Angiotensin 2 receptor antagonists 2 indications and contraindications. Angiotensin II receptor antagonists: new prospects for clinical use. Combination of sartans with diuretic drugs

Angiotensin (AT) is a hormone from the genus of oligopeptides, which is responsible for vasoconstriction and an increase in blood pressure in the body. The substance is part of the renin-angiotensin system that regulates vasoconstriction. In addition, the oligopeptide activates the synthesis of aldosterone, the adrenal hormone. Aldosterone also contributes to high blood pressure. The precursor of angiotensin is the angiotensinogen protein produced by the liver.

Angiotensin was isolated as an independent substance and synthesized in the 30s of the last century in Argentina and Switzerland.

Briefly about angiotensinogen

Angiotensinogen is a prominent representative of the class of globulins and contains more than 450 amino acids. Protein is produced and released into the blood and lymph constantly. Its level may change throughout the day.

An increase in the concentration of globulin occurs under the action of glucocorticoids, estrogen and thyroid hormones. This explains the persistent increase in blood pressure when using oral contraceptives based on estrogens.

If the blood pressure drops and the Na+ content drops sharply, the renin level rises and the rate of angiotensinogen production increases significantly.

The amount of this substance in the plasma of a healthy person is approximately one mmol / l. With the development of hypertension, angiotensinogen in the blood rises. In this case, periods of renin activity are observed, which is expressed by the concentration of angiotensin 1 (AT 1).

Under the influence of renin synthesized in the kidneys, AT 1 is formed from angiotensinogen. The element is biologically inactive, its only purpose is to be a precursor of AT 2, which is formed in the process of cleavage of the last two atoms from the C-terminus of the inactive hormone molecule.

It is angiotensin 2 that is the main hormone of the RAAS (renin-angiotensin-aldosterone system). It has a pronounced vasoconstrictive activity, retains salt and water in the body, increases OPSS and blood pressure.

We can conditionally distinguish two main effects that angiotensin II has on the patient:

• Proliferative. It is manifested by an increase in the volume and mass of cardiomyocytes, connective tissue of the body, arteriolar cells, which causes a decrease in the free lumen. There is an uncontrolled growth of the inner mucous membrane of the kidney, an increase in the number of mesangial cells.
• Hemodynamic. The effect is manifested in a rapid increase in blood pressure and systemic vasoconstriction. The narrowing of the diameter of the blood vessels occurs at the level of the renal arterioles, resulting in an increase in blood pressure in the capillaries.

Under the influence of angiotensin II, the level of aldosterone rises, which retains sodium in the body and removes potassium, which provokes chronic hypokalemia. Against the background of this process, muscle activity decreases, persistent hypertension is formed.

The amount of AT 2 in plasma increases with the following ailments:

• kidney cancer that secretes renin;
• nephrotic syndrome;
• renal hypertension.

The level of active angiotensin may be reduced. This occurs with the development of such diseases:

• acute renal failure;
• Kohn's syndrome.

The removal of the kidney can lead to a decrease in the concentration of the hormone.

Angiotensin III and IV

Angiotensin 3 was synthesized in the late 70s of the last century. The hormone is formed upon further splitting of the effector peptide to 7 amino acids.

Angiotensin III has a lesser vasoconstrictive effect than AT 2, but is more active against aldosterone. Raises mean blood pressure.

Under the action of aminopeptidase enzymes, AT III is cleaved to 6 amino acids and forms angiotensin IV. It is less active than AT III and is involved in the process of hemostasis.

The main function of the active oligopeptide is to maintain a constant blood volume in the body. Angiotensin influences the process through AT receptors. They are of different types: AT1-, AT2-, AT3-, AT4-receptors and others. The effects of angiotensin depend on its interaction with these proteins.

AT 2 and AT1 receptors are the closest in structure, so the active hormone primarily binds to AT1 receptors. As a result of this connection, blood pressure rises.

If at high activity of AT 2 there are no free AT1 receptors, the oligopeptide binds to AT 2 receptors. to which they are less prone. As a result, antagonistic processes are launched, and blood pressure decreases.

Angiotensin II can affect the body both through direct action on arteriole cells, and indirectly through the central or sympathetic nervous system, hypothalamus and adrenal glands. Its effect extends to terminal arteries, capillaries and venules throughout the body.

The cardiovascular system

AT 2 has a directed vasoconstrictor effect. In addition to the vasoconstrictor effect, angiotensin II changes the force of contraction of the heart. Working through the central nervous system, the hormone shifts sympathetic and parasympathetic activity.

The effect of AT 2 on the body as a whole and the cardiovascular system in particular can be transient or long-term.

The short-term effect is expressed by vasoconstriction and stimulation of aldosterone production. Long-term exposure is determined by tissue AT2, which is formed in the endothelium of the vascular regions of the heart muscle.

The active peptide provokes an increase in the volume and mass of the myocardium and disrupts metabolism. In addition, it raises the resistance in the arteries, which provokes vasodilatation.

As a result, the effect of angiotensin II on the cardiovascular system develops hypertrophy of the left ventricle of the myocardium and arterial walls, intraglomerular hypertension.

CNS and brain

AT 2 has an indirect effect on the nervous system and brain through the pituitary and hypothalamus. The oligopeptide stimulates the production of ACTH in the anterior pituitary gland and activates the synthesis of vasopressin by the hypothalamus.

Adiuretin, in turn, has a bright antidiuretic effect, which generates:

• Water retention in the body, increasing the reabsorption of fluid from the cavity of the renal tubules into the blood. This contributes to an increase in the volume of blood circulating in the body and its dilution.
• Enhances the vasoconstrictor effect of angiotensin II and catecholamines.

ACTH stimulates the adrenal glands and increases the production of glucocorticoids, of which cortisol is the most biologically active. The hormone, although it does not have a vasoconstrictor effect, enhances the vasoconstrictive effect of catecholamines secreted by the adrenal glands.

With a sharp increase in the synthesis of vasopressin and ACTH, patients develop a feeling of thirst. This is facilitated by the release of norepinephrine with a direct effect on the sympathetic NS.

adrenal glands

Under the influence of angiotensin in the adrenal glands, the release of adolsterone is activated. The result is:

• water retention in the body;
• increase in the amount of circulating blood;
• increase in the frequency of myocardial contractions;
• strengthening of the vasoconstrictor action of AT 2.

All these processes together lead to an increase in blood pressure. The effect of excessive levels of aldosterone can be observed during the luteal phase of the monthly cycle in women.

kidneys

Under normal conditions, angiotensin II has little effect on kidney function. The pathological process unfolds against the background of excessive activity of the RAAS. A sharp decrease in blood flow in the tissues of the kidney leads to ischemia of the tubules, making filtering difficult.

The process of reabsorption, which causes a decrease in the amount of urine and the excretion of sodium, potassium and free fluid from the body, often leads to dehydration and the appearance of proteinuria.

For a short-term effect of AT 2 on the kidneys, an increase in intraglomerular pressure is characteristic. With prolonged exposure, mesangium hypertrophy develops.

What is the functional activity of angiotensin II

A short-term increase in the level of the hormone does not have a pronounced negative effect on the body. A long-term increase in AT 2 affects a person in a completely different way. It often gives rise to a number of pathological changes:

• Myocardial hypertrophy, cardiosclerosis, heart failure, heart attack. These ailments occur against the background of depletion of the heart muscle, turning into myocardial dystrophy.
• Thickening of the walls of blood vessels and a decrease in the lumen. As a result, arterial resistance increases and blood pressure rises.
• The blood supply to the tissues of the body worsens, oxygen starvation develops. First of all, the brain, myocardium and kidneys suffer from poor blood circulation. Gradually, dystrophy of these organs is formed, dead cells are replaced by fibrous tissue, which further exacerbates the symptoms of circulatory failure. Memory deteriorates, frequent headaches appear.
• Insulin resistance (reduced sensitivity) to insulin develops, which provokes an exacerbation of diabetes.

Prolonged activity of the oligopeptide hormone leads to a persistent increase in blood pressure, which can only be controlled by medication.

Norm of angiotensin I and II

To determine the level of the effector peptide, a blood test is performed, which is no different from a regular hormone test.

In patients with arterial hypertension, the study reveals the activity of renin in plasma. Blood is taken for analysis from a vein after an eight-hour night's sleep and a salt-free diet for 3 days.

As you can see, angiotensin II plays a huge role in the regulation of blood pressure in the body. You should be wary of any changes in the level of AT 2 in the blood. Of course, this does not mean that with a slight excess of the hormone, blood pressure will immediately rise to 220 mm Hg. Art., and heart rate - up to 180 contractions per minute. At its core, the oligopeptide hormone cannot directly increase blood pressure and provoke the development of hypertension, but, nevertheless, it is always actively involved in the formation of the disease.

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

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Mechanism of action and pharmacological effects

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

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

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

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

The activity of receptors of the 1st type of angiotensin 2 in relation to internal organs:

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



Metabolic effects and classification

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

ARBs have also been shown to act on specific PPRAγ receptors to directly increase cellular insulin sensitivity and stimulate an anti-inflammatory response, reduce triglycerides and free fatty acids. Recent studies have shown that ARBs can prevent the development of type 2 diabetes.

ARB classification:



Clinical pharmacology

All drugs are highly active in the blood, have good bioavailability and long-term effect when taken orally, so they are recommended to be taken once a day. ARBs are predominantly eliminated by the liver and, to a lesser extent, by the kidneys, making their cautious use in renal failure possible. Since ARBs are similar in activity to ACE inhibitors, angiotensin II blockers should not be prescribed for stenosis of both renal arteries. Eprosartan and Telmisartan are relatively contraindicated in diseases of the liver and bile ducts, since more than 90% of their concentration is eliminated by the liver. Clinical pharmacology of the main list of drugs is presented in Table 3.

Pharmacokinetic parameters of angiotensin II receptor antagonists:



ARBs affect neurohumoral interactions in the body, including the main regulatory systems: the RAAS and the sympathetic-adrenal system (SAS), which are responsible for increased blood pressure, the appearance and progression of cardiovascular pathologies.



Indications and contraindications

The main indications for the appointment of angiotensin receptor blockers:

• arterial hypertension;
• chronic heart failure (CHF of functional classes II–IV according to the classification of the New York Heart Association NYHA in combinations of drugs, if ACE inhibitor therapy is not possible or effective) in complex treatment;
• an increase in the percentage of patients with acute myocardial infarction complicated by left ventricular failure and / or systolic left ventricular dysfunction, with stable hemodynamics;
• a decrease in the likelihood of developing acute cerebrovascular accidents (strokes) in patients with arterial hypertension and left ventricular hypertrophy;
• nephroprotective function in patients with type 2 diabetes mellitus associated with proteinuria in order to reduce it, regression of kidney pathology, reduce the risk of progression of chronic renal failure to the terminal stage (prevention of hemodialysis, the likelihood of an increase in serum creatinine concentration).

Contraindications to the use of ARBs: individual intolerance, bilateral stenosis of the arteries of the kidneys or stenosis of the artery of a single kidney, pregnancy, lactation.



Side effects

Studies have shown that ARBs have the fewest reported side effects. Unlike a similar class of antihypertensive drugs, ACE inhibitors, angiotensin II receptor blockers are significantly less likely to cause cough. With an increase in dosages and in combination with the use of diuretics, hypersensitivity reactions and orthostatic hypotension may develop.

In the case of the appointment of ARBs in patients with chronic renal failure or undiagnosed renal artery stenosis, hyperkalemia, an increase in creatinine and blood urea may develop, which requires a reduction in drug dosages. Data on an increased risk of developing cancer with long-term use of angiotensin receptor blockers as a result of numerous studies have not been identified.

Pharmacological interactions

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

Drug interactions of angiotensin II receptor blockers:

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

List of drugs and their trade names

Currently, in a market economy, there are a significant number of brands of drugs containing the same active substance. To choose the right drug, you need to consult a specialist.



List of most prescribed ARBs and their trade names:

Active substance	Trade names (manufacturer)	Features of the drug
Valsartan	Valz (Actavis Group hf.), Valsakor (KRKA), Valsartan-SZ (Northern Star), Diovan (Novartis Pharma)	It is used in patients after suffering an acute violation of coronary blood flow (myocardial infarction). It should be used carefully in case of need to drive vehicles, as a violation of concentration is possible
Irbesartan	Aprovel (Sanofi Clear SNC), Irsar (Canonpharma Production ZAO)	Not recommended for use in patients suffering from primary hyperaldosteronism, in case of high stages of chronic renal failure, in patients who have recently undergone a kidney transplant
Candesartan	Angiakand (Canonpharma production ZAO), Ordiss (Teva), Xarten (VERTEX ZAO)	During treatment, dizziness and increased fatigue may occur. This should be taken into account before operating machinery or driving vehicles.
Losartan	Lorista (Krka-Rus), Vazotens (CNN PHARMA LIMITED), Lozap (Zentiva a.s)	The most frequently prescribed. It has an additional uricosuric effect. Can be recommended in the complex therapy of gout
Telmisartan	Telsartan (Dr. Reddy's), Mikardis (Boehringer Ingelheim Pharma)	Reliably prevents the development of acute disorders of cerebral circulation and acute disorders of coronary blood flow (myocardial infarction), has a pronounced nephroprotective effect

Before starting the use of such drugs, be sure to consult a doctor.

It remains to investigate the effect of only two chemicals in the blood, which can be suspected of being able to play the role of humoral sources of hypertension. These are angiotensin II and vasopressin.

In recent years, angiotensin II, without the necessary justification, has been made a kind of scarecrow. It is believed that this substance directly leads to the onset of hypertension. Scientists do not take into account that vasoconstriction does not determine the development of hypertension. Such an erroneous view leads experts to even neglect the fact that anti-giotensin drugs have the most harmful side effects.

“Angiotensin is endowed with physiological properties. The most pronounced of them are cardiostimulating and vasoconstrictor actions, exceeding the effect of norepinephrine by more than 50 times ”(A.D. Nozdrachev).

This is an important warning. It is necessary to be extremely careful about any changes in the concentration of angiotensin II in the blood. Of course, this does not mean that with the appearance of negligible amounts of excess angiotensin II in the blood, blood pressure will rise to 500 mm Hg. Art., and heart rate - up to 350 contractions per minute.

We find very important information about angiotensin II in the book by M. D. Mashkovsky "Medicines". The author reports that angiotensin II constricts blood vessels, especially precapillary arterioles, and causes a strong and rapid increase in blood pressure (by the strength of the pressor action, angiotensin II is about 40 times more active than norepinephrine).

“Under the influence of angiotensin II, the vessels of the skin and the area innervated by the celiac nerve narrow especially strongly. Blood circulation in skeletal muscles and coronary vessels does not change significantly. The drug does not have a direct effect on the heart and does not cause arrhythmias in therapeutic doses.

"The drug does not have a direct effect on the heart." This makes it possible to deny the cardiostimulatory effect of angiotensin II on the systolic output of the heart, and, consequently, on the pulse pressure.

Above, in Chapter 10, A. D. Nozdrachev’s words were quoted that angiotensin II does not cause the release of blood from the depot, and this is explained by the presence of angiotensin-sensitive receptors only in precapillary arterioles. However, there is no pulse pressure of blood in the arterioles, there is only a minimum arterial pressure. This finally excludes the effect of angiotensin II on pulse arterial pressure and systolic output of the heart, that is, on the development of hypertension..

We will consider possible cases of maintaining pulse pressure in arterioles separately.

The reference to the vasoconstrictor (vasoconstrictor) effect of angiotensin II is certainly true.

A. D. Nozdrachev:

“The strongest vasoconstrictive effect of angiotensin is manifested in the internal organs and skin, and the vessels of the skeletal muscles, brain, and heart are less sensitive; they almost do not react to the vessels of the lungs.

Yes, the chemical vasoconstrictor action of angiotensin is impressive (50 times stronger than norepinephrine!). However, this does not give any reason to declare angiotensin II to be the culprit in the development of hypertension. An increase in the concentration of angiotensin II in the blood only affects the value of the minimum blood pressure, and, as will be shown below, in the direction of its decrease!

The possibility of the influence of angiotensin II on the development of hypertension seems to be excluded. It would be possible to stop at this, if not for the question: how does antiangiotensin drugs briefly reduce blood pressure in hypertensive patients?

To answer this question, it is necessary to touch upon a whole layer of phenomena that have not found an explanation in medicine.

The pronounced effect of angiotensin II on the cardiovascular system cannot be a direct vasoconstriction, it manifests itself by affecting the kidneys!

A. D. Nozdrachev:

“Its (angiotensin P. - M. Zh.) effect on the kidneys is especially pronounced, which is expressed in a decrease in renal hemodynamics, a violation of glomerular filtration and an indirect effect of aldosterone as a regulator of tubular filtration and water-electrolyte balance. Pronounced ganglion-stimulating effects were noted.

... Angiotensin II affects vascular tone, the rate of Na reabsorption by tubular cells, it is an important physiological stimulator of aldosterone secretion by the cells of the adrenal cortex. Angiotensin II is very rapidly inactivated in the blood by angiotensinases.

I emphasize that angiotensin II, unlike adrenaline, does not cause the release of blood from the depot. But its main feature, the meaning of existence is a decrease in blood flow in the kidneys!

Angiotensin II becomes an extremely active octopeptide only after two transformations of the completely harmless serum angiotensinogen beta-globulin. The first of these conversions requires the renal proteolytic enzyme renin, which converts angiotensinogen to inactive angiotensin I. Another enzyme, peptidase, converts angiotensin I to angiotensin II.

So, for the production of angiotensin II, renal renin is required. This gave grounds to talk about the renin-angiotensin system. The renal enzyme renin plays a very important role in it.

“Many different factors have been described that affect the rate of renin secretion. One of the stimuli is an increase in the concentration of NaCl in the distal tubule.

Another important stimulus is the stimulation of stretch receptors localized in the wall of the afferent (bringing. - M. Zh.) arteriole. A decrease in its blood supply activates the release of renin. The homeostatic significance of both reactions is obvious - the decrease in glomerular filtration caused by renin secretion will lead to the preservation of circulating volume and prevent the kidney from losing excess sodium salts ”(A.D. Nozdrachev).

What is the mechanism of action of angiotensin II on vascular tone and minimal blood pressure in hypertension?

Any increase in blood pressure inevitably automatically causes an increase in the blood supply to the afferent (bringing) arterioles of the kidneys, as a result, the secretion of renin by the kidneys decreases. This causes a decrease in the concentration of angiotensin in the blood. The reninangiotensin system in this case lowers the minimum blood pressure!

To increase the concentration of angiotensin II in the blood, a preliminary increase in the secretion of renin by the kidneys is necessary. This is possible only with a decrease in blood pressure in the arterioles. At the same time, an increase in the concentration of angiotensin II will reduce glomerular filtration in the kidneys and preserve the circulating blood volume, which will lead to the restoration of blood pressure in the arterioles of the kidneys and reduce the concentration of renin, and then angiotensin in the blood.

In this way, The renin-angiotensin system is designed to control the excretory function of the kidneys, ensure their ability to rid the body of excess water and sodium and, at the same time, maintain the necessary amount of these vital substances in the body. The activity of the reninangiotensin system is not aimed at increasing blood pressure.

According to the pressor effect on blood vessels under experimental conditions, angiotensin II is 50 times greater than the main regulator of vascular tone - norepinephrine. Such a powerful "club", which tones the blood vessels, could do a lot of trouble in a living organism. But evolution protected man: on the way of converting angiotensinogen to angiotensin II, nature put a double barrier in the form of renin and peptidase enzymes. The concentration of angiotensin II in the blood is especially carefully controlled by a rigid negative feedback of the concentration of renin with blood pressure.

So, the renin-angiotensin system does not even affect the minimum blood pressure, not to mention the pulse difference. Nevertheless, this system is almost always involved in the development of hypertension!

Researchers have not yet found a correct explanation for this phenomenon. The most paradoxical fact is the increased concentration of renin and angiotensin II in almost all hypertensive patients. It would seem that elevated blood pressure should lead to a decrease in the concentration of angiotensin and renin II in the blood. We will consider this completely puzzling problem in a separate chapter.

One hundred percent misunderstanding of the essence of the processes, of course, is accompanied by erroneous and primitive actions. Antiangiotensin drugs have been developed. These drugs reduce the level of angiotensin II in the blood, that is, they cause additional pathology without affecting the cause of hypertension. Artificially increases the hemodynamics of the kidneys and increases the excretion of urine.

The harm is such that surgery is often required to restore kidney function.

It must be remembered that the action antiangiotensin drugs (saralazine, captopril, capoten, tetrotide and the like) similar to the action of the worst diuretics.

It is known that diuretics reduce pulse pressure for a short time. But what is the mechanism of this action? And this question turned out to be a mystery for modern medicine. Later we will return to it, but for now we can say that the use of diuretics has nothing to do with the cure of hypertension. If a jug of wine is heavy, no one punches holes in it. The use of diuretics for hypertension is tantamount to punching holes in a jug. In the time of Catherine II, blood was opened, now diuretics are used or, due to monstrous incompetence, leeches are used.

It remains to consider the hypertensive role of vasopressin. An increased amount of this hormone in the blood enhances the reabsorption of water from urine that has entered the collecting ducts of the kidneys. The volume of urine decreases, the concentration of salts in the urine increases. At the same time, salts are excreted with a relatively small amount of urine, the body gets rid of salts, while maintaining the required amount of water. With the intake of excess water, the secretion of vasopressin (antidiuretic hormone) decreases, diuresis increases and the body is freed from excess water.

For more information about vasopressin, we turn to authoritative sources.

"Clinical Endocrinology" (edited by N. T. Starkova, 1991):

“Vasopressin and oxytocin accumulate in the posterior pituitary gland. The hormones under consideration exhibit a variety of biological effects: they stimulate the transport of water and salts through membranes, have a vasopressor effect, increase contractions of the smooth muscles of the uterus during childbirth, and increase the secretion of the mammary glands.

It should be noted that vasopressin has a higher antidiuretic activity than oxytocin, and the latter has a stronger effect on the uterus and mammary gland. The main regulator of vasopressin secretion is water intake.

"Biological Chemistry" (M. V. Ermolaev, 1989):

“The regulation of water-salt metabolism is carried out under the control of the nervous system and other factors, including hormones. Thus, vasopressin (hormone of the posterior pituitary gland) has an antidiuretic effect, that is, it promotes the reabsorption of water in the kidneys. Therefore, in the clinic it is often called antidiuretic hormone (ADH).

The secretion of vasopressin is controlled by the magnitude of osmotic pressure, the increase of which enhances the production of the hormone. As a result, water reabsorption in the kidneys increases, the concentration of osmotically active substances in the blood decreases, and blood pressure normalizes. In this case, a small amount of highly concentrated urine is excreted.

“Antidiuretic hormone (vasopressin) and oxytocin are synthesized in the nuclei of the hypothalamus, enter the posterior pituitary via nerve fibers and are deposited here. Deficiency of antidiuretic hormone or hypofunction of the posterior lobe leads to the so-called diabetes insipidus. At the same time, there is a release of very large quantities of urine that does not contain sugar, and intense thirst. The introduction of the hormone to patients normalizes urine output. The mechanism of action of antidiuretic hormone is to increase the reabsorption of water by the walls of the collecting ducts of the kidneys. Oxytocin stimulates uterine smooth muscle contraction at the end of pregnancy.”

"Bioorganic Chemistry" (N. Tyukavkina, Yu. Baukov, 1991):

“In 1933, V. Du Vignot established the structure of two hormones - oxytocin and vasopressin, secreted by the posterior pituitary gland. Oxytocin is found in females. Vasopressin is found in both female and male organisms. It regulates mineral metabolism and fluid balance (antidiuretic hormone). It has been established that vasopressin is one of the most powerful memory stimulants.

So, the main regulator of vasopressin secretion is water intake. In this case, vasopressin acts in the body in the same direction as angiotensin II. The combined action of angiotensin II and vasopressin is sometimes considered as the influence of the pressor macrosystem, which supposedly can participate in the development of hypertension. Such a macrosystem is not directly related to an increase in pulse blood pressure and the development of hypertension. It is regrettable that this error occurs in the work of Academician I. K. Shkhvatsabay (“Hypertension Markers”, 1982). Another misconception: he believes that antidiuretic hormone and vasopressin are two different hormones. We read in his article:

“The excretory function of the kidneys, their ability to rid the body of water and sodium, depends on the renin-angiotensin system. The vasopressor system, through the antidiuretic hormone, slows down the excretion of water, sodium and vasopressin by the kidneys, which stimulates the reduction of the lumen of peripheral vessels. The activity of all these and some other links of neurohormonal regulation, which together make up the so-called pressor macrosystem, is aimed at increasing blood pressure.

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

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

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

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

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

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

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

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

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

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

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

Mechanism hypotensive action angiotensin II receptor antagonists is to eliminate vasoconstriction caused by angiotensin II, reduce the tone of the sympathetic-adrenal system, increase sodium excretion. Almost all drugs in this group show a hypotensive effect when taken 1p / day and allow you to control blood pressure for 24 hours.

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

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

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

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

Antiproliferative action angiotensin II receptor antagonists causes organoprotective (cardio- and renoprotective) effects of these drugs.

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

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

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

• With the appointment of angiotensin II receptor antagonists, a more pronounced elimination of the biological effects of angiotensin II in tissues is observed than with the use of ACE inhibitors.
• The stimulatory effect of angiotensin II on angiotensin II receptors enhances the vasodilating and antiproliferative effects of angiotensin II receptor antagonists.
• From the side of angiotensin II receptor antagonists, there is a milder effect on renal hemodynamics than against the background of the use of ACE inhibitors.
• When prescribing angiotensin II receptor antagonists, there are no undesirable effects associated with the activation of the kinin system.

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

Renoprotective effects of angiotensin II receptor antagonists are observed when they are used in lower doses than doses that give a hypotensive effect. This may be of additional clinical importance in patients with severe chronic renal failure or heart failure.

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

Compliance with a diet low in sodium chloride potentiates the renal and neurohumoral effects of angiotensin II receptor antagonists: aldosterone levels decrease more significantly, plasma renin levels increase, and natriuresis is stimulated against the background of an unchanged glomerular filtration rate. With an increased intake of salt in the body, these effects weaken.

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

Depending on lipophilicity, the volume of distribution of angiotensin II receptor antagonists changes. In telmisartan, this figure is the highest.

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

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

After ingestion of drugs of angiotensin II receptor antagonists, the maximum concentrations of these drugs in the blood are reached after 2 hours. With long-term regular use, stationary, or equilibrium, concentration is established after 5-7 days.

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

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

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

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

Pharmacokinetic parameters of angiotensin II receptor antagonists

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

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

Tangiotensin is a hormone produced by the kidneys, its action is aimed at vasoconstriction. With its increased concentration, blood pressure may rise. In this case, drugs that block the action of the hormone will be effective.

General information

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

Among the positive properties of drugs, it can also be noted that they have a beneficial effect on the prognosis of a patient suffering from hypertension, are able to protect the brain, kidneys and heart from damage.

The most common groups of drugs:

• sartans;
• angiotensin receptor antagonists;
• angiotensin receptor blockers.

Research on these drugs is currently only in its infancy and will continue for at least another 4 years. There are some contraindications to the use of angiotensin II receptor blockers.

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

Classification of drugs

Angiotensin receptor blockers can be divided into 4 groups according to their chemical components:

• Telmisartan. Nebifinil derivative of tetrazole.
• Eprosartan. Non-biphenyl netetrazole.
• Valsartan. Non-cyclic connection.
• Losartan, Candesartan, Irbesartan. This group belongs to biphenyl derivatives of tetrazole.

There are many trade names for sartans. Some of them are shown in the table:

How do blockers work?

During the time when blood pressure begins to drop in the kidneys, against the background of hypoxia (lack of oxygen), renin is produced. It affects inactive angiotensinogen, which is transformed into angiotensin 1. It is affected by an angiotensin-converting enzyme, which is converted to angiotensin 2 form.

Entering into communication with receptors, angiotensin 2 dramatically increases blood pressure. ARA act on these receptors, which is why the pressure decreases.

Angiotensin receptor blockers not only fight hypertension, but also have the following effect:

• reduction of left ventricular hypertrophy;
• reduction of ventricular arrhythmia;
• decrease in insulin resistance;
• improvement of diastolic function;
• reduction of microalbuminuria (protein excretion in the urine);
• improving kidney function in patients with diabetic nephropathy;
• improvement of blood circulation (with 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, ARA may contain active metabolites in its composition. In some drugs, the active metabolites last longer than the drugs themselves.

Indications for use

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

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

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

• myocardial infarction;
• diabetic nephropathy;
• metabolic syndrome;
• atrial fibrillation;
• intolerance to ACE inhibitors.

Additional effects

Among the actions of angiotensin 2 receptor blockers, there is also a reduced level of low-density lipoprotein cholesterol and total cholesterol, improving lipid metabolism. Also, these drugs reduce the level of uric acid in the blood.

Sartans have the following additional clinical effects:

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

Side effects from taking blockers

Angiotensin II receptor blockers are well tolerated by the patient's body. In principle, these drugs do not have specific side effects, unlike other groups of drugs with a similar effect, but 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:

• pain in the muscles;
• pain in the joints;
• increase in body temperature;
• manifestation of symptoms of SARS (runny nose, cough, sore throat).

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

Application features

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

Angiotensin 2 blockers may differ in their spectrum of action.

Features of taking Losartan

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 water 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, lowering blood pressure, the dosage of the drug should be reduced.
• In patients with hepatic and renal insufficiency, the drug is prescribed with caution and in small doses.

Contraindications to taking Valsartan

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 can harm.

Caution should be exercised in the use of the drug in patients who have such pathologies:

• Obstruction of the biliary tract. The drug is excreted from the body with bile, so patients who have abnormalities in the functioning of this organ are not recommended to use valsartan.
• Renovascular hypertension. In patients with this diagnosis, it is necessary to control the level of urea in the blood serum, as well as creatinine.
• Imbalance of water-salt metabolism. In this case, the correction of this violation is required without fail.

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

With caution, you should take the drug during work that requires maximum concentration.

Appointment of Ibersartan

The action of the drug is aimed at:

• reducing the load on the heart;
• elimination of the vasoconstrictive action of angiotensin 2;
• decrease .

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 involves daily intake at the same time. If you miss a dose, doubling the dose is strongly discouraged.

Adverse reactions when taking Ibersartan:

• headache;
• nausea;
• dizziness;
• weakness.

The effectiveness of Eprosartan

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

Eprosartan has the following side effects:

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

Adverse reactions, as a rule, are of a short-term nature and do not require dose adjustment or complete discontinuation of the drug.

Features of taking Telmisartan

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

Telmisartan is contraindicated in patients with:

• primary aldosteronism;
• severe violations of the liver and kidneys.

Do not prescribe the drug during pregnancy and lactation, as well as 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 the application can be achieved after a month of regular use of the drug. Therefore, it is important not to adjust the dosage on your own in the first weeks of admission.

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