic nerves, and the activity of the central part of the sympathetic nervous system increases. Anigotensin II increases the synthesis of aldosterone, which causes sodium retention and increased potassium excretion.
The release of vasopressin also increases, which leads to water retention in the body. It is significant that angiotensin II inhibits plasminogen activator and promotes the release of the most powerful pressor agent, endothelin I. They also indicate a cytotoxic effect on the myocardium, and, in particular, an increase in the formation of superoxide anion, which can oxidize lipids and inactivate nitric oxide.
Angiotensin II inactivates bradykinin, thereby causing a decrease in nitric oxide production. As a result, the positive effects of nitric oxide are significantly weakened - vasodilation, antiproliferative processes, platelet aggregation. The effects of angiotensin II are realized through specific receptors.
Two main subtypes of angiotensin II receptors have been discovered: AT1 and AT2. AT1s are the most common and mediate most of the effects of angiotensin listed above (vasoconstriction, salt and water retention, and remodeling processes). Angiotensin II receptor blockers replace angiotensin II at the AT1 receptor and thereby prevent the development of the above adverse effects.
There are two types of effects on angiotensin II: reduction of its formation using angiotensin-converting enzyme (ACE inhibitors) and blockade of receptors for angiotensin II (angiotensin receptor blockers). Reducing the formation of angiotensin II using ACE inhibitors has long been well established in clinical practice, but this possibility does not affect non-ACE-dependent pathways of angiotensin II formation (such as endothelial and renal peptidases, tissue plasminogen activator, chymase, cathepsin G and elastase, which can be activated compensatory when using ACE inhibitors), and is incomplete.
In addition, the effect of angiotensin II on all types of receptors for this substance is nonselectively weakened. In particular, the effect of angiotensin II on AT2 receptors (receptors of the second type), through which completely different properties of angiotensin II (anti-proliferative and vasodilating) are realized, which have a blocking effect on pathological remodeling of target organs.
With long-term use of ACE inhibitors, an “escape” effect occurs, expressed in a decrease in its effect on neurohormones (the synthesis of aldosterone and angiotensin is restored), since the non-ACE-dependent pathway for the formation of angiotensin II gradually begins to activate. Another way to reduce the effect of angiotensin II is selective blockade of receptors AT1, which also stimulates AT2 receptors;
at the same time, there is no effect on the kallikreinkin system (the potentiation of the action of which determines part of the positive effects of ACE inhibitors). Thus, if ACE inhibitors carry out a non-selective blockade of the negative effect of AT II, then AT II receptor blockers (ARB II) carry out a selective (complete) blockade of the effect of AT II on AT1 receptors.
In addition, angiotensin II stimulation of unblocked AT2 receptors may have an additional beneficial role by increasing nitric oxide production through both bradykinin-dependent and bradykinin-independent mechanisms. Thus, theoretically, the use of angiotensin II receptor blockers can have a double positive effect - both through blockade of AT1 receptors and through stimulation of unblocked AT2 receptors by angiotensin II.
The first angiotensin II receptor blocker was losartan, registered for the treatment of arterial hypertension in 1994. Subsequently, drugs of this class appeared, such as valsartan, candesartan, irbesartan, and eprosartan, recently registered in Russia. Since the introduction of these drugs into clinical practice, a large number of studies have been carried out confirming their high efficiency and favorable effect on endpoints.
Let's consider the most important clinical studies. The multicenter randomized, double-blind LIFE (Losartan Intervention For Endpoint reduction in hypertension study) study, which lasted about 5 years, became one of the central ones demonstrating the effective effect of losartan on endpoints in hypertension.
The LIFE study involved 9193 patients aged 55-80 years with hypertension and signs of left ventricular hypertrophy (ECG criteria). After a 1-2 week run-in period on placebo, patients with a systolic blood pressure level of 160-200 mm Hg. and diastolic blood pressure - 95-115 mm Hg. were randomized to receive losartan or atenolol.
If the blood pressure level was insufficiently reduced, the addition of hydrochlorothiazide or other antihypertensive drugs, with the exception of ACE inhibitors, sartans and β-blockers, was allowed. When summing up the results, it turned out that in the losartan group, death from all causes occurred in 63 patients, and in the atenolol group - in 104 patients (p = 0.002).
The number of deaths due to cardiovascular pathology was 38 in the losartan group and 61 in the atenolol group (p = 0.028). Ischemic stroke developed in 51 patients receiving losartan and in 65 patients receiving atenolol (p = 0.205), and acute heart attack myocardium - in 41 and 50 patients, respectively (p=0.373).
Hospitalization for exacerbation of CHF was required in 32 patients in the losartan group and 55 in the atenolol group (p = 0.019). Among patients with diabetes mellitus (DM) in the LIFE study, primary endpoints were observed in 17 patients receiving losartan and 34 receiving atenolol. From cardiovascular diseases 4 patients with diabetes treated with losartan and 15 patients treated with atenolol died.
The number of deaths from other causes was 5 and 24, respectively. The average blood pressure level at the end of observation in the losartan and atenolol groups was 146/79 and 148/79 mmHg. respectively, the decrease was 31/17 and 28/17 mmHg. from the initial indicators, respectively. In patients with diabetes who received losartan, albuminuria was significantly less likely to be observed compared with the atenolol group (8 and 15%, respectively, p = 0.002), which indicates the renoprotective properties of losartan and its ability to normalize endothelial function, one of the signs of impairment of which is albuminuria.
Losartan was significantly more effective than atenolol in terms of regression of left ventricular myocardial hypertrophy, which seems especially important since myocardial hypertrophy is considered an important predictor of adverse cardiovascular complications. In patients with diabetes, the degree of glycemia in the groups taking losartan and atenolol did not differ, however, further analysis showed that taking losartan was associated with an increase in tissue sensitivity to insulin.
While taking losartan, the level uric acid in the blood serum of patients decreased by 29% (p = 0.004), which reflected the uricosuric effect of the drug. Elevated uric acid levels are associated with cardiovascular morbidity and may be considered a risk factor for hypertension and its complications.
Of all the sartans, only losartan has such a pronounced effect on the level of uric acid, which can be used in patients with hypertension with hyperuricemia. Currently, ACE inhibitors retain a leading position as a treatment for hypertension in diabetes, but the use of sartans in this category of patients is considered just as appropriate , since these drugs also have antiproliferative and antisclerotic effects on renal tissue, that is, they have nephroprotective properties, reducing the severity of microalbuminuria and proteinuria.
Due to its nephroprotective properties, the degree of reduction in the amount of protein excreted in the urine when using losartan exceeds 30%. In summary, in the LIFE study, during a 5-year follow-up, losartan-treated patients compared with the atenolol group had a 13% reduction in major cardiovascular events (primary endpoint) with no difference in the risk of myocardial infarction, but with a 25% reduction in major cardiovascular events. -m difference in the incidence of strokes.
These data were obtained against the background of more pronounced regression of LVH (according to ECG data) in the group receiving losartan. One of the most important properties of angiotensin receptor blockers is their nephroprotective effect, which has been studied in many randomized studies. This class of drugs has been shown in several placebo-controlled studies to delay the progression of end-stage renal disease or significant increases in serum creatinine and reduce or prevent the development of microalbuminuria or proteinuria in patients with both diabetic and nondiabetic nephropathy.
When comparing different treatment regimens, data were obtained on the superiority of angiotensin receptor blockers or ACE inhibitors in patients with proteinuric diabetic nephropathy and nondiabetic nephropathy over calcium antagonists in preventing the development of end-stage renal failure.
Currently, much attention is paid to the prevention of microalbuminuria or proteinuria. Angiotensin receptor blockers have been shown to be more effective in reducing protein excretion compared to β-blockers, calcium antagonists or diuretics. The nephroprotective properties of losartan were demonstrated in a 6-month multicenter prospective study, RENAAL (Reduction of Endpoints in NIDDM with the All Antagonist Losartan), which included 422 patients with type 2 diabetes mellitus and arterial hypertension.
The study included patients with proteinuria (albumin/creatinine ratio in the first morning urine of at least 300 mg/l) and a serum creatinine level of 1.3-3.0 mg/dl. Losartan (50 mg per day) or placebo was added to therapy with conventional antihypertensive drugs (except for ACE inhibitors and sartans).
If the target blood pressure level was not achieved within 4 weeks, the daily dose of losartan was increased to 100 mg. If the hypotensive effect was insufficient, at the 8th month of treatment, diuretics, calcium antagonists, β-blockers or centrally acting drugs were added to the regimen. The observation period averaged 3-4 years.
The level of daily urinary albumin excretion decreased from 115±85 mg to 66±55 mg (p=0.001), and the level of glycosylated hemoglobin - from 7.0±1.5% to 6.6±1.26% (p=0.001 ) . The addition of losartan to the antihypertensive regimen reduced the rate of achievement of the primary endpoints by an overall 16%. Thus, the risk of doubling serum creatinine levels decreased by 25% (p = 0.006), the probability of developing end-stage renal failure - by 28% (p = 0.002). In the losartan group, the degree of proteinuria reduction was 40% (p
Historical information
Angiotensin receptor blockers (ARBs) 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 undeniable advantage - they have practically no side effects.
The most common groups of drugs:
- sartans;
- angiotensin receptor blockers.
Studies of these drugs have this moment, are still only in 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 breastfeeding, with hyperkalemia, as well as in patients with severe renal failure and bilateral renal artery stenosis. These drugs should not be used by children.
One of the first groups of medications that affected the humoral regulation of blood pressure were ACE inhibitors. But practice has shown that they are not effective enough. After all, the substance that increases blood pressure (angiotensin 2) is produced under the influence of other enzymes. In the heart, its occurrence is promoted by the enzyme chymase.
Accordingly, it was necessary to find a drug that would block the production of angiotensin 2 in all organs or act as its antagonist. In 1971, the first peptide drug, saralazin, was created. In its structure, it is similar to angiotensin 2. And therefore binds to angiotensin receptors (AT), but does not increase blood pressure.
- The synthesis of saralasine is a labor-intensive and expensive process.
- In the body, it is instantly destroyed by peptidases; it acts for only 6-8 minutes.
- The drug must be administered intravenously, by drip.
Therefore it was not widespread. It is used to treat hypertensive crisis. The search for a more effective, long-term active drug continued. In 1988, the first non-peptide drug, losartan, was created. It began to be widely used in 1993. Later it was discovered that angiotensin receptor blockers are effective for the treatment of hypertension even in such conditions. concomitant diseases, How:
- diabetes mellitus type 2;
- nephropathy;
- chronic heart failure.
Most of the medications in this group have a short-acting effect, but now various BARs have been created that provide a long-term decrease in pressure.
Angiotensin II receptor blockers are one of the new classes of drugs for normalizing blood pressure. The names of drugs in this group end in “-artan”. Their first representatives synthesized in the early 90s of the twentieth century. Angiotensin II receptor blockers inhibit the activity of the renin-angiotensin-aldosterone system, thereby promoting a number of beneficial effects.
We list synonyms for these drugs:
- blockers angiotensin-II receptors;
- angiotensin receptor antagonists;
- sartans.
Angiotensin II receptor blockers have the best adherence to treatment among all classes of blood pressure pills. It has been established that the proportion of patients who stably continue to take medications for hypertension for 2 years is the highest among those patients who are prescribed sartans. The reason is that these drugs have the lowest incidence of side effects, comparable to the use of placebo. The main thing is that patients practically do not experience a dry cough, which is a common problem when prescribing ACE inhibitors.
Angiotensin 2 receptor blockers: drugs and mechanism of action
Both prevention and treatment of cardiovascular diseases require a responsible and serious approach. These kinds of problems are increasingly worrying people today. Therefore, many tend to treat them somewhat frivolously. Such people often either completely ignore the need to undergo treatment, or take medications without a doctor’s prescription (on the advice of friends).
However, it is important to remember: just because a drug has helped someone else does not guarantee that it will help you too. Forming a treatment regimen requires sufficient knowledge and skills that only specialists have. It is also possible to prescribe any drugs only taking into account the individual characteristics of the patient’s body, the severity of the disease, the characteristics of its course and medical history.
In addition, today there are many effective medications that only specialists can select and prescribe. For example, this applies to sartans - a special group medicinal substances(these are also called angiotensin 2 receptor blockers). What are these drugs?
How do angiotensin 2 receptor blockers work? Contraindications to the use of substances apply to which groups of patients? In what cases would it be appropriate to use them? What drugs are included in this group substances? The answers to all these and some other questions will be discussed in detail in this article.
The group of substances in question is also called as follows: angiotensin 2 receptor blockers. Drugs belonging to this group of drugs were produced through careful study of the causes of diseases of cardio-vascular system. Today, their use in cardiology is becoming increasingly widespread.
Before you start using prescribed medications, it is important to understand exactly how they work. How do angiotensin 2 receptor blockers affect the human body? The drugs in this group bind to receptors, thus blocking a significant increase in blood pressure.
With a decrease in blood pressure and a lack of oxygen (hypoxia), a special substance is formed in the kidneys - renin. Under its influence, inactive angiotensinogen is converted into angiotensin I. The latter, under the action of angiotensin-converting enzyme, is transformed into angiotensin II. A widely used group of drugs, angiotensin-converting enzyme inhibitors, acts specifically on this reaction.
Angiotensin II is highly active. By binding to receptors, it causes a rapid and persistent increase in blood pressure. It is clear that angiotensin II receptors are an excellent target for therapeutic intervention. ARBs, or sartans, act specifically on these receptors, preventing hypertension.
Angiotensin I is converted to angiotensin II not only under the action of angiotensin-converting enzyme, but also as a result of the action of other enzymes - chymases. Therefore, angiotensin-converting enzyme inhibitors cannot completely block vasoconstriction. ARBs are more effective drugs in this regard.
Classification of drugs
There are several types of sartans, differing in their chemical structure. It is possible to choose angiotensin 2 receptor blockers that are suitable for the patient. The drugs, a list of which will be given below, are important to research and discuss the appropriateness of their use with your doctor. So, there are four groups of sartans:
- Biphenyl tetrazole derivatives.
- Non-biphenyl tetrazole derivatives.
- Non-biphenyl netetrazole.
- Non-cyclic compounds.
According to their chemical structure, there are four groups of sartans:
- losartan, irbesartan and candesartan are biphenyl tetrazole derivatives;
- telmisartan is a non-biphenyl tetrazole derivative;
- eprosartan – non-biphenyl netetrazole;
- valsartan is a non-cyclic compound.
Sartans began to be used only in the 90s of the twentieth century. There are now quite a few trade names of essential drugs. Here is a partial list of them:
- losartan: blocktran, vasotens, zisacar, carzartan, cozaar, lozap, lozarel, losartan, lorista, lozacor, lotor, presartan, renicard;
- eprosartan: teveten;
- valsartan: valaar, valz, valsafors, valsacor, diovan, nortivan, tantordio, tareg;
- irbesartan: aprovel, ibertan, irsar, firmasta;
- candesartan: angiakand, atakand, hyposart, candecor, candesar, ordiss;
- telmisartan: micardis, prytor;
- olmesartan: cardosal, olimestra;
- azilsartan: edarbi.
Ready-made combinations of sartans with diuretics and calcium antagonists, as well as with the renin secretion antagonist aliskiren, are also available.
Angiotensin receptor blockers can be divided into 4 groups based on their chemical components:
- Telmisartan. Non-bifinyl tetrazole derivative.
- Eprosartan. Non-biphenyl netetrazole.
- Valsartan. Non-cyclic connection.
- Losartan, Candesartan, Irbesartan. This group belongs to biphenyl tetrazole derivatives.
How do blockers work?
The 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 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 myocardial hypertrophy and remodeling is of therapeutic importance in the treatment of ischemic and hypertensive cardiomyopathy, as well as cardiosclerosis in patients with coronary disease hearts. Angiotensin II receptor blockers also neutralize the participation of angiotensin II in the processes of atherogenesis, reducing atherosclerotic damage to heart vessels.
Indications for the use of angiotensin II receptor blockers (2009)
The kidney is a target organ for hypertension, the function of which is significantly affected by angiotensin II receptor blockers. They usually reduce protein excretion in the urine (proteinuria) in patients 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 (cause the body to eliminate salt in the urine) by inhibiting the reabsorption of sodium in the proximal tubule, as well as by inhibiting the synthesis and release of aldosterone. A decrease in the reabsorption of sodium into the blood in the distal tubule due to aldosterone 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, as application experience accumulated, the problems associated with their purpose became apparent. 5-25% of patients develop a dry cough, which may be so painful that it requires 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 speed glomerular filtration, which is accompanied by an increase in creatinine and potassium levels in the blood. The risk of such complications is increased for patients diagnosed with atherosclerosis of the renal arteries, congestive heart failure, hypotension and a decrease in circulating blood volume (hypovolemia).
A distinctive feature of angiotensin II receptor blockers is their good tolerability, comparable to placebo. Side effects when taking them are observed much less frequently than when using ACE inhibitors. Unlike the latter, the use of angiotensin II blockers is not accompanied by the appearance of a dry cough. Angioedema also develops much less frequently.
Like ACE inhibitors, these drugs can cause a fairly rapid decrease in blood pressure in hypertension, which is caused by increased renin activity in the blood plasma. In patients with bilateral narrowing of the renal arteries, renal function may deteriorate. The use of angiotensin II receptor blockers in pregnant women is contraindicated due to the high risk of fetal development disorders and fetal death.
Despite all these undesirable effects, sartans are considered the most well tolerated group of drugs for lowering blood pressure by patients, with the lowest incidence of adverse reactions. They go well with almost all groups of drugs that normalize blood pressure, especially with diuretics.
As blood pressure begins to decrease in the kidneys, renin is produced against the background of hypoxia (lack of oxygen). It affects inactive angiotensinogen, which is transformed into angiotensin 1. It is acted upon by angiotensin-converting enzyme, which is converted into the form of angiotensin 2.
By interacting with receptors, angiotensin 2 sharply increases blood pressure. ARAs act on these receptors, which is why blood pressure decreases.
Angiotensin receptor blockers not only fight hypertension, but also have the following effects:
- reduction of left ventricular hypertrophy;
- decrease ventricular arrhythmia;
- reduction of insulin resistance;
- improvement of diastolic function;
- reduction of microalbuminuria (protein excretion in urine);
- improving kidney function in patients with diabetic nephropathy;
- improvement of blood circulation (for chronic heart failure).
Sartans can be used to prevent structural changes in the tissues of the kidneys and heart, as well as atherosclerosis.
In addition, ARAs may contain active metabolites. In some drugs, active metabolites last longer than the drugs themselves.
Indications for use
The use of angiotensin 2 receptor blockers is recommended for patients with the following pathologies:
- Arterial hypertension. Hypertonic disease– the main indication for the use of sartans. Angiotensin receptor antagonists are well tolerated by patients and the effect can be compared with placebo. Practically do not cause uncontrolled hypotension. Also, these drugs, unlike beta blockers, do not affect metabolic processes or sexual function, and there is no arrhythmogenic effect. Compared to angiotensin-converting enzyme inhibitors, ARAs practically do not cause cough and angioedema, and do not increase the concentration of potassium in the blood. Angiotensin receptor blockers rarely cause 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. An improvement in the prognosis is influenced by a decrease in excreted protein in the urine, which slows down the development of renal failure. Recent research suggests that ARAs reduce proteinuria (protein excretion in the urine) while protecting the kidneys, but these results have not yet been 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, this improves the activity of the heart, performing a compensatory function. As the disease progresses, myocardial remodeling occurs, which ultimately leads to its dysfunction. Treatment with angiotensin receptor blockers for 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;
- intolerance to ACE inhibitors.
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, and diabetic nephropathy is being clarified during clinical trials.
A distinctive feature of the new class of antihypertensive drugs is good tolerability, comparable to placebo. Side effects with their use are observed much less frequently than 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 resulting cough. Angioedema is also observed much less frequently.
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, renal function may deteriorate. Patients with chronic renal failure are at risk of developing hyperkalemia due to inhibition of aldosterone release during treatment.
The use of AT1 receptor blockers during pregnancy is contraindicated due to the possibility of disturbances in fetal development and death.
Despite the above-mentioned 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 combine well with almost all groups of antihypertensive drugs. Their combination with diuretics is especially effective.
Losartan
It is the first non-peptide AT1 receptor blocker, which became the prototype of this class of antihypertensive drugs. It is a benzylimidazole derivative and does not have agonistic activity on AT1 receptors, which it blocks 30,000 times more actively than AT2 receptors. The half-life of losartan is short - 1.5-2.5 hours.
During its first passage through the liver, losartan is metabolized to form the active metabolite EPX3174, which is 15 to 30 times more active than losartan and has a longer half-life of 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 the absence of agonist activity.
The bioavailability of losartan when taken orally is only 33%. Its excretion is carried out with bile (65%) and urine (35%). Impaired renal function has little effect on the pharmacokinetics of the drug, while with liver dysfunction, the clearance of both active agents decreases and their concentration in the blood increases.
Some authors believe that increasing the dose of the drug to more than 50 mg per day does not provide additional antihypertensive effect, while others observed a more significant decrease in blood pressure when the dose was increased to 100 mg/day. Further increase in dose does not lead to an increase in the effectiveness of the drug.
Great hopes were associated with the use of losartan in patients with chronic heart failure. The basis was data from the ELITE study (1997), in which therapy with losartan (50 mg/day) for 48 weeks helped reduce the risk of death by 46% in patients with chronic heart failure compared with captopril prescribed 50 mg 3 times a day.
Since this study was conducted on a relatively small cohort (722) of patients, a larger study was undertaken, ELITE II (1992), which included 3152 patients. The goal 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 forecast - the mortality of patients during treatment with captopril and losartan was almost the same.
Irbesartan
Irbesartan is a highly specific AT1 receptor blocker. According to its chemical structure, it belongs to imidazole derivatives. It has a high affinity for AT1 receptors, being 10 times more selective than losartan.
When comparing the antihypertensive effect of irbesartan at a dose of 150-300 mg/day and losartan at a dose of 50-100 mg/day, it was noted that 24 hours after administration, irbesartan reduced DBP more significantly than losartan. After 4 weeks of therapy, increasing the dose to achieve the target DBP level ((amp)lt;90 mm Hg) was required in 53% of patients receiving irbesartan and in 61% of patients receiving losartan. Additional administration of hydrochlorothiazide more significantly enhanced the antihypertensive effect of irbesartan than losartan.
Numerous studies have found 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 the drugs on the intrarenal and systemic action 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.
Several studies have examined 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 effectiveness of irbesartan and amlodipine in patients with hypertension due to diabetic nephropathy.
Telmisartan
Telmisartan has an inhibitory effect on AT1 receptors, 6 times greater than that of losartan. It is a lipophilic drug, due to which it penetrates well into tissues.
Comparison of the antihypertensive effectiveness of telmisartan with others modern means shows that he is not inferior to any of them.
The effect of telmisartan is dose-dependent. Increasing the daily dose from 20 mg to 80 mg is accompanied by a twofold increase in the effect on SBP, as well as a more significant decrease in DBP. Increasing the dose to more than 80 mg per day does not provide an additional reduction 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 blood pressure monitoring indicates that valsartan does not disrupt the normal circadian rhythm, and the T/P indicator is, according to various sources, 60-68%.
In the VALUE study, which began in 1999 and included 14,400 patients with hypertension from 31 countries, a comparative assessment of the effectiveness of the influence of valsartan and amlodipine on endpoints will help resolve the question of whether they, as relatively new drugs, have advantages in influencing risk development of complications in patients with hypertension compared with diuretics and beta-blockers.
You can take substances from this group only as prescribed by your doctor. There are several cases in which it would be reasonable to use angiotensin 2 receptor blockers. Clinical aspects The use of drugs in this group is as follows:
- Hypertension. It is this disease that is considered the main indication for the use of sartans. This is due to the fact that angiotensin 2 receptor blockers do not have a negative effect on metabolism, do not provoke erectile dysfunction, or impair bronchial patency. The effect of the drug begins two to four weeks after the start of treatment.
- Heart failure. Angiotensin 2 receptor blockers inhibit the action of the renin-angiotensin-aldosterone system, whose activity provokes the development of the disease.
- Nephropathy. Due to diabetes mellitus and arterial hypertension, serious disturbances in the functioning of the kidneys occur. Angiotensin 2 receptor blockers protect these internal organs and prevents too much protein from being excreted in the urine.
Hypertonic disease. Arterial hypertension is one of the main indications for the use of ARBs. The main advantage of this group is its good tolerability. They rarely cause uncontrolled hypotension and collapse reactions. These drugs do not change metabolism, do not worsen bronchial obstruction, do not cause erectile dysfunction and do not have an arrhythmogenic effect, which distinguishes them from beta blockers. Compared with angiotensin-converting enzyme inhibitors, sartans are significantly less likely to cause a dry cough, increased potassium concentrations in the blood, and angioedema. The maximum effect of ARBs develops after 2–4 weeks from the start of use and is persistent. Tolerance (resistance) to them is much less common.
ARBs selectively suppress the activity of the renin-angiotensin-aldosterone system, which explains their use in heart failure. The combination of sartans with beta blockers and aldosterone antagonists has especially good prospects in this regard.
Additional clinical effects
Sartans have the following additional clinical effects:
- arrhythmic effect;
- protection of nervous system cells;
- metabolic effects.
Protection of nervous system cells. ARBs protect the brain in patients with hypertension. This reduces the risk of strokes in such patients. This effect is associated with the hypotensive effect of sartans. However, they also have a direct effect on receptors in the brain vessels. Therefore, there is evidence of their benefits in people with normal level blood pressure, but a high risk of vascular accidents in the brain.
ARBs improve lipid metabolism by reducing the content of total cholesterol, low-density lipoprotein cholesterol and triglycerides. These drugs reduce the level of uric acid in the blood, which is important during simultaneous long-term therapy with diuretics. The effect of some sartans in diseases has been proven connective tissue, in particular, with Marfan syndrome.
Valsartan
Angiotensin 2 receptor blockers are well tolerated by the patient. In principle, these drugs do not have specific side effects, unlike other groups of drugs similar action, but can cause allergic reactions, like any other drug.
Some of the few side effects include:
- dizziness;
- headache;
- insomnia;
- abdominal pain;
- nausea;
- vomit;
- constipation.
In rare cases, the patient may experience the following disorders:
- muscle pain;
- 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.
Features of the use of BAR
As a rule, drugs that block angiotensin receptors are produced in the form of tablets, which can be taken regardless of food intake. The maximum stable concentration of the drug is achieved after two weeks of regular use. The elimination period 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 reduces the concentration of uric acid in the blood and removes sodium from the body. The dosage is adjusted by the attending physician based on the following indicators:
- Combination treatment, including 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, decreased blood pressure, the dosage of the drug must be reduced.
- In patients with liver and kidney failure, 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, as there is a risk that the drug may cause harm.
Patients who have the following pathologies should approach the use of the drug with caution:
- Obstruction of the bile ducts. The drug is excreted from the body with bile, so patients who have disturbances in the functioning of this organ are not recommended to use valsartan.
- Renovascular hypertension. In patients with this diagnosis, it is necessary to monitor serum urea levels, as well as creatinine.
- Imbalance 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, and decreased sexual function. While taking the drug, there is a risk of developing various viral infections.
The drug should be taken with caution when performing work that requires maximum concentration attention.
The effect of taking this drug is achieved after 3 hours. After completing the course of taking Ibersartan, blood pressure gradually 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 is to be taken daily at the same time. If you miss a dose, doubling the dose is strictly not recommended.
Adverse reactions when taking Ibersartan:
- headache;
- nausea;
- dizziness;
- weakness.
In the treatment of hypertension, it has a mild and lasting effect throughout the day. Not observed upon discontinuation of use sharp jumps pressure. Eprosartan is prescribed even for diabetes mellitus, as it does not affect blood sugar levels. The drug can also be taken by patients with kidney failure.
Eprosartan has the following side effects:
- cough;
- runny nose;
- dizziness;
- headache;
- diarrhea;
- chest pain;
- dyspnea.
Adverse reactions, as a rule, are short-term and do not require dose adjustment or complete discontinuation of the drug.
The drug is not prescribed to pregnant women, during breastfeeding and to children. Eprosartan is not prescribed to patients with renal artery stenosis, as well as with primary hyperaldosteronism.
Most strong drug among the sartans. Displaces angiotensin 2 from its connection with AT-1 receptors. It can be prescribed to patients with impaired renal function, but 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 dysfunction of the liver and kidneys.
The drug is not prescribed during pregnancy and lactation, as well as for children and adolescents.
Among the side effects of using Telmisartan are:
- dyspepsia;
- diarrhea;
- angioedema;
- lower back pain;
- muscle pain;
- development of infectious diseases.
Telmisartan belongs to a group of drugs that act by accumulation. The maximum effect of use can be achieved after a month of regular use of the drug. Therefore, it is important not to adjust the dosage yourself in the first weeks of use.
Despite the fact that drugs that block angiotensin receptors have minimal contraindications and side effects, they should be taken with caution due to the fact that these drugs are still at the research stage. 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.
Unlike Saralazine, the new drugs have a longer lasting effect and can be taken in tablet form. Modern blockers angiotensin receptors bind well to plasma proteins. The minimum period for removing them from the body is 9 hours. They can be taken regardless of food intake.
The largest amount of the drug in the blood is achieved after 2 hours. With continuous use, a steady-state concentration is established within a week. BAR is also used to treat hypertension if ACE inhibitors are contraindicated. The dose depends on the type of medication chosen and the individual characteristics of the patient. BAP is recommended with caution, since at the moment research is ongoing and all side effects have not been identified. Most often prescribed:
- valsartan;
- irbesartan;
- candesartan;
- losartan;
- telmisartan;
- eprosartan.
Although all of these drugs are angiotensin 2 blockers, their action is somewhat different. Only a doctor can choose the most effective drug depending on the individual characteristics of the patient.
It is prescribed for the treatment of hypertension. It exclusively blocks AT-1 receptors, which are responsible for toning the vascular wall. After a single use, the effect appears after 2 hours. The dose is prescribed by the doctor depending on the individual characteristics of the patient, since in some cases the drug can be harmful.
Due to insufficient knowledge, valsartan is not prescribed to children, pregnant women, or lactating women. Use with caution with other medications.
Irbesartan
Reduces the concentration of aldosterone, eliminates the vasoconstrictor effect of angiotensin 2, reduces the load on the heart. But it does not suppress the kinase that destroys bradykin. The drug has maximum effect 3 hours after administration. When the therapeutic course is stopped, blood pressure gradually returns to its original value.
Unlike most BARs, irbesartan does not affect lipid metabolism and therefore does not prevent the development of atherosclerosis. The drug must be taken daily at the same time. If you miss a dose, then the dose cannot be doubled next time. Irbesartan can cause: Unlike valsartan, it can be combined with diuretics.
Candesartan
The medicine dilates blood vessels, reduces heart rate and tone of the vascular wall, improves renal blood flow, and accelerates the excretion of water and salts. The hypotensive effect appears gradually and lasts for a day. The dose is selected individually depending on various factors.
Losartan potassium
Although the drug has no significant adverse reactions or contraindications, it is not recommended during pregnancy, lactation, or children. The optimal dose is selected by the doctor.
Telmisartan
One of the most powerful BAR. It is able to displace angiotensin 2 from its connection with AT 1 receptors, but does not show affinity for other AT receptors. The dose is prescribed individually, since in some cases even a small amount of the drug is enough to cause hypotension. Unlike losartan and candesartan, the dosage is not changed in case of impaired renal function. Telmisartan is not recommended:
- patients with primary aldosteronism;
- with severe impairment of liver and kidney function;
- pregnant, lactating children and adolescents.
Telmisartan can cause diarrhea, dyspepsia, and angioedema. The use of the drug provokes the development of infectious diseases. Pain in the lower back and muscles may occur. Important to know! The maximum hypotensive effect is achieved no earlier than a month after the start of treatment. Therefore, the dose of telmisartan should not be increased if treatment is not effective in the first weeks.
Eprosartan
Pathways of angiotensin II formation
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 present in the circulating blood in two forms: as a decapeptide and an octapeptide, subsequently 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, through the process of chemical transformation, is converted into the active octapeptide angiotensin II, which is a powerful vasoconstrictor factor.
In addition to angiotensin II, the physiological effects of the renin-angiotensin system are carried out by several other biologically active substances. The most important of them is angiotensin (1-7), formed mainly from angiotensin I, and also (to a lesser extent) from angiotensin II. Heptapeptide (1-7) has a vasodilating and antiproliferative effect. Unlike angiotensin II, it does not affect the secretion of aldosterone.
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). Angiotensin III is associated with processes that contribute to an increase in blood pressure - stimulation of angiotensin receptors and the formation of aldosterone.
Research over the past two decades has shown that angiotensin II is formed not only in the systemic circulation, but also in various fabrics, where all components of the renin-angiotensin system (angiotensinogen, renin, ACE, angiotensin receptors) are found, and the expression of renin and angiotensin II genes is also detected.
In accordance with the concept of the two-component nature of the renin-angiotensin system, the systemic link is assigned the leading role in its short-term physiological effects. The tissue component 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 stimulation by angiotensin are immediate reactions, occurring within seconds, in accordance with their physiological role, which is to support blood circulation after blood loss, dehydration or during orthostatic changes.
Other effects - myocardial hypertrophy, heart failure - develop over a long period. For the pathogenesis of chronic diseases of the cardiovascular system, slow responses carried out at the tissue level are more important than fast ones implemented by the systemic link of the renin-angiotensin system.
In addition to the ACE-dependent conversion of angiotensin I to angiotensin II, alternative pathways for its formation have been established. It was found that the accumulation of angiotensin II continues despite almost complete blockade ACE with its inhibitor enalapril. Subsequently, it was found that at the level of the tissue link of the renin-angiotensin system, the formation of angiotensin II occurs without the participation of ACE.
The conversion of angiotensin I to angiotensin II is carried out with the participation of other enzymes - tonin, chymases and cathepsin. These specific proteinases are able not only to convert angiotensin I to angiotensin II, but also to cleave angiotensin II directly from angiotensinogen without the participation of renin. In organs and tissues, the leading place is occupied by ACE-independent pathways for the formation of angiotensin II. Thus, in the human myocardium, about 80% of it is formed without the participation of ACE.
In the kidneys, the content of angiotensin II is twice as high as the content of its substrate angiotensin I, which indicates the prevalence of alternative formation of angiotensin II directly in the tissues of the organ.
Angiotensin II receptor blocking drugs
Attempts to achieve blockade of the renin-angiotensin system at the receptor level have been made for a long time. In 1972, the peptide angiotensin II antagonist saralazine was synthesized, but it did not find therapeutic use due to its short half-life, partial agonist activity, and the need for intravenous administration.
The basis for the creation of the first non-peptide angiotensin receptor blocker was the research of Japanese scientists, who in 1982 obtained data on the ability of imidazole derivatives to block AT1 receptors. In 1988, a group of researchers led by R. Timmermans synthesized the non-peptide angiotensin II antagonist losartan, which became the prototype of a new group of antihypertensive drugs. Used in the clinic since 1994.
Subsequently, a number of AT1 receptor blockers were synthesized, but currently only a few drugs have found clinical use. They differ in bioavailability, level of absorption, distribution in tissues, rate of elimination, and the presence or absence of active metabolites.
Summing up
Maintaining your health is the personal responsibility of every person. And what older age, the more effort you will have to put into this. However, the pharmaceutical industry provides invaluable assistance in this regard, constantly working to create better and more effective drugs.
The angiotensin 2 receptor blockers discussed in this article are also actively used in the fight against cardiovascular diseases. The drugs, the list of which was given and discussed in detail in this article, should be used and applied as prescribed by the attending physician who is well acquainted with the current the patient’s health condition, and only under his constant supervision.
If you want to start self-medicating, it is important to remember the dangers associated with this. Firstly, when using the medications in question, it is important to strictly follow the dosage and adjust it from time to time depending on the current condition of the patient. Only a professional can carry out all these procedures correctly.
Since only the attending physician can, based on the examination and test results, prescribe appropriate dosages and accurately formulate a treatment regimen. After all, therapy will be effective only if the patient adheres to the doctor’s recommendations. On the other hand, it is important to do everything possible to help improve one’s own physical condition by following the rules healthy image life.
Such patients need to properly adjust their sleep and wakefulness patterns, maintain water balance, as well as regulate eating habits (after all, poor-quality nutrition that does not provide the body sufficient quantity necessary nutrients, will not allow you to recover in a normal rhythm).Choose quality medicines. Take care of yourself and your loved ones. Be healthy!
Side effects and contraindications
- heart failure;
- arterial hypertension;
- reducing the risk of stroke in those patients who have the prerequisites for this.
It is forbidden to use “Losartan” during pregnancy and during breastfeeding, as well as in the case of individual sensitivity to individual components of the drug. Angiotensin 2 receptor blockers, which include the drug in question, can cause certain side effects, such as dizziness, insomnia, sleep disturbances, taste disturbances, vision disturbances, tremor, depression, memory impairment , pharyngitis, cough, bronchitis, rhinitis, nausea, gastritis, toothache, diarrhea, anorexia, vomiting, cramps, arthritis, pain in the shoulder, back, legs, palpitations, anemia, renal dysfunction, impotence, decreased libido, erythema, alopecia, rash, itching, swelling, fever, gout, hyperkalemia.
The drug should be taken once a day, regardless of meals, in doses prescribed by the attending physician. This drug effectively reduces myocardial hypertrophy, which occurs due to the development of arterial hypertension. Withdrawal syndrome does not appear after stopping the use of the drug, although it is caused by some angiotensin 2 receptor blockers (the description of the sartan group helps to clarify which drugs this property applies to).
The tablets are taken orally. They should be swallowed without chewing. The dose of the drug is prescribed by the attending physician. But the maximum amount of a substance that can be taken during the day is six hundred and forty milligrams. Sometimes they can have an effect on the body negative impact angiotensin 2 receptor blockers.
Side effects that Valsartan can cause: decreased libido, itching, dizziness, neutropenia, loss of consciousness, sinusitis, insomnia, myalgia, diarrhea, anemia, cough, back pain, vertigo, nausea, vasculitis, edema, rhinitis. If any of the above reactions occur, you should immediately contact a specialist.
ARBs inhibit (slow down) type 1 angiotensin receptors, through which negative influences angiotensin II, 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.
ARBs affect neurohumoral interactions in the body, including the main regulatory systems: the RAAS and the sympathoadrenal system (SAS), which are responsible for increasing blood pressure and the emergence and progression of cardiovascular pathologies. The main indications for the use of angiotensin receptor blockers:
- arterial hypertension;
- chronic heart failure (CHF functional classes II–IV according to the New York Heart Association NYHA classification in combinations of drugs, when it is impossible to use or ineffective ACE inhibitor therapy) in complex treatment;
- an increase in the percentage of patients who suffered acute myocardial infarction, complicated by left ventricular failure and/or systolic left ventricular dysfunction, with stable hemodynamics;
- reducing the likelihood of developing acute disorders cerebral circulation(stroke) 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 kidney pathology, reduce the risk of progression of chronic renal failure to the terminal stage (prevention of hemodialysis, the likelihood of increasing serum creatinine concentrations).
Contraindications to the use of ARBs: individual intolerance, bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney, pregnancy, lactation.
The effects of angiotensin II antagonists are due to their ability to bind to specific receptors of the latter. Having high specificity and preventing the action of angiotensin II at the tissue level, these drugs provide more complete blockade of the renin-angiotensin system compared to ACE inhibitors.
Blockade of AT1 receptors by angiotensin II antagonists leads to 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
The main hemodynamic effect of AT1 receptor blockers is vasodilation and, consequently, a decrease in blood pressure.
The antihypertensive effectiveness 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
- decreased Na reabsorption due to the direct action of angiotensin II on the renal tubules and through decreased aldosterone release
- elimination of sympathetic stimulation due to angiotensin II
- regulation of baroreceptor reflexes due to inhibition of the structures of the renin-angiotensin system in brain tissue
- an increase in the content of angiotensin, which stimulates the synthesis of vasodilatory prostaglandins
- decreased vasopressin release
- modulating effect on vascular endothelium
- increased production of nitric oxide by the 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 the 6-8th week of treatment. Most drugs have a dose-dependent reduction in blood pressure. They do not disrupt his normal daily rhythm.
Available clinical observations indicate that with long-term administration of angiotensin receptor blockers (for 2 years or more), resistance to their action does not develop. Canceling treatment does not lead to a rebound increase in blood pressure. AT1 receptor blockers do not reduce blood pressure if it is within normal limits.
Valsartan
BAPs are insufficiently studied but effective antihypertensive drugs
Search for a reliable antihypertensive drug with minimal adverse reactions lasts for several centuries. During this time, the causes of high blood pressure were identified, and many groups of drugs were created. They all have different mechanisms of action. But the most effective are medications that affect the humoral regulation of blood pressure. The most reliable among them at the moment are considered to be angiotensin receptor blockers (ARBs).
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