Functions of angiotensin in the human body. Angiotensin II receptor antagonists
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 practically do not have 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.
Studies of these drugs 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 II receptor blockers.
The use of drugs is unacceptable during pregnancy and during lactation, with hyperkalemia, as well as in patients with a severe form kidney failure and bilateral stenosis 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 on 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.
V 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 you experience side effects such as headache, dizziness, decreased blood pressure the dosage of the drug must be reduced.
- In patients with hepatic and renal insufficiency, the drug is prescribed with caution and in small doses.
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 biliary tract. The drug is excreted from the body with bile, so patients who have disorders 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 systematically returns to its original value.
Ibersartan does not prevent the development of atherosclerosis, unlike most angiotensin receptor antagonists, since it does not affect lipid metabolism.
Important! The drug suggests 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 with diabetes 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.
Subgroup drugs excluded. Turn on
Description
Angiotensin II receptor antagonists, or AT 1 receptor blockers, are one of the new groups of antihypertensive drugs. It combines drugs that modulate the functioning of the renin-angiotensin-aldosterone system (RAAS) through interaction with angiotensin receptors.
RAAS plays an important role in the regulation of blood pressure, the pathogenesis of arterial hypertension and chronic heart failure (CHF), as well as a number of other diseases. Angiotensins (from angio- vascular and tensio- tension) - peptides formed in the body from angiotensinogen, which is a glycoprotein (alpha 2-globulin) of blood plasma, synthesized in the liver. Under the influence of renin (an enzyme formed in the juxtaglomerular apparatus of the kidneys), the angiotensinogen polypeptide, which does not have pressor activity, is hydrolyzed, forming angiotensin I, a biologically inactive decapeptide that is easily subjected to further transformations. Under the action of angiotensin-converting enzyme (ACE), which is formed in the lungs, angiotensin I is converted into an octapeptide - angiotensin II, which is a highly active endogenous pressor compound.
Angiotensin II is the main effector peptide of the RAAS. It has a strong vasoconstrictor effect, increases OPSS, causes a rapid increase in blood pressure. In addition, it stimulates the secretion of aldosterone, and in high concentrations it increases the secretion of antidiuretic hormone (increased reabsorption of sodium and water, hypervolemia) and causes sympathetic activation. All these effects contribute to the development of hypertension.
Angiotensin II is rapidly metabolized (half-life - 12 minutes) with the participation of aminopeptidase A with the formation of angiotensin III and then under the influence of aminopeptidase N - angiotensin IV, which have biological activity. Angiotensin III stimulates the production of aldosterone by the adrenal glands, has a positive inotropic activity. Angiotensin IV is thought to be involved in the regulation of hemostasis.
It is known that in addition to the RAAS of the systemic circulation, the activation of which leads to short-term effects (including such as vasoconstriction, increased blood pressure, aldosterone secretion), there are local (tissue) RAAS in various bodies 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 as myocardial hypertrophy, myofibrosis, atherosclerotic damage to cerebral vessels, kidney damage, etc.
It has now been shown that in humans, in addition to the ACE-dependent pathway of converting angiotensin I to angiotensin II, there are alternative pathways involving chymases, cathepsin G, tonin, and other serine proteases. Chymases, or chymotrypsin-like proteases, are glycoproteins with a molecular weight of about 30,000. Chymases have a high specificity for angiotensin I. In various organs and tissues, either ACE-dependent or alternative pathways for the formation of angiotensin II predominate. Thus, cardiac serine protease, its DNA and mRNA were found in human myocardial tissue. The largest amount of this enzyme is found in the myocardium of the left ventricle, where the chymase pathway accounts for more than 80%. Chymase-dependent formation of angiotensin II prevails in the myocardial interstitium, adventitia, and vascular media, while ACE-dependent formation occurs in blood plasma.
Angiotensin II can also be formed directly from angiotensinogen by reactions catalyzed by tissue plasminogen activator, tonin, cathepsin G, etc.
It is believed that the activation of alternative pathways for the formation of angiotensin II plays an important role in the processes of cardiovascular remodeling.
The physiological effects of angiotensin II, like other biologically active angiotensins, are realized at the cellular level through specific angiotensin receptors.
To date, the existence of several subtypes of angiotensin receptors has been established: AT 1, AT 2, AT 3 and AT 4, etc.
In humans, two subtypes of membrane-bound, G-protein-coupled angiotensin II receptors, the AT 1 and AT 2 subtypes, have been identified and most thoroughly studied.
AT 1 receptors are localized in various organs and tissues, mainly in vascular smooth muscle, heart, liver, adrenal cortex, kidneys, lungs, and in some areas of the brain.
Most of the physiological effects of angiotensin II, including adverse ones, are mediated by AT 1 receptors:
Arterial vasoconstriction, incl. vasoconstriction of the arterioles of the renal glomeruli (especially the efferent ones), increased hydraulic pressure in the renal glomeruli,
Increased sodium reabsorption in the proximal renal tubules,
Secretion of aldosterone by the adrenal cortex
Secretion of vasopressin, endothelin-1,
renin release,
Increased release of norepinephrine from sympathetic nerve endings, activation of the sympathetic-adrenal system,
Proliferation of vascular smooth muscle cells, intimal hyperplasia, cardiomyocyte hypertrophy, stimulation of vascular and heart remodeling processes.
In arterial hypertension against the background of excessive activation of the RAAS, the effects of angiotensin II mediated by AT 1 receptors directly or indirectly contribute to an increase in blood pressure. In addition, stimulation of these receptors is accompanied by a damaging effect of angiotensin II on cardiovascular system, including the development of myocardial hypertrophy, thickening of the walls of arteries, etc.
The effects of angiotensin II mediated by AT 2 receptors have only been discovered in recent years.
A large number of AT 2 receptors found in the tissues of the fetus (including in the brain). In the postnatal period, the number of AT 2 receptors in human tissues decreases. Experimental studies, in particular in mice in which the gene encoding AT 2 receptors has been destroyed, suggest their participation in the processes of growth and maturation, including cell proliferation and differentiation, development of embryonic tissues, and the formation of exploratory behavior.
AT 2 receptors are found in the heart, blood vessels, adrenal glands, kidneys, some areas of the brain, reproductive organs, incl. in the uterus, atrezirovannyh ovarian follicles, as well as in skin wounds. It has been shown that the number of AT 2 receptors can increase with tissue damage (including blood vessels), myocardial infarction, and heart failure. It is suggested that these receptors may be involved in the processes of tissue regeneration and programmed cell death (apoptosis).
Recent studies show that the cardiovascular effects of angiotensin II, mediated by AT 2 receptors, are opposite to those caused by excitation of AT 1 receptors, and are relatively mild. Stimulation of AT 2 receptors is accompanied by vasodilation, inhibition of cell growth, incl. suppression of cell proliferation (endothelial and smooth muscle cells of the vascular wall, fibroblasts, etc.), inhibition of cardiomyocyte hypertrophy.
The physiological role of angiotensin II type II receptors (AT 2) in humans and their relationship with cardiovascular homeostasis is currently not fully understood.
Highly selective AT 2 receptor antagonists (CGP 42112A, PD 123177, PD 123319) have been synthesized, which are used in experimental studies of RAAS.
Other angiotensin receptors and their role in humans and animals have been little studied.
Subtypes of AT 1 receptors, AT 1a and AT 1b, were isolated from the cell culture of rat mesangium, differing in their affinity for angiotensin II peptide agonists (these subtypes were not found in humans). The AT 1c receptor subtype has been isolated from the placenta of rats, the physiological role of which is not yet clear.
AT 3 receptors with affinity for angiotensin II are found on neuronal membranes, their function is unknown. AT 4 receptors are found on endothelial cells. Interacting with these receptors, angiotensin IV stimulates the release of a type 1 plasminogen activator inhibitor from the endothelium. AT 4 receptors are also found on the membranes of neurons, incl. in the hypothalamus, presumably in the brain, they mediate cognitive functions. In addition to angiotensin IV, angiotensin III also has a tropism for AT 4 receptors.
Long-term studies of the RAAS have not only revealed the importance of this system in the regulation of homeostasis, in the development of cardiovascular pathology, and influencing the functions of target organs, among which the most important are the heart, blood vessels, kidneys and brain, but also led to the creation medicines, purposefully acting on individual parts of the RAAS.
The scientific basis for the creation of drugs that act by blocking angiotensin receptors was the study of angiotensin II inhibitors. Experimental studies show that angiotensin II antagonists that can block its formation or action and thus reduce the activity of RAAS are angiotensinogen formation inhibitors, renin synthesis inhibitors, ACE formation or activity inhibitors, antibodies, angiotensin receptor antagonists, including synthetic non-peptide compounds, specifically blocking AT 1 receptors, etc.
The first angiotensin II receptor blocker introduced into therapeutic practice in 1971 was saralazine, a peptide compound similar in structure to angiotensin II. Saralazin blocked the pressor action of angiotensin II and lowered the tone of peripheral vessels, reduced the content of aldosterone in plasma, lowered blood pressure. However, by the mid-70s, experience with the use of saralazine showed that it has the properties of a partial agonist and in some cases gives a poorly predicted effect (in the form of excessive hypotension or hypertension). At the same time, a good hypotensive effect was manifested in conditions associated with a high level of renin, while against the background of a low level of angiotensin II or with a rapid injection of blood pressure increased. Due to the presence of agonistic properties, as well as due to the complexity of the synthesis and the need for parenteral administration, saralazine has not received wide practical application.
In the early 1990s, the first non-peptide selective AT 1 receptor antagonist effective when taken orally, losartan, was synthesized, which received practical application as an antihypertensive agent.
Currently, several synthetic non-peptide selective AT 1 blockers are being used or undergoing clinical trials in world medical practice - valsartan, irbesartan, candesartan, losartan, telmisartan, eprosartan, olmesartan medoxomil, azilsartan medoxomil, zolarsartan, tazosartan (zolarsartan and tazosartan are not yet registered in Russia).
There are several classifications of angiotensin II receptor antagonists: by chemical structure, pharmacokinetic features, mechanism of binding to receptors, etc.
According to the chemical structure, non-peptide blockers of AT 1 receptors can be divided into 3 main groups:
Biphenyl derivatives of tetrazole: losartan, irbesartan, candesartan, valsartan, tazosartan;
Biphenyl netetrazole compounds - telmisartan;
Non-biphenyl netetrazole compounds - eprosartan.
By the presence of pharmacological activity, AT 1 receptor blockers are divided into active dosage forms and prodrugs. So, valsartan, irbesartan, telmisartan, eprosartan themselves have pharmacological activity, while candesartan cilexetil becomes active only after metabolic transformations in the liver.
In addition, AT 1 blockers differ depending on the presence or absence of active metabolites in them. Active metabolites are found in losartan and tazosartan. For example, the active metabolite of losartan, EXP-3174, has a stronger and longer-lasting effect than losartan (in terms of pharmacological activity, EXP-3174 exceeds losartan by 10-40 times).
According to the mechanism of binding to receptors, AT 1 receptor blockers (as well as their active metabolites) are divided into competitive and non-competitive angiotensin II antagonists. Thus, losartan and eprosartan bind reversibly to AT 1 receptors and are competitive antagonists (i.e., under certain conditions, for example, with an increase in the level of angiotensin II in response to a decrease in BCC, they can be displaced from binding sites), while valsartan, irbesartan , candesartan, telmisartan, and the active metabolite of losartan EXP-3174 act as non-competitive antagonists and bind irreversibly to the receptors.
The pharmacological action of this group of drugs is due to the elimination of the cardiovascular effects of angiotensin II, incl. vasopressor.
It is believed that the antihypertensive effect and other pharmacological effects of angiotensin II receptor antagonists are realized in several ways (one direct and several indirect).
The main mechanism of action of drugs in this group is associated with the blockade of AT 1 receptors. All of them are highly selective AT1 receptor antagonists. It has been shown that their affinity for AT 1 - exceeds that for AT 2 receptors thousands of times: for losartan and eprosartan more than 1 thousand times, for telmisartan - more than 3 thousand, for irbesartan - 8.5 thousand, for the active metabolite of losartan EXP-3174 and candesartan - 10 thousand times, olmesartan - 12.5 thousand times, valsartan - 20 thousand times.
Blockade of AT 1 receptors prevents the development of the effects of angiotensin II mediated by these receptors, which prevents the adverse effect of angiotensin II on vascular tone and is accompanied by a decrease in elevated blood pressure. Long-term use of these drugs leads to a weakening of the proliferative effects of angiotensin II in relation to vascular smooth muscle cells, mesangial cells, fibroblasts, a decrease in cardiomyocyte hypertrophy, etc.
It is known that AT 1 receptors in the cells of the juxtaglomerular apparatus of the kidneys are involved in the regulation of renin release (by the principle of negative feedback). Blockade of AT 1 receptors causes a compensatory increase in renin activity, an increase in the production of angiotensin I, angiotensin II, etc.
Under conditions of an increased content of angiotensin II against the background of blockade of AT 1 receptors, the protective properties of this peptide are manifested, which are realized through stimulation of AT 2 receptors and are expressed in vasodilation, slowing down of proliferative processes, etc.
In addition, against the background of an increased level of angiotensins I and II, angiotensin-(1-7) is formed. Angiotensin-(1-7) is formed from angiotensin I under the action of neutral endopeptidase and from angiotensin II under the action of prolyl endopeptidase and is another RAAS effector peptide that has vasodilatory and natriuretic effects. The effects of angiotensin-(1-7) are mediated through so-called, not yet identified, AT x receptors.
Recent studies of endothelial dysfunction in hypertension suggest that the cardiovascular effects of angiotensin receptor blockers may also be related to endothelial modulation and effects on nitric oxide (NO) production. The obtained experimental data and the results of individual clinical studies are rather contradictory. Perhaps, against the background of blockade of AT 1 receptors, endothelium-dependent synthesis and release of nitric oxide increase, which contributes to vasodilation, a decrease in platelet aggregation and a decrease in cell proliferation.
Thus, the specific blockade of AT 1 receptors allows for a pronounced antihypertensive and organoprotective effect. Against the background of the blockade of AT 1 receptors, the adverse effect of angiotensin II (and angiotensin III, which has affinity for angiotensin II receptors) on the cardiovascular system is inhibited and, presumably, its protective effect is manifested (by stimulating AT 2 receptors), and the action also develops. angiotensin-(1-7) by stimulating AT x receptors. All these effects contribute to vasodilation and weakening of the proliferative action of angiotensin II in relation to vascular and heart cells.
Antagonists of AT 1 receptors can penetrate the blood-brain barrier and inhibit the activity of mediator processes in the sympathetic nervous system. By blocking presynaptic AT 1 receptors of sympathetic neurons in the CNS, they inhibit the release of norepinephrine and reduce stimulation of adrenoceptors of vascular smooth muscles, which leads to vasodilation. Experimental studies show that this additional mechanism of vasodilatory action is more characteristic of eprosartan. Data on the effect of losartan, irbesartan, valsartan, etc. on the sympathetic nervous system (which manifested itself at doses exceeding therapeutic ones) are very contradictory.
All AT 1 receptor blockers act gradually, the antihypertensive effect develops smoothly, within a few hours after taking a single dose, and lasts up to 24 hours. With regular use, a pronounced therapeutic effect is usually achieved after 2-4 weeks (up to 6 weeks) of treatment.
The pharmacokinetic features of this group of drugs make it convenient for patients to use them. These medicines can be taken with or without food. A single dose is enough to provide a good hypotensive effect during the day. They are equally effective in patients of different sex and age, including patients over 65 years of age.
Clinical studies show that all angiotensin receptor blockers have a high antihypertensive and pronounced organoprotective effect, good tolerance. This allows them to be used, along with other antihypertensive drugs, for the treatment of patients with cardiovascular pathology.
The main indication for the clinical use of angiotensin II receptor blockers is the treatment of arterial hypertension of varying severity. Possible monotherapy (for mild arterial hypertension) or in combination with other antihypertensive drugs (for moderate and severe forms).
Currently, according to the recommendations of the WHO / IOH (International Society for Hypertension), preference is given to combination therapy. The most rational for angiotensin II receptor antagonists is their combination with thiazide diuretics. The addition of a low-dose diuretic (eg, 12.5 mg hydrochlorothiazide) can improve the effectiveness of therapy, as evidenced by the results of randomized multicenter trials. Preparations have been created that include this combination - Gizaar (losartan + hydrochlorothiazide), Co-diovan (valsartan + hydrochlorothiazide), Coaprovel (irbesartan + hydrochlorothiazide), Atakand Plus (candesartan + hydrochlorothiazide), Micardis Plus (telmisartan + hydrochlorothiazide), etc. .
A number of multicenter studies (ELITE, ELITE II, Val-HeFT, etc.) have shown the effectiveness of some AT 1 receptor antagonists in CHF. The results of these studies are mixed, but in general they indicate high efficacy and better (compared with ACE inhibitors) tolerability.
The results of experimental and clinical studies indicate that AT 1 -subtype receptor blockers not only prevent the processes of cardiovascular remodeling, but also cause the regression of left ventricular hypertrophy (LVH). In particular, it was shown that during long-term therapy with losartan, patients showed a tendency to a decrease in the size of the left ventricle in systole and diastole, an increase in myocardial contractility. LVH regression has been noted with long-term use of valsartan and eprosartan in patients arterial hypertension. Some AT 1 subtype receptor blockers have been found to improve renal function, incl. with diabetic nephropathy, as well as indicators of central hemodynamics in CHF. So far, clinical observations regarding the effect of these drugs on target organs are few, but research in this area is actively ongoing.
Contraindications to the use of angiotensin AT 1 receptor blockers are individual hypersensitivity, pregnancy, breastfeeding.
Animal data suggest that agents that act directly on the RAAS may cause fetal injury, fetal and neonatal death. Especially dangerous is the effect on the fetus in the II and III trimesters of pregnancy, because. possible development of hypotension, hypoplasia of the skull, anuria, renal failure and lethal outcome at the fetus. There are no direct indications of the development of such defects when taking AT 1 receptor blockers, however, the funds of this group should not be used during pregnancy, and if pregnancy is detected during the treatment period, they must be stopped.
There is no information on the ability of AT 1 receptor blockers to penetrate into breast milk women. However, in experiments on animals, it was found that they penetrate into the milk of lactating rats (in the milk of rats, significant concentrations of not only the substances themselves, but also their active metabolites) are found. In this regard, AT 1 receptor blockers are not used in lactating women, and if therapy is necessary for the mother, breastfeeding is stopped.
Pediatric use of these medicinal products should be avoided as their safety and efficacy in children have not been determined.
For therapy with AT 1 angiotensin receptor antagonists, there are a number of limitations. Caution should be exercised in patients with reduced BCC and / or hyponatremia (during treatment with diuretics, limiting salt intake with diet, diarrhea, vomiting), as well as in patients on hemodialysis, tk. possible development of symptomatic hypotension. An assessment of the risk / benefit ratio is necessary in patients with renovascular hypertension due to bilateral renal artery stenosis or renal artery stenosis of a single kidney, because. excessive inhibition of the RAAS in these cases increases the risk of severe hypotension and renal failure. Caution should be used in aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy. Against the background of impaired renal function, it is necessary to monitor the levels of potassium and serum creatinine. Not recommended for patients with primary hyperaldosteronism, tk. in this case, drugs that inhibit the RAAS are ineffective. There are no sufficient data on the use in patients with severe liver disease (eg, cirrhosis).
Side effects reported so far with angiotensin II receptor antagonists are usually mild, transient, and rarely warrant discontinuation of therapy. The overall frequency of side effects is comparable to placebo, as evidenced by the results of placebo-controlled studies. The most common adverse effects are headache, dizziness, general weakness, etc. Angiotensin receptor antagonists do not directly affect the metabolism of bradykinin, substance P, and other peptides and, as a result, do not cause dry cough, which often occurs during treatment with ACE inhibitors.
When taking drugs in this group, there is no effect of hypotension of the first dose, which occurs when taking ACE inhibitors, and sudden withdrawal is not accompanied by the development of rebound hypertension.
The results of multicenter placebo-controlled studies show high efficacy and good tolerability of angiotensin II AT 1 receptor antagonists. However, so far their use is limited by the lack of data on long-term effects of use. According to WHO / MOH experts, their use for the treatment of arterial hypertension is advisable in case of intolerance to ACE inhibitors, in particular, in the case of a history of cough caused by ACE inhibitors.
There are currently numerous clinical researches, incl. and multicenter, devoted to the study of the efficacy and safety of the use of angiotensin II receptor antagonists, their impact on mortality, duration and quality of life of patients and comparison with antihypertensive and other drugs in the treatment of arterial hypertension, chronic heart failure, atherosclerosis, etc.
Preparations
Preparations - 4133 ; Trade names - 84 ; Active ingredients - 9
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For citation: Sidorenko B.A., Preobrazhensky D.V., Zaikina N.V. PHARMACOTHERAPY OF HYPERTENSION. Part VI. Type I angiotensin receptor blockers as antihypertensive drugs // RMJ. 1998. No. 24. S. 4
The physiology of the renin-angiotensin system and the role of its increased activity in pathogenesis are considered. hypertension. Comparative characteristics of type I angiotensin receptor blockers are presented.
The paper considers the physiology of the renin-angiotensin system and the role of its increased activity in the pathogenesis of essential hypertension. It comparatively characterizes antihypertensive angiotensin I receptor antagonists.
B.A. Sidorenko, D.V. Preobrazhensky,
N.V. Zaikina - Medical Center of the Office of the President Russian Federation, Moscow
V. A. Sidorenko, D. V. Preobrazhensky,
N. V. Zaikina - Medical Center, Administration of Affairs of the President of the Russian Federation, Moscow
Part VI. Type I angiotensin receptor blockers as antihypertensive drugs
Increased activity of the renin-angiotensin system (RAS) in the bloodstream and tissues is known to be an important factor in the pathogenesis of hypertension (AH) and some secondary forms of arterial hypertension. High plasma renin activity, reflecting RAS hyperactivity, is a prognostically unfavorable indicator in HD. Thus, in patients with hypertension with high plasma renin activity, the risk of developing myocardial infarction is 3.8 times higher than in patients with low renin activity. The high activity of renin in the blood plasma is combined with an increase in the likelihood of developing cardiovascular complications by 2.4 times and mortality from all causes - by 2.8 times. Until recently, sympatholytic agents have been used to suppress excessive RAS activity in patients with HD centrally acting agents (reserpine), agonists of central a 2 -adrenergic receptors (methyldopa, clonidine), b-blockers (propranolol, atenolol, metoprolol, etc.) and angiotensin-converting enzyme (ACE) inhibitors. In the 1990s, a new group of highly effective antihypertensive drugs appeared, the action of which is based on the inhibition of RAS activity at the level of type I angiotensin receptors (AT 1 receptors) for angiotensin II. These drugs are called AT-1 blockers. receptors, or angiotensin II receptor antagonists.
Physiology of the renin-angiotensin system
For a better understanding of the mechanisms of antihypertensive action of AT 1 blockers receptors, it is necessary to dwell on the molecular and functional aspects of the RAS.
The main effector peptide of the RAS is angiotensin II, which is formed from inactive angiotensin I under the action of ACE and some other serine proteases. The action of angiotensin II at the cellular level is mediated by two types of membrane receptors - AT 1 and AT 2 . Almost all known physiological (cardiovascular and neuroendocrine) effects of angiotensin II are mediated by AT. 1 -receptors. For example, in GB such mediated antibodies are important 1 -receptor effects of angiotensin II, such as arterial vasoconstriction and aldosterone secretion, as well as stimulation of the proliferation of cardiomyocytes and smooth muscle cells of the vascular wall. All these effects of angiotensin II are believed to contribute to an increase in blood pressure (BP), the development of left ventricular hypertrophy and thickening of the walls of the arteries, which is accompanied by a decrease in their lumen, in patients with HD.
Table 1. Physiological effects of angiotensin II mediated by AT1 and AT2 receptors (according to C. Johnston and J. Risvanis)
| AT 1 receptors | AT 2 receptors |
| Vasoconstriction | Stimulation of apoptosis |
| Stimulation of the synthesis and secretion of aldosterone | Antiproliferative effect |
| Reabsorption of sodium in the renal tubules | Differentiation and development of embryonic tissues |
| Hypertrophy of cardiomyocytes | Growth of endothelial cells |
| Proliferation of smooth muscle cells of the vascular wall | Vasodilation |
| Increased peripheral norepinephrine activity | |
| Increased activity of the central link of the sympathetic | |
| nervous system | |
| Stimulation of vasopressin release | |
| Decreased renal blood flow | |
| Inhibition of renin secretion |
Angiotensin II effects mediated by AT 2 receptors have become known only in recent years. In hypertension, the most important physiological effects of angiotensin II (as well as angiotensin III), which are mediated by AT 2 -receptors, namely vasodilation and inhibition of cell proliferation, including cardiomyocytes, fibroblasts and smooth muscle cells of the vascular wall (Table 1). As can be seen, upon stimulation of AT 2 receptor angiotensin II partially attenuates its own effects associated with AT stimulation 1-receptors.
Scheme 1. Pathways for the formation of two main RAS effector peptides - angiotensin II and angiotensin-(I-7). Angiotensin II is further converted into angiotensin III and angiotensin IV, which have some biological activity, which is mediated, respectively, by AT 3 and AT 4 receptors (not shown in the diagram).
AT 1 -receptors on the membranes of hepatocytes and cells of the juxtaglomerular apparatus (JGA) of the kidneys mediate negative feedback mechanisms in the RAS. Therefore, under conditions of blockade of AT 1 -receptors as a result of violations of these negative feedback mechanisms, the synthesis of angiotensinogen in the liver and the secretion of renin by JGA cells of the kidneys increase. In other words, with the blockade of AT 1 receptors, reactive activation of the RAS occurs, which is manifested by an increase in the level of angiotensinogen, renin, as well as angiotensin I and angiotensin II.
Increased formation of angiotensin II in conditions of AT blockade 1 receptor leads to the fact that the effects of angiotensin II mediated by AT 2 begin to predominate -receptors. Therefore, the consequences of the blockade of AT 1-receptors are twofold. Direct effects are associated with the weakening of the pharmacological effects mediated by AT 1 -receptors. Indirect effects are the result of AT stimulation 2 receptor angiotensin II, which, under conditions of blockade of AT 1 -receptors are formed in an increased amount.
The third mechanism of antihypertensive action of AT blockers 1 -receptors is explained by increased formation in conditions of blockade of AT 1 -receptors of another RAS effector peptide - angiotensin-(I-7), which has vasodilating properties. Angiotensin-(I-7) is formed from angiotensin I by neutral endopeptidase and from angiotensin II by prolyl endopeptidase. In conditions of AT blockade 1 -receptors elevated level angiotensin I and angiotensin II in the blood predisposes to their increased conversion to angiotensin-(I-7).
Angiotensin-(I-7) has vasodilatory and natriuretic properties mediated by prostaglandins I2, kinins and nitric oxide. These effects of angiotensin-(I-7) are due to its action on yet unidentified AT receptors - ATx receptors (Scheme 1).
Thus, the mechanisms of antihypertensive action in AT blockers 1 There are three receptors - one direct and two indirect. The direct mechanism is related to the weakening of the effects of angiotensin II, which are mediated by AT 1 -receptors. Indirect mechanisms are associated with reactive activation of the RAS under conditions of AT blockade 1 -receptors, which leads to increased production of both angiotensin II and angiotensin-(I-7). Angiotensin II has an antihypertensive effect by stimulating unblocked antibodies. 2 receptors, while angiotensin-(I-7) has an antihypertensive effect by stimulating ATX receptors (Scheme 2).
Clinical pharmacology of AT blockers 1 -receptors
There are two main types of AT receptors - AT 1 and AT 2 . Accordingly, selective AT blockers are distinguished 1 - and AT 2 -receptors. V clinical practice AT blockers are used 1 receptors that have an antihypertensive effect. At least eight non-peptide selective AT blockers are currently in use or in clinical trials. 1 -receptors: valsartan, zolarsartan, irbesartan, candesartan, losartan, tazozartan, telmisartan and eprosartan.
According to the chemical structure, non-peptide AT blockers 1 receptors can be divided into three main groups:
. biphenyl derivatives of tetrazole - losartan, irbesartan, candesartan, etc.;
. non-biphenyl derivatives of tetrazole - eprosartan and others;
. non-heterocyclic compounds - valsartan and others.
Some AT blockers 1 -receptors themselves have pharmacological activity (valsartan, irbesartan), others (for example, candesartan cilexetil) become active only after a series of metabolic transformations in the liver. Finally, for such active antibodies 1 -blockers, like losartan and tazozartan, have active metabolites that have a stronger and longer-lasting effect than the drugs themselves. Therefore, AT blockers 1 -receptors can be divided into active drugs and prodrug forms of antibodies 1 - blockers.
According to the mechanism of binding to AT 1 AT receptors available 1-blockers are divided into competitive and non-competitive angiotensin II antagonists. To competitive AT 1 -blockers include valsartan, irbesartan and losartan, non-competitive - the active form of candesartan cilexetil (candesartan) and the active metabolite of losartan (E-3174).
Duration of antihypertensive action of AT blockers 1 -receptors is defined as the strength of their connection with AT 1-receptors, and the half-life of drugs or their active dosage forms and active metabolites (Table 2).
Along with AT 1 blockers receptors, there are selective AT blockers 2 receptors - CGP 42112 and PD 123319. Unlike AT 1 -blockers AT blockers 2-receptors do not have an antihypertensive effect and are not yet used in clinical practice.
Losartan- the first non-peptide blocker of AT 1 -receptors, which has successfully passed clinical trials and is approved for use in the treatment of hypertension and chronic heart failure.
After oral administration, losartan is absorbed into gastrointestinal tract; the concentration of the drug in blood plasma reaches a maximum within 30-60 minutes. When first passing through the liver, losartan is largely metabolized, resulting in its systemic bioavailability of 19-62% (mean 33%). The half-life of losartan in blood plasma is 2.1 ± 0.5 hours. However, the antihypertensive effect of the drug persists for 24 hours, which is explained by the presence of its active metabolite - E-3174, which blocks AT 10-40 times more strongly. 1 receptors than losartan. In addition, E-3174 has a longer half-life in plasma - from 4 to 9 hours. Losartan and E-3174 are excreted from the body both through the kidneys and through the liver. Approximately 50% of the total amount of E-3174 is excreted through the kidneys.
The recommended dose of losartan in the treatment of arterial hypertension is 50-100 mg / day in one dose.
Valsartan- high selective blocker AT 1 -receptors. It is more selective than losartan. While losartan has an affinity for AT 1 -receptors are 10,000 times higher than to AT 2 -receptors, in valsartan the AT 1 -selectivity is 20,000 - 30,000: 1. Unlike losartan, valsartan has no active metabolites. Its half-life in plasma is about 5-7 hours and is comparable to that of the active metabolite of losartan E-3174. This explains why the antihypertensive effect of valsartan persists for 24 hours. The main route of elimination of valsartan is excretion with bile and feces.
Patients with GB are prescribed valsartan at a dose of 80-160 mg / day in one dose.
Irbesartan- selective AT blocker 1 -receptors. Like AT 1 It is less selective than valsartan as a blocker. AT index 1 -selectivity in irbesartan is the same as in losartan - 10,000: 1. Irbesartan binds 10 times more strongly to AT 1 -receptors than losartan, and somewhat stronger than the active metabolite of losartan E-3174.
The bioavailability of irbesartan is 60-80%, which is significantly higher than that of other AT blockers. 1-receptors. 
Scheme 2. Direct and indirect consequences of the blockade of AT 1 receptors. The decrease in blood pressure during treatment with selective AT 1 receptor blockers is a consequence of not only a weakening of the effects of angiotensin II mediated by AT 1 receptors, but also an increase in the effects of angiotensin II mediated by AT 2 receptors, and the effects of angiotensin-(I-7) mediated by AT x receptors.
Unlike losartan and valsartan, the bioavailability of irbesartan is independent of food intake. The half-life of irbesartan in plasma reaches 11-17 hours. Irbesartan is excreted from the body mainly with bile and feces; approximately 20% of the drug dose is excreted in the urine.
For the treatment of GB, irbesartan is prescribed at a dose of 75-300 mg / day in one dose.
Candesartan cilexetil- prodrug form of AT 1 -blocker. After oral administration of candesartan, cilexetil is not detected in the blood, since it quickly and completely turns into the active compound, candesartan (CV-11974). Affinity of candesartan for AT 1 -receptors more than 10,000 times higher than the affinity for antibodies 2 -receptors. Candesartan binds 80 times more strongly to AT 1 -receptors than losartan, and 10 times stronger than the active metabolite of losartan E-3174.
Candesartan binds strongly to AT 1-receptors, its dissociation from the connection with AT 1 -receptors occurs slowly. These data on the kinetics of the binding of candesartan to antibodies 1 receptors suggest that, unlike losartan, candesartan acts as a non-competitive angiotensin II antagonist.
After taking candesartan cilexetil, the maximum concentration of its active form - candesartan - in blood plasma is detected after 3.5 - 6 hours. The half-life of candesartan in blood plasma ranges from 7.7 to 12.9 hours, averaging 9 hours. excreted through the kidneys, as well as with bile and feces.
The average dose of candesartan cilexetil for the treatment of arterial hypertension is 8-16 mg / day in one dose.
Eprosartan- selective blocker AT 1 -receptors. Its chemical structure differs from other ATs. 1 -blockers in that it is a non-biphenyl derivative of tetrazole. Eprosartan has an important additional property: it blocks presynaptic antibodies 1 receptors in the sympathetic nervous system. Due to this property, eprosartan (unlike valsartan, irbesartan and losartan) inhibits the release of noradrenaline from the endings of sympathetic nerve fibers and thereby reduces the stimulation of a1-adrenergic receptors in vascular smooth muscles. In other words, eprosartan has an additional mechanism of vasodilating action. In addition, eprosartan and valsartan, unlike losartan and irbesartan, do not affect the activity of enzymes of the cytochrome P-450 system and do not interact with other drugs.
Table 2. Comparative characteristics of the main AT1 receptor blockers
| A drug | Bioavailability, % | Active metabolite |
Half-life, h |
|
| drug | active metabolite | |||
| Valsartan | 10 - 35 | Not | 5 - 7 | - |
| Irbesartan | 60 - 80 | Not | 11 - 17 | - |
| Candesartan cilexetil | ? | Candesartan | 3,5 - 4 | 8 - 13 |
| Losartan | 19 - 62 | E-3174 | 1,5 - 2 | 4 - 9 |
| Eprosartan | 13 | Not | 5 - 9 | - |
Eprosartan is an active form of the AT 1 receptor blocker. Its oral bioavailability is about 13%. The concentration of eprosartan in plasma reaches a maximum within 1 to 2 hours after taking the drug inside. The half-life of eprosartan in plasma is 5-9 hours. Eprosartan is excreted from the body mainly with bile and feces unchanged; Approximately 37% of the oral dose of the drug is excreted in the urine.
For the treatment of arterial hypertension, eprosartan is prescribed at a dose of 600-800 mg / day in one or two doses.
Table 3. Main cardiovascular and neuroendocrine effects of AT1 receptor blockers
| . Cardiovascular (and renal) effects:
Systemic arterial vasodilation (decrease in blood pressure, decrease in total peripheral vascular resistance and afterload on the left ventricle); Neuroendocrine effects: Increased levels of angiotensin II, angiotensin I and plasma renin activity; |
Pharmacological effects of AT blockers 1
-receptors
According to the mechanism of action, AT blockers 1-receptors in many ways resemble ACE inhibitors. AT blockers 1 -receptors and ACE inhibitors suppress the excessive activity of the RAS by acting on various levels of this system. Therefore, the pharmacological effects of AT 1 -blockers and ACE inhibitors are generally similar, but the former, being more selective inhibitors of the RAS, are much less likely to give side effects.
Main cardiovascular and neuroendocrine effects of AT blockers 1 -receptors are given in table. 3.
Indications and contraindications for the appointment of AT 1 -blockers also largely coincide with those for ACE inhibitors. AT blockers 1 -receptors are intended for long-term therapy of hypertension and chronic heart failure. It is believed that the use of AT may be promising. 1 -blockers in the treatment of diabetic nephropathy and other kidney disorders, including renovascular hypertension.
Contraindications to the appointment of AT blockers 1 -receptors are considered: individual intolerance to the drug, pregnancy, breastfeeding. Great care is required when prescribing AT blockers 1 -receptors in stenosing lesions of both renal arteries or the artery of a single functioning kidney.
Experience with AT blockers 1 receptors in the treatment of GB
In recent years, AT blockers 1 α-receptors are increasingly being used as antihypertensive agents. This is because AT 1 β-blockers combine high antihypertensive efficacy with excellent tolerability. In addition, AT blockers 1 -receptors give a clinically significant protective effect. They are able to reverse the development of left ventricular hypertrophy and suppress hypertrophy of the smooth muscles of the vascular wall, reduce intraglomerular hypertension and proteinuria. In the heart and kidneys 1 -blockers weaken the development of fibrotic changes.
In most cases, AT blockers 1 receptors have a significant and uniform antihypertensive effect, which lasts up to 24 hours. Therefore, all available AT 1 Blockers are recommended to be taken once a day. If the antihypertensive effect of an AT blocker 1 -receptors are insufficient, a diuretic is added.
Losartan was the first AT blocker 1 receptor, which has been used to treat GB. According to the literature, losartan at a dose of 50 - 100 mg / day reduces systolic blood pressure by an average of 10 - 20%, diastolic - by 6 - 18%. The antihypertensive efficacy of losartan is comparable to that of enalapril, atenolol, and felodipine retard, and is significantly superior to that of captopril.
The experience of a clinical study of the efficacy and safety of losartan in almost 3000 patients with GB indicates that side effects with its use occur with the same frequency as with placebo (15.3 and 15.5%, respectively).
Unlike ACE inhibitors, losartan and other antigens 1 -receptors do not cause painful dry cough and angioedema. Therefore, AT 1 α-blockers are generally recommended for the treatment of hypertension in patients with contraindications to ACE inhibitors.
Losartan is the only AT 1 -blocker, which is known to be able to increase the life expectancy of patients with chronic heart failure to a greater extent than the ACE inhibitor captopril. Given the data on the preventive efficacy of losartan in chronic heart failure, all AT blockers 1 -receptors are recommended as first-line antihypertensive drugs for the treatment of arterial hypertension in patients with left ventricular systolic dysfunction.
Valsartan is prescribed at a dose of 80 - 160 mg / day. At a dose of 160 mg/day, valsartan appears to be more effective as an antihypertensive drug than losartan at a dose of 1 00 mg/day Like other ATs 1 blockers, valsartan has excellent tolerability. The frequency of side effects with its long-term use does not differ from that with placebo (15.7 and 14.5%, respectively).
Irbesartan is prescribed at a dose of 150 - 300 mg / day. At a dose of 300 mg/day, the drug is more effective than losartan at a dose of 100 mg/day. The frequency of side effects in the treatment with irbesartan and the appointment of placebo is the same.
Candesartan cilexetil appears to be the most potent available currently AT 1 blockers -receptors. It is prescribed at a dose of 4 - 16 mg / day. At a dose of 16 mg/day, candesartan lowers blood pressure to a much greater extent than losartan at a dose of 50 mg/day. Candesartan appears to have a longer lasting antihypertensive effect than losartan. Candesartan is well tolerated by patients. Due to the development of side effects, the drug had to be discontinued in 1.6 - 2.2% of patients with GB versus 2.6% of patients receiving placebo.
Eprosartan is prescribed at a dose of 600 and 800 mg / day one take. In severe hypertension, eprosartan and enalapril reduced diastolic blood pressure to the same extent (by an average of 20.1 and 16.2 mm Hg, respectively), but eprosartan caused a significantly greater decrease in systolic blood pressure than enalapril (by an average of 29.1, respectively). and 21.1 mm Hg). The incidence of side effects with eprosartan is the same as with placebo.
Thus, AT 1 blockers -receptors represent a new class of antihypertensive drugs. Antihypertensive efficacy of AT 1-blockers is comparable to that of ACE inhibitors with much better tolerability.
Literature:
1. Alderman MN, Ooi WL, Madhavan S, et al. Plasma renin activity: A risk factor for myocardial infection in hypertensive patients. amerJ Hypertens 1997;10:1-8.
2. Johnston CI, Risvanis J. Preclinical pharmacology of angiotensin II receptor anta-
gonists. Amer J Hypertens 997;10:306S-310S.
3. Preobrazhensky D.V., Sidorenko B.A., Sokolova Yu.V., Nosova I.K. Physiology and pharmacology of the renin-angiotensin system. Cardiology 1997;11:91-5.
4. Bauer JH, Reams GP. The angiotensin II type receptor antagonists. Arch Intern Med 1955;155:1361-8.
5. Sidorenko B.A., Preobrazhensky D.V., Sokolova Yu.V. Losartan is the first representative of a new class of antihypertensive drugs. Cardiology 1996;1:84-9.
6. Goa KL, Wagstaff A. Losartan potassium. A review of its pharmacology. Drugs 1996;51:820-45.
7. McIntyre M, Caffe SE, Machalar RA, Reid JL. Losartan, an orally active angiotensin (AT1) receptor antagonist: A review of its efficacy and safety in essential hypertension. Pharmacol Ther 1997;74:181-94.
8. Markham A, Goa KL. Valsartan. A review of its pharmacology and therapeutic use in essential hypertension. Drugs 1997;54:299-311.
9. Brunner HR. The new angiotensin II receptor antagonist, irbesartan. Pharmacokinentec and pharmacodynamic considerations. Amer J Hypertens 1997;10:311S-317S.
10. Nishikawa K, Naka T, Chatani F, Ioshimure I. Candesartan cilexetil: A review of its preclinical pharmacology. J Hum Hypertens 1997;11(suppl 2):9-17.
11. Edwards RM, Aiyar N, Ohlstein EH, et al. Pharmacological characterization of non-peptide angiotensin II receptor antagonist, SK&F 108566. J Pharmacol Exp Ther 1992;260:175-81.
12. SidorenkoB.A., Nosova I.K., Preobrazhensky D.V. AT antagonists 1
-angiotensin receptors - a new group medicines for the treatment of arterial hypertension and chronic heart failure. Wedge. Gazette 1997;4:26-8.
13. Pitt B, Segal R, Martynez FA, et al. Randomized trial of losartan versus captopril in patients over 65 with hert failure (Evaluation of Losartan in the Elderly study, ELITE). Lancet 1997;349:747-52.
14. Pool JL, Gutlirie RM, Littlejohn TW, et al. Dose-related antihypertensive effects of irbesartan in patients with mild-to-moderate hypertension. Amer J Hypertens 1998;11:462-70.
15. Andersson OK, Neldam S. The antihypertensive effect and tolerability of candesartan cilexetil, a new generation angiotensin II antagonist, in comparison with losartan. Blood Pressure 1998;7:53-9.
16. Belcher G, Häbner R, George M, et al. Candesartan cilexetil: safety and tolerability in healthy volunteers and patients with hypertension. J Hum Hypertens 1997;11(suppl 2):85-9.
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 continuously by the liver. Angiotensin levels may 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, its release into the blood. This process triggers the synthesis of angiotensin.
Angiotensin I and angiotensin II
Under influence renin angiotensinogen produces the following substance - angiotensin I. This substance does not carry any biological activity, its main role is to be a precursor angiotensin II. The last hormone is already active: it provides the synthesis of aldosterone, constricts blood vessels. This system is a target for drugs that lower α, 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, and this, in turn, leads to an increase in blood pressure. This activity is ensured by the chemical bonds that are formed during the interaction of the hormone with a special receptor. Also, among the functions related to the cardiovascular system, aggregation can be distinguished platelets, regulation of adhesion and prothrombotic effect. It is this hormone that is responsible for the hormones that arise in our body. It causes an increase in secretion in neurosecretory cells in a part of the brain such as hypothalamus, as well as the secretion of adrenocorticotropic hormone in pituitary gland. This results in a rapid release of norepinephrine. Hormone aldosterone , secreted by the adrenal glands, is released into the blood just due to angiotensin. Plays an important role in maintaining electrolyte and water balance, renal hemodynamics. Sodium retention by this substance is provided 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 this hormone in the blood, a routine blood test is given, as well as for any other hormones. Its excess may indicate an increased concentration estrogen , observed when using oral birth control pills and during, after a binephrectomy, Itenko-Cushing's disease may be a symptom of the disease. A low level of angiotensin is observed with glucocorticoid deficiency, for example, with liver diseases, Addison's disease.
- 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.
- Vasodilation.
- Natriuretic action.
- Release of NO and prostacyclin.
- antiproliferative action.
- Stimulation of apoptosis.
- Biphenyl derivatives of tetrazole (losartan, candesartan, irbesartan).
- Non-biphenyl derivatives of tetrazole (telmisartan).
- Non-biphenyl netetrazoles (eprosartan).
- Non-heterocyclic derivatives (valsartan).
- 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, more soft influence on renal hemodynamics than with the use of ACE inhibitors.
- When prescribing angiotensin II receptor antagonists, there are no undesirable effects associated with the activation of the kinin system.
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 :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 :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:
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:
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 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.