Kandesartan - Blocator AT1-angiotensin receptors of longer action: features of pharmacology and the experience of clinical use D.V. Preobrazhensky, S.A. Pataraya. The use of angiotensin Angiotensin at1 receptor blockers in pathogenetic therapy
Catad_TEMA Heart Failure - Articles
Achievements of medication therapy for chronic heart failure. Part II.
»» № 1 "2000
Reviews of literature Sidorenko B.A., Preobrazhensky D.V.
Presidential Medical Center Russian Federation, Moscow
The desire to increase the effectiveness of drug treatment of chronic heart failure (CHHN) makes it takes to use other drugs in combination with an angiotensin-converting enzyme inhibitors (ACE), diuretics, heart glycosides and beta-adrenoblockers. In the 80s, randomized studies were conducted to assess the effectiveness and safety in patients with HSN medicinal preparationsbelonging to the classes of aldosterone receptor blockers, antiarrhythmic drugs, Blockers AT1-angiotensin receptors, vasodilators and black-eyed inotropic drugs.
Unldosterone receptor blockers
A new approach to the treatment of HSN is associated with the use of aldosterone (mineralocorticoid) receptors - Spironolactone and Eplerenon, which in the past were considered just as representatives of one of the subgroups of potassium-saving diuretics.
Until recently, the Aldosterone receptor blocker is Spironolokton (Aldakton, Veroshpiron, Spironol) at CHF used only as a potassium-saving means for the correction of hypokalemia caused by loop and thiazide diuretics. In the 90s, in the treatment of HSN began to be widely used aPF inhibitorswhich can effectively prevent hypokalemia development in patients receiving loop and thiazide diuretics. As a result of this, patients with HSN hyperkalemia is now found much more often than hypokalemia. And therefore, in the overwhelming majority of cases in patients with HSN, receiving ACE inhibitors, there is no reason to fear the development of hypokalemia, and therefore, to prescribe potassium-saving diuretics.
For CXN, elevated concentrations of aldosterone in blood plasma are characteristic. According to some observations, with CXN hyperaldosteronemia is a prognostically unfavorable sign.
Hyperldosteronemium in patients with CXN is associated not only with the increased secretion of aldosterone as a result of the hyperactivity of the renin-angiogenic system (races), but also with a decrease in its inactivation in the liver. In turn, violation of the inactivation of aldosterone may be a consequence of both the reduction of hepatic blood flow and violations of its capture hepatocytes. It is known that violation of the degrees of aldosterone in the liver, in itself it can cause a 3-4-fold increase in its plasma concentrations due to a significant lengthening of the aldosterone half-life in the blood plasma from 30-35 to 70-100 min. Recently discovered that aldosterone plays an important role in the pathogenesis of the CHF. Aldosterone not only regulates water-electrolyte homeostasis, contributing to sodium delay and enhancing the elimination of potassium n magnesium by the kidneys. Long-term hyperaldosteronism, as it turned out, causes structural changes in the cardiovascular system. In particular, hyperaldosteroneism contributes to the development of hypertrophy of cardiomyocytes, the proliferation of fibroblasts and the elevated synthesis of collagen in the heart and the wall of the arteries. It is assumed that the elevated concentrations of aldosterone in the blood plasma are one of the reasons for the development of hypertrophy and diffuse interstitial myocardial fibrosis, as well as thickening of the middle shell of arteries and perivascular fibrosis in patients with CXN.
The dual mechanism of hyperaldosteronemia in patients with CXN explains why the suppression of excessive activity of races using ACE inhibitors does not lead to normalization of plasma concentrations of aldosterone. For the weakening of the undesirable effects of hyperaldosteronemia, the use of specific aldosterone antagonists is required, among which the most famous is spironolactone.
Spironolacton is a specific blockator of aldosterone (mineralocorticoid) receptors, which, in addition to renal tubules and adrenal glands, are found in the heart and wall of the arteries. Spironolacton can also slow down the activity of aldosteronsinttase and, thus, reduce the synthesis of aldosterone. In addition, it slows down the activity of the 5alph reduction. As a result, the formation of an alpha isomer of aldosterone is reduced, which has greater mineralocorticoid activity than its beta isomer.
Recently, in the experiment it was shown that spirironolacton prevents the remodeling of the cardiovascular system caused by aldosterone. With the joint appointment of aldosterone and spiroranolakton, neither the hypertrophy of the left ventricle, nor myocardiobrosis, does not develop.
Considering the antagonism of Spironolakton regarding the adverse effects of aldosterone in patients with CXN, a randomized placebo-controlled study of Rales Mortality Trial was taken.
The purpose of this study was to estimate the effect of low doses of spironolactone on the mortality rate of patients with HSN III-IV FC and with a fraction of left ventricular emission of less than 35%, which received standard therapy, including ACE inhibitors, loop diuretics and heart glycosides. After randomization, 822 patients additionally obtained spirironolacton (25 mg / day) and 841 patients - placebo.
In August 1998, the study of Rales Mortality Trial was early suspended after a significantly lower mortality in a group of patients treated with spironolactone, compared with the control group. Mortality from all reasons in the group of patients treated with spironolactone was 27% lower than among patients receiving placebo (95% confidence interval from 14 to 37%; p \u003d 0.0001). Mortality from heart causes decreased by 31%, the total number of hospitalizations - by about 17%, and hospitalizations in connection with the decompression of the CHF - approximately 36%. The total number of deaths and hospitalization when adding spironolactone decreased by about 22% (p<0,0002). Не было значительных различий между группами в средних уровнях калия или частоте выраженной гиперкалиемии. Лишь у 15% больных, леченных спиронолактоном, отмечались признаки гиперкалиемии, которые потребовали снижения дозы препарата. Единственным существенным побочным эффектом была гинекомастия, которая встречалась у 10% мужчин, получавших спиронолактон .
Thus, in the study of Rales Mortality Trial, it was shown that the use of Spironolakton's aldosterone receptor blocker can significantly improve the survival of patients with severe HCN.
Eplenenone is more selective than spironolactone, anldosterone (mineralocorticoid) receptor blocker, so the probability of the development of gynecomastia is significantly lower than when using Spironolactone.
Amiodaron and Dfethylide
Except for beta-adrenoblockers, then amiodarone, essentially, is the only antiarrhythmic drug that can be used for long-term therapy of ventricular rhythm disorders, and therefore for prevention sudden death In patients with hsn. The use of dfethylide, a new antiarrhythmic drug belonging to III classification by E. Vaughan Williams-B is also promising. Singh-d. Harrison.
In the early 90s, two major placebo-controlled studies were performed, in which the efficacy and safety of amiodarone was evaluated in patients with HSN.
In the study of GESICA in patients with HSN II-IV FC mortality in the group of patients treated with amiodarone, was significantly lower (by 28%) than in the control group (p \u003d 0.024). An inaccurate decline is noted, both cases of sudden death (by 27%) and deaths from progressive heart failure (by 23%). Especially effective amiodar was found in women (decrease in mortality by 48%) and in patients with stomaching ventricular tachycardia (decrease in mortality by 34%).
Some other data relating to the effectiveness of amiodarone in patients with CXN were obtained in a placebo-controlled raged CHF-STAT study. In this study, Amiodaron did not have a significant impact on the forecast of the life of patients with HSN II-IV FC. At the same time, the dependence of the effectiveness of long-term therapy with amiodarone from the etiology of the CHF was noted. Thus, a clear tendency was observed for improving survival in the treatment of the amiodarone patients with XSN of non-haemic etiology, which accounted for about 30% of all patients included in the study (P \u003d 0.07).
According to the consolidated data of five randomized studies, in patients with CXN, Amiodaron significantly reduces mortality - on average by 17%.
The reasons for the incomprehension of the results of research GESICA and CHF-STAT are not quite clear. Perhaps this is due to differences in patients involved in the study. For example, in the GESICA study prevailed (about 60%) patients with XSN non-haemic etiologies, which, according to the CHF-Stat study, amiodarone, apparently increases survival. In the GESICA study, Amiodaron significantly improved survival rate only in women (decrease in mortality by 48%), which accounted for about 20% of all patients. It was much less effective in men - a decrease in mortality by an average of 26% (5%-clerical interval from -2 to + 46%). Meanwhile, in the CHF-Stat study among patients was only 1% of women.
Despite the contraction of the results of research GESICA and CHF-STAT, it is clear that amiodarone at a dose of up to 300 mg / day can improve the distant prognosis in patients with XSN of non-ahematic etiology, i.e., first of all, in patients with dilatation cardiomyopathy. Amiodaron, apparently, is particularly effective in women, as well as in patients with source tachycardia (CSS\u003e 90, 1 min) and episodes of stomaging tachycardia according to 24-hour monitoring ECG.
Thus, at present, amiodarons should not be widely used for the treatment of asymptomatic and low-almptomic glacity arrhythmias in patients with systolic dysfunction Left ventricle with the aim of preventing sudden death.
In a multicenter placebo-controlled study of DIAMOND in patients with post-infarction systolic dysfunction of the left ventricle, diefethylide unreliable reduced mortality from all causes and from heart causes - on average by 6% and 7%. At the same time, the pephethyde reduced the need for hospitalization of patients due to heart failure, which explains the ability of the drug to prevent the development of atrial flications.
Consequently, along with beta-adrenobloclockers, amiodarons and dfethylides can be used to improve the forecast in patients with post-infarction systolic dysfunction of the left ventricle and ventricular arrhythmias.
Blockers AT1-angiotensin receptors
Blockers AT1-angiotensin receptors are a new group of drugs, the use of which is considered promising in the treatment of CXN.
AT1-angiotensin receptor blockers have important advantages over ACE inhibitors: (1) they are more efficient than ACE inhibitors suppress the activity of races, as they act at a lower level - at the level of cell receptors; (2) Their action is more selectively, as they suppress the activity of only races, but do not affect the kallicrein-kininic and other neuro-humoral systems, playing a role in the pathogenesis of CXN; and (3) AT1-angiotensin receptor blockers are much better tolerated than ACE inhibitors.
Thus, AT1-angiotensin receptor blockers provide a more efficient, more selective (selective) and a more specific approach to the braking of excessive activity of races compared with ACE inhibitors, and, moreover, are characterized by excellent portability.
The first Blocker AT1 angiotensin receptors, effective when taking inside, is Lozartan (Kozar), which was synthesized in 1988 in the mid-90s, clinical trials of other AT1-angiotensin receptor blockers were completed, such as Kakovargang, Zollarzartan, Irbezartan, Candaitan , Lozartan, Tazozart, Telmizarttan and Eprozartan.
In total, in just two long randomized studies, the effectiveness and safety of the Blockers of AT1-angiotensin receptors were studied at long use In patients with hsn.
In a multicenter study, ELITE mortality in a group of patients with HSN II-IV FC and with a fraction of emission of the left ventricle no more than 40%, treated with losartan, was roughly twice the lower (an average of 46%) than in the group of patients receiving an ACE captitor inhibitor. The total number of deaths and (or) hospitalization due to heart failure significantly decreased under the influence of the treatment of losartan, on average, by 32%.
The data obtained during the ELITE study can serve as indirect evidence high efficiency, safety and superior tolerability of losartan in patients with HSN due to systolic dysfunction of the left ventricle. Nevertheless, the results of these studies do not allow to recommend the widespread use of any Blockers of AT1-angiotensin receptors for the treatment of HC instead of ACE inhibitors. The fact is that in a randomized controlled study of Resolvd, it was not possible to detect any advantages of another Blocker AT1-angiotensin receptors (candy-seed) inhibitor inhibitor by ENALAPRAL in patients with systolic dysfunction of the left ventricle. Research Resolvd was early terminated after a higher mortality was found in groups of patients who received a candyanthane (6.1%) and a combination of candezartan and enalapril (8.7%), compared with patients treated with enalapril (3.7% ). The results of the ELITE-II study were not so encouraging, in which the effects of long-term therapy with losartan and cappos on the survival of patients with CHF were compared. In the ELITE-II study (in contrast to the ELITE-I study), the total number of deaths and hospitalization in connection with the decompression of the CHF in the group of patients treated with losartan was unreliable than in the group receiving captopril (by 6%; p \u003d 0, 21)
Thus, there is currently no indisputable evidence of a favorable effect of AT1-angiotensin receptor blockers for mortality and (or) the need for hospitalization (compared to ACE inhibitors) patients with HSN. Therefore, AT1-angiotensin receptor blockers are recommended for the treatment of HSN only in those few cases when ACE inhibitors cannot be used due to the development of angioedema edema or painful cough.
Calcium antagonists
Calcium antagonists as powerful arterial vasodilators can be useful to reduce the disposage on the left ventricle in patients with HSN. Unfortunately, all calcium antagonists have a negative inotropic effect, which is most pronounced in such cardooselective drugslike Verapamil and Dilgiam. For this reason, verapamil and dilgiam are not suitable for long-term therapy of patients with systolic dysfunction of the left ventricle.
Theoretically, the Calcium L-type calcium antagonists from the Dihydropyridine derivatives, as well as the Calcium antagonist T-type mibifradila, are most safest. Hope that in the treatment of CHF will be useful nifedipine, not justified. Adding nifedipine to standard CHH therapy increased the probability of decompensation. A more promising was to use in the treatment of patients with Calcium dihydropyridine antagonists with higher vase selectivity than Nifedipine, Amlodipine and Felodipine, as well as mibifradila.
The efficacy and safety of amlodipine was evaluated in a multicenter randomized by a placebo-controlled PRAISE study, in which 1153 patients with HSN III-IV FC and a fraction of emission of left ventricle less than 30% were participating. The total mortality rate was unreliable below (on average by 16%) in the group of patients treated by amlodipine than in the control group. When analyzing the effectiveness of amlodipine, depending on the Ethiology of CXN, it was found that in patients with dilatation cardiomyopathy, the addition of amlodipine leads to a decrease in mortality, on average by 46% (95% confidence interval from 21 to 63%;<0,001). Интересно, что терапия амлодипином сопровождалась значительным снижением риска внезапной смерти у больных с ХСН, обусловленной дилатационной кардиомиопатией (на 44%; р=0,05).
The long-term effects of felodipine in 450 patients with HSN II-III FC and a fraction of emission of the left ventricle less than 45% were studied in a multicenter placebo-controlled V-Heft III study. No significant effect of felodipine neither on mortality or at the frequency of hospitalizations, although he prevented the deterioration of the tolerance of patients to the physical exertion and the quality of life of patients.
In a randomized by a placebo-controlled study of the MAS-I mortality in the group of patients with HSN II-IV FC and a fraction of the left ventricular emission of less than 35% treated with calcium antagonist Mibeffrad, was 12% higher than in the control group, but the differences are not reached a statistically significant value. At the same time, a reliable increase in mortality in the appointment of Mibifradil to women, patients with atrial flications and patients receiving antiarrhythmic drugs, which can cause the development of ventricular tachycardia type "Torsades de Pointes) was noted.
Thus, today, amlodipine is the only calcium antagonist, which is known that it can improve the survival in patients with dilatation cardiomyopathy with CHNI III-IV FC receiving "triple" combined therapy. Neither Felodipine nor Mibifradil improves the survival of patients with HSN.
Other vasodilators
Along with the ACE inhibitors, the Blocages of AT1-angiotensin receptors and calcium antagonists, other drugs with a vasodilatory action are trying to use to reduce the disposage on the left ventricle in patients with HSN.
In 1991, the results of a randomized study of V-Heft (Vasodilator-Heart Failure Trial) II, in which the double-blind method was compared the effectiveness of the ACE inhibitor Enalapril and a combination of hydralazine and isosorbide of dinitrate in 804 patients with CHHN treated with digoxin and diuretics.
Observation of the patients continued from 6 months to 5.7 years (an average of 2.5 years). During the observation, the total mortality rate was slightly lower among patients treated with enalapril, compared with patients with a combination of dinitrate hydralazine and isosorbide (32.8% against 38.2%; p \u003d 0.08).
Analysis of the effectiveness of enalapril in various subgroups showed that it significantly improves the survival rate compared with the combined therapy in patients with CXH I-II FC, with normal heart sizes (cardiotorecaling index less than 0.50) and with high levels of renin and norepinephrine in blood plasma. On the other hand, a combination of hydralazine (up to 300 mg / day) and isosorbide of dinitrate (up to 160 mg / day) was not inferior to enalapril on the effectiveness in patients with HSN III-IV FC and with a slight activation of sympathetic-adrenal or renin-angiotensin systems.
Research data V-Heft II on a favorable effect of a combination of hydralazine and isosorbide of dinitrate on the survival of patients with CXN coincide with the results of a placebo-controlled study of V-Heft I (1986), in which it has been shown for the first time that in the first three years after the start of therapy, such a combination reduces such a combination Mortality of patients with HSN, on average, by 36% (p<0,05).
Therefore, in some patients with HSN, a combination of hydralazine and isosorbide dinitrate can be used as an alternative to ACE inhibitors, especially in cases where ACE inhibitors are contraindicated or cause serious side effects.
Necklikosida inotropic drugs
Neglyosoidal inotropic drugs have a more pronounced cardiotonic effect than heart glycosides, and therefore, they were considered more promising to improve the disturbed contractile function of the left ventricle in patients with HSN. In addition, they can reduce the disposition on the left ventricle, as they have a vasodilatory action. From here, by the way, another name of the non-zerkosidan inotropic drugs is inodilates.
Neglikosida inotropic drugs intended for intakes are separated into the following groups, depending on the mechanism of action:
1. Beta-adrenergic receptor agents (XoMoterol, Pibbuterol, Prealterol, etc.);
2. Phosphodiesterase III inhibitors (Amrinon, Milrinon, Enoximon, etc.)
3. DA-DOPAMERGICIC AGONISTS (IBOPAMIN, PENOLDOV, etc.); and
4. Preparations with a complex or unknown mechanism of positive inotropic action (Vespenarin, Levosimenan, Pimobhendan, Floosekvinan, Forskolin, etc.).
In the 80-90s, several dozen randomized placebo-controlled studies were performed, in which patients with CXN III-IV FC studied the effectiveness and safety of long-term therapy with non-alarcosidan inotropic drugs with a different mechanism of action. In all studies, mortality in the groups of patients who received these drugs was higher than in control groups. Some of the studies for this reason were early suspended.
Considering that the blacklyosidane inotropic drugs can increase mortality, they are not suitable for long-term therapy of patients with CXN. In the editorial article of the magazine "LANCET" J. Niebauer and A. Coats recommend even to impose a moratorium on the tests of non-geographic inotropic drugs in humans until the experimental studies have received convincing evidence of the ability of these drugs to lengthen life expectancy. Currently, it is not recommended to apply black-eyed inotropic drugs for a long time even in the treatment of patients with severe CHSN. Only in patients with refractory symptoms of HSN is allowed to assign non-bold inotropic drugs in the form of continuous intravenous infusion within a few days.
Thus, based on the results of randomized controlled studies, four groups of drugs are recommended for long-term therapy of patients with HSN: ACE inhibitors, thiazide or loop diuretics, heart glycosides and beta-adrenoblays. The clinical efficacy and safety of these drugs is currently no doubt. ACE inhibitors and beta-adrenoblays, along with symptomatic improvement, are able to reduce the need for hospitalization and improve survival. Tiazide or loop diuretics are the only group of drugs that allows you to eliminate fluid delay in patients with CXN. Heart glycosides do not improve survival, but reduce the need for hospitalization due to the decompensation of CXN and control the frequency of the ventricular rhythm in the tachiisistolic form of the atrial flication.
Other drug groups can also be useful in certain situations, but they should only be applied in addition to "basic" drugs or in cases where any of the "basic" drugs are contraindicated or causes serious side effects.
LITERATURE
1. Sidorenko B.A., Preobrazhensky D.V. Treatment and prevention of chronic heart failure. // Moscow, 1997.
2. Weber K.T., BRILLA S.G. Pathological Hypertrophy and Cardiac Interstitium: Fibrosis and Renin-Angiotensin-Aldosterone System. // Circulation, 1991; 83: 1849-1865.
3. Weber K.T., BRILLA S.G., Camphell S.E. et al. Pathological Hypertrophy with FIBROSIS: The Structural Basis for Myocardial Failure. // Blood Pressure, 1992, 1: 75-85.
4. Weber K.N., Villarreal D. Heart Failure: A SALT-SENSITIVE DISORDER. // Columbia Missuri (USA), 1997.
5. Richardson M., Cockbum N., Cleland J.g.f. Update of Recent Clinical Trials in Heart Failure and Myocardial Infarction. // EUROP. J. Heart Failure, 1999; 1 (1): 109-115.
6. Packer M., Cohn J.N. (EDS) CONSENSUS RECOMMENDATIONS FOR THE MANAGEMENT OF CHRONIC HEART FAILURE. // Amer. J. Cardiol., 1999; 83 (2a): IA-38A.
7. Doval H.c., NUL D.R., Doval H.C, GRANCELLI H.O. et al. Randomised Tial of Low-Dose Aittiodarone in Severe Congestive Heart Failure. // LanCet, 1994; 344 (8921): 493-498.
8. Singh S.N., Fletcher R.D., Fisher S.G. et al. Amiodarone in Patients with Congestive Heart Failure and Asymptomatic Ventricular Arrhythmia. // NEW ENGL. J. Med., 1995; 333 (2): 77-82.
9. Amiodarone Trials Meta-Analysis Investigators. Effect of Prouchylactic Amiodarone On Mortality After Myocardial Infarction and in Congestive Heart Failure: Meta-Analysis of Individual Data From 6500 Patients in Randomised Trial. // LanCet, 1997; 350: 1417-1427.
10. Kober L. The Diamond Study Group. A Clinical Trial of Dofetilide in Patients with Acute Myocardial Infarction and Left Ventricular Dysfunction: The Diamond Mi Study. // EUROP. Heart J., 1998; 19 (Suppl.): 90 (Abstract NO P639).
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13. Pitt V., Segal R., Martinez F.A. et al. Randomised Trial of Losartan Versus Captopril in Patients Over 65 with Heart Failure (Evaluation of Losartan in The Elderly Study, Elite). // LanCet, 1997; 349 (9054): 747-452.
14. Willenheimer R., Dahlia B., Rydberg E., Erhardt L. AT1-Receptor Blockers in Hypertension and Heart Failure: Clinical Experience and Future Directions. // EUROP. Heart J., 1999, 20 (14): 997-1008.
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These drugs have a number of common characteristics with ACE inhibitors. Their impact on mortality and life expectancy is actively studied in numerous clinical studies that ended in 4-6 years. Blockers AT 1 -Repceptors are shown in the intolerance of the IAPF and are contraindicated during pregnancy, bilateral stenosis of renal arteries, hypercalemia.
ACE inhibitors do not completely block the formation of the A-II, since the products of this hormone are also controlled by the tissue activator of plasminogen, the cathosphereship, himaz, and this path of the formation A-I6 pathological conditions is the leading.
By chemical structure, AT 1 blockers are derived from the following compounds:
Bifenylterazoli (losartan);
Nebiffenylterazoli (Eposartan, Telmisartan);
Negroerocyclic (Waltzartan).
Lozartan (Kozar), Irbesartan (Approvnel), Kandesartan (Ataandan), Telmisartan (Primetor, Macardis), Eprozartan (Teveten).
Lozartanassign 50-100 mg 1 time per day, with high doses of diuretics and in disruption of the liver and kidney function, the initial dose is reduced to 25 mg / day.
adrenoblocators
It is safe and effectively reduced blood pressure, are the means of choosing when DGPA and the uterine mioma. Possible indications of their purpose are the violation of glucose tolerance and dyslipidemia. The relative contraindication is orthostatic hypotension, so the elderly patients -ak should be used with caution under the control of blood pressure in the standing position.
In February 2000, the Security Committee was interrupted by the use of Doxazazyin in the AllHAt Research Research with a reliably greater frequency of development of congestive heart failure compared to other treatment schemes.
Allocate 2 main groups:
1 -AB: Prazozin, Doxazozin, Terasosin;
1 2 -AB: Ketanserin, Indoranmine.
Doxazozin(Cardura). Hell decreases gradually, the maximum effect is observed after 2-6 hours and continues 24 hours. Dose varies from 1 to 16 mg / day. Treatment should be started with a dose of 1 mg 1 time per day for 1-2 weeks, then in the next 1-2 weeks the dose should be increased to 2 mg / day. To achieve the desired effect, the daily dose should be increased gradually, by observing uniform intervals, up to 4, 8 and 16 mg, depending on the severity of the patient's reaction. Usually the dose is 2-4 mg 1 time per day.
Fantolamine(Dibazin) - is produced in a solution for intravenous administration of 5 mg of fantolamine along with 25 mg of mannitol in one ampoule, as well as in tablets of 0.02. The beginning of the effect occurs immediately, the peak effect is 2-5 minutes after intravenous administration, duration Actions 5-10 minutes. It is shown in hypertensive crises at the feuhromocytoma. At crises, intravenously in the form of a bolus of 5-20 mg is administered, then intravenous infusion is 100-500 mg / l with a speed of 0.5-1 mg / min, or the re-administration of the bolus after 1-2 hours.
Selective J1 receptor agonists (imidazoline)
J 1 The receptors are located in the rosy ventricular segment of the oblong brain, are responsible for tonic and reflex control over the sympathetic nervous system. The activation of these receptors leads to the inhibition of inserting neurons of the intermediate zone cm, which causes the suppression of sympathetic progeniconary neurons, see This is accompanied by the oppression of the SNA activity, followed by a decrease in emissions.
Stimulation of peripheral imidazoline recipers affects metabolic homeostasis: an increase in glucose-dependent insulin release and transfer of glucose inside cells, followed by a decrease in glycemia, enhancing the aerobic oxidation of glucose and glycogen synthesis, reduction of lactate products, increase sensitivity to brain tissue glucose.
Moxonidine(Cint, physiotension) in EG is used in the initial dose of 0.2 mg 1 time per day, in the future, if necessary, the dose can be increased to 0.4 - 0.6 mg 1 time per day. Contraindications:
AB blockade II-III protection;
Severe arrhythmias;
Bradycardia less than 50 per minute;
Severe heart failure;
Unstable angina;
Liver and renal failure;
Instructions for Otch Qinkie in history.
With metabolic syndrome, the use of a combination of the IAPF and Zint is justified.
Citation:Podzoldov V.I., Osadchy K.K. Blockers AT1-angiotensin receptors in the treatment of arterial hypertension: focus on Valsartan // RMW. 2009. №8. P. 552.
The choice of the drug for the treatment of arterial hypertension (AG) remains a difficult task. Currently, doctors have at the disposal of at least 7 groups of antihypertensive drugs, 5 of which are, according to modern international and domestic recommendations, first row drugs. On the one hand, the presence of a plurality of drugs provides a doctor wide possibilities for the individual selection of the necessary treatment in each individual case, and on the other hand, generates the problem of choosing a particular medication. This choice should be carried out taking into account the set of factors, among which both features of the patient and the flow of its illness and the properties of the drug.
In recent years, the requirements for drug preparations for the treatment of AG have changed significantly. Although the decrease in blood pressure (AD) itself remains the most important task of antihypertensive therapy, the presence of the drug only antihypertensive effect today cannot be considered sufficient today. The modern drug for treating AG should meet the set of requirements. First, it is antihypertensive efficiency. Under it today is understood not only the decrease in blood pressure as such, but also the ability of the drug to have a persistent antihypertensive effect, that is, the possibility of long-term retention of the test values \u200b\u200bof blood pressure on the background of treatment. It is desirable that the drug has favorably influenced the daily profile of blood pressure and was effective in special groups of patients: in the elderly, in patients with diabetes mellitus (sd), with an isolated systolic ag (Isag), etc. Secondly, this ability of the drug There is a positive effect on the state of target organs (heart, kidney, vessels), that is, organoprotective properties. These properties are estimated mainly by the ability of drugs to influence such markers as the mass of myocardial left ventricle (MML), microalbuminuria (Mau), the thickness of the intima / media complex, etc. Third, a modern antihypertensive drug should demonstrate an effect on endpoints. In the course of randomized clinical trials (RCI). It is desirable that these were "hard" endpoints, such as cardiovascular, and ideally, the total mortality rate. Fourth, a modern antihypertensive drug must be safe. Under this is not only a favorable profile of unwanted side effects and the overall tolerance of treatment, but also the lack of a negative impact on various organs and systems of the body in the long run. Today it is especially important that the antihypertensive drug does not contribute to the development of DE NOVO SD, that is, did not possess the so-called "predabegenic" effect, was metabolically neutral, did not contribute to the progression of atherosclerosis, did not deteriorate the sexual function. And, finally, the modern antihypertensive drug must be convenient for use, preferably 1 time per day, which helps to increase patients commitment to treatment.
Of the existing 5 main classes of antihypertensive drugs, Angiotensin II AT1 receptor blockers (sconce) are the most new. But at the same time, during his short story, they proved compliance with all the requirements in contrast to some classes on which the debate continues.
Pharmacodynamic effects of scan are associated with their ability to block the renin-angiotensin-aldosterone system (RAAS) at the level of type angiotensin receptors (AT1). It is through the activation of these receptors in modern concepts that the pathological effect of high concentrations of the main effector of RAAS angiotensin II during cardiovascular diseases are realized (Fig. 1).
The first class of drugs blocking Raas implemented in clinical practice was the class of angiotensin-shring enzyme inhibitors (IAPF). These drugs have greatly proven themselves in the treatment of hypertension, coronary heart disease (IBS), chronic heart failure (CHHN) and chronic kidney disease. However, as well as, in addition to the classical APF dependent injection paths of angiotensin II, there are also alternatives associated with an impact on angiotensinogen and angiotensin I Himaz, Cathepsin G and Callianin-like enzymes. The inhibitory of ACE cannot fully block the formation of angiotensin II, especially in tissues, where alternative ways of its formation are most active. It is of great importance, because It is exactly the actuativity of the tissue Raas, the leading role in the development of the defeat of the target organs during the AG is given. On the other hand, a decrease in the formation of angiotensin II under the action of the IAPP leads to a decrease in the stimulation of AT2 receptors, probably providing a certain counter-regulatory effect on the effects of AT1 receptors (Fig. 1). On the contrary, the direct blockade of AT1-re-charts with the help of the sconium ensures the stimulation of AT2 receptors in the constant concentration of angiotensin II and, moreover, does not affect the processes of bradykinin degradation. As a result, the frequency of cough development is sharply reduced - the main side effect of the IAPF.
The first synthetic sconce created back in 1971 (by the way, earlier than the first ACE inhibitor) was peptide Saralazine. However, he possessed the properties of a partial agonist and could only be used for parenteral administration. For the first time, non-prophetic sconium was synthesized on the basis of imidazoline derivatives in the mid-80s of the 20th century and were prototypes for the modern generation of these drugs. These substances had advantages in the form of sufficient absorption from the gastrointestinal tract, bioavailability, the absence of partial activity of agonist and selectivity in the blockade of type angiotensin receptors. In the clinical practice, the sconce was introduced in 1994, when the first drug of this group was registered for the treatment of AG - Losartan. Valsartan, Irbesartan, Kandesartan, Telmisartan and Eprosartan were created later. The main pharmacokinetic properties of modern score are presented in Table 1.
In modern recommendations for the treatment of agrarium, the first row preparations are suitable for starting therapy of uncomplicated ag. In addition, the additional effects of the SDS identified during clinical trials allowed a number of additional indications for the use of these drugs in patients with targets by target organs, with various clinical situations and in the presence of concomitant states (Table 2), which was reflected in National Recommendations for the Treatment of AG.
The most important feature of the sconce is their unique portability profile. The results of the set of rocks invariably show that the frequency of side effects when using drugs of this group, even in high dosages is extremely low and comparable to placebo. For a long time, it served as a reason to consider the sconium a peculiar replacement of the IAPF in the intolerance to the latter. However, in recent years, a large evidence base has been accumulated, indicating that both according to the main pharmacodynamic effects, and on the effects of endpoints of the sconium are not inferior to other classes of antihypertensive drugs.
In 2008, a major meta-analysis was published, in which the EFFECT effectiveness was compared with AG. Results of 61 studies with direct comparison of the score and IAPF were analyzed, including 47 RCCs. As a result, the almost the same ability of the score and IAPF decrease blood pressure in patients with hypertension was shown. In 37 rock differences in antihypertensive efficiency, the score and the IAPF were found no, in 8 RCIs there was a higher efficiency of the brain, and in 2 studies - IAPF. At the same time, it was noted that the incidence of therapy is much higher against the background of the use of the IAPF, while the sconium was better transferred to patients and therefore ensured a greater commitment to treatment. In terms of the frequency of such side effects, as headache and dizziness, the score and the EAPP did not differ significantly, but the cough was 3 times less as soon as possible, and in cohort studies, its total frequency did not exceed 0.6%. In this Me-Ta-Ana Lisa, there was no significant difference between the IAPF and the SCHA on the effect on the main endpoints (myocardial infarction, stroke, CXN), as well as on the quality of life, lipid levels, GLB, etc.
In another recent meta-analysis, 46 RCs, which included 13,451 patients with AG, was estimated antihypertensive efficiency of 9 different sconces. It was shown that all the scaves have a similar ability to reduce blood pressure, not inferior to such an AAPF. At the same time, from 60 to 70% of the maximum antihypertensive effect was achieved when using 1 / 8-1 / 4 from the maximum recommended dose of the sconce, and the use of 1/2 from the maximum dose provided 80% of the effect.
One of the widespread sconces is Valsartan. It is quickly absorbed from the gastrointestinal-core path, the maximum concentration in the blood plasma is achieved in 2-4 hours after intake; On the same time the antihypertensive effect of the drug is manifested. A long half-life (about 9 h), as well as a durable connection with AT1 receptors provides 24-hour maintenance effect, which allows the drug to take 1 time per day. This year, the drug Valsakor (Pharmaceutical Company "Krka") appeared on the Russian pharmaceutical market), tablets of 40 mg, 80 mg and 160 mg of Valsartan.
The anti-hyper-ten-ziva efficiency of Valsartan is confirmed in a number of RCK, including in comparison with other antihypertensive drugs. In particular, in two studies of Valsartan at a dose of 80 mg / day. I did not give up the effectiveness of 20 mg of Enalapril at the same time the frequency of cough against the background of Walssart would be lower than on the background of Enalapril almost 6 times.
Large-scale data was obtained during an open multicenter randomized VAL-MARC test for assessing the effect of reduction of blood pressure on the concentration of C-reactive protein in 1668 patients with AG 2 Art. . The use of Valsartan in a dose of 160-320 mg provided a decrease in systolic blood pressure (Garden) and diastolic blood pressure (DDA) by 18 and 9 mm Hg. respectively. Interestingly, the antihypertensive effect of Valsartan is manifested, starting with very low dosages (20-40 mg / day), and increases as a dose increases. At the same time, the decrease in blood pressure on the background of receiving Valsartan in the dosage of 80-320 mg occurs with the preservation of normal daily rhythm. Later, these data were confirmed by a combined analysis of the results of 9 studies that included 803 patients with AH 1 Art., Where it was shown both the increase in the antihypertensive effect and the frequency of achieving the target blood pressure while increasing the dose of Valsartan from 80 to 160 mg / day. . The performance shown in a wide range of doses makes Valsartan convenient for use in patients with hypertension with varying degrees of blood pressure and in combination therapy when low dosage of the drug can be useful.
Interesting data was obtained in a small test of valsartan using an outpatient su-accurate blood pressure monitoring. In 90 patients AG 1-2 Art. Equal decrease in the average daily values \u200b\u200bof the garden and dad both in the morning and during the evening reception of 160 mg of the drug was noted. Thus, the reception time of Valsartan does not affect the stability of its antihypertensive action. These data are essential, as they allow the doctor to use the drug more flexibly, take into account the individual characteristics of the patient under conditions of polymorbidity and inevitable polypragmasia. Ultimately, this can increase the commitment to therapy, which is an indispensable condition for the effective treatment of AG.
When comparing the antihypertensive efficacy of valsartan and enalapril in elderly patients, the degree of decrease in the blood pressure was the same. The effectiveness of Valsartan in Isag was studied in the VAL-SYST study in comparison with amlodipine. It was shown that both drugs effectively reduced the garden, but on the background of Valsartan, the frequency of unwanted phenomena was one and a half times lower. Thus, the reception of Valsartan in some cases can be an alternative to the usual treatment of AG in the elderly patients.
It is important to note that the sconium has pronounced organoprotective properties. Thus, the meta analysis, which included 3767 patients out of 146 groups of treatment and 346 patients out of 17 placebo groups, standardized the duration of treatment and the value of DDA, showed that the sconium provides the greatest decrease in the mass of the myocardial mass of the left ventricle (MML) (-13%), surpassing calcium antagonists (-11%), IAPF (-10%), diuretics (-8%) and β
- Farm blocks (-6%).
The ability of Valsartan to reduce the severity of the GLB in patients with AG is demonstrated in several studies. In particular, in a comparative study with amlodipine, it was noted that with the same decrease in the pressure, the MMLG index in the Valsartan group significantly decreased by 16%, and in the Amlodipine group, only 1.2%, and unreliable.
Important results were obtained in research Val-Prest and Valvace. It is shown that therapy Wolnzartan reduces the risk of developing restenosis and repeated interventions in patients who have undergone transmuminal balloon angioplasty of coronary arteries. Cardioprotective properties also testified by Value and Val-Heft's ability to reduce the risk of developing new atrial fibrillation in patients with AH and HSN.
The advantages of the score include their proven nephroprotective effect, the most important component of which is antiproteinurically. The recently published meta-analysis was evaluated by the influence of SCT in comparison with placebo or other antihypertensive preparations, as well as combinations of brave and IAPFs on proteinuria in chronic kidney disease. Analyzed data 49 data (total 6181 patients), included 72 comparisons with a surveillance duration of 1 to 4 months. and 38 comparisons with a surveillance duration from 5 to 12 months. The results of the meta-analysis showed that the sconium is more effective than placebo and calcium antagonists reduce proteinuria both for 1-4 months. And 5-12 months. Interestingly, the Branch and IAPF combination turned out to be more effective in reducing proteinuria than each of the groups of drugs separately.
Nephroprotective properties of valsartan in patients with ag on the background of type 2 SD 2 were studied in a multicenter randomized comparative examination of Marval. As a result, with the same decrease in blood pressure in both groups, the excretion of albumin (UEA) in the Valsartan group decreased by 44%, and in the Amlodipine group, only 8%, the difference between the groups was reliable. The proportion of patients who have reached the level of normalbuminuria, against the background of the intake of Valsartan (29.9%), was significantly higher on the background of receiving amlodipine (14.5%). At the same time, the decrease in UEA in the Valsartan group began with the first weeks of treatment and at low doses (80 mg / day). On the contrary, in the Amlodipine group in the first 8 weeks of UEA increased, and its decline began only after an increase in the dose of the drug was twice as well (up to 10 mg / day), that is, against the background of amplifying antihypertensive effect. In addition, Valsartan influenced UEA not only in patients with hypertension, but also in patients with initially normal blood pressure. These data allowed us to assume that Valsartan is able to reduce the degree of albuminuria regardless of the ability to reduce blood pressure.
Later, the antiproteinururic efficiency of Valsartan with AG and type 2 type 2 received a confirmation in the Japanese single-member comparative SMART comparative study. It was shown that with the same antihypertensive efficiency, the Albumin / Creatine (UAC) ratio in the urine in the treatment group was significantly decreased by 32%, and in the group of treatment with amlodipin - increased by 18%. The proportion of patients who have a remission or regression of the MAU was reliably more in the Valsartan group in comparison with Amlodipin. And in this study, against the background of the reception of Valsartan, there was a continuous progressive decrease in OAI. In the Amlodipine reception group, the decrease in the EAC was identified only in patients who have reached the target values \u200b\u200bof blood pressure. If the target hell in the Amlodipine group, OAC increased by 40%. Thus, reaffirmed the assumption that Valsartan reduces Mau regardless of decreased blood pressure.
Interesting data on the influence of various valsartan dosages to the level of proteinuria in patients with AG and SD 2 types were obtained in the DROP study. Patients randomized in 3 groups in which Valsartan was prescribed in one of the dosages - 160, 320 or 640 mg per day. As a result, a reliable decrease in UEA was noted when using the drug at a dose of 160 mg by 36%, and in doses of 320 and 640 mg - by 44 and 48%, respectively. The proportion of patients who have reached normal WEA values \u200b\u200b(<20 мкг/мин.), составила 12,4% в группе, получавшей 160 мг валсартана, 19,2% - на дозе 320 мг и 24,3% - на дозе 640 мг. При оценке влияния разных доз валсартана на уровень АД выявилась аналогичная картина: снижение САД/ДАД на дозах 160 и 320 мг достигало 13,7/8 мм рт.ст. и 14,7/8 мм рт.ст. соответственно, а на дозе 640 мг - 17,4/10 мм рт.ст., что достоверно превзошло эффект меньших доз по влиянию на ДАД и эффект 160 мг по влиянию на САД. Важно, что доля пациентов, достигших целевых значений АД (<130 и 80 мм рт.ст.) составила для доз 160, 320 и 640 мг - 30, 32 и 47% соответственно. Таким образом, в исследовании DROP не только подтверждена антигипертензивная эффективность валсартана и его способность существенно уменьшать протеинурию у больных АГ и СД 2 типа, но и была показана эффективность и безопасность применения препарата в высокой дозе - 640 мг/сут. Этот факт имеет большое значение, учитывая трудности достижения целевых значений АД и обеспечения нефропротекции у больных АГ на фоне СД 2 типа.
The influence of Valsartan on the end points was convincingly demonstrated in the Jikei Heart Study study, made on the initiative of researchers. In this RKK included 3081 patients with hypertension and / or IBS, and / or XSN. Randomized in 2 groups, they were in addition to standard therapy received Valsartan (40-160 mg / day) or normal treatment (not included in the sconce). The study was terminated early for ethical considerations, since after 3.1 years of observation, reliable advantages of Walssartan were noted. Against the background of Wovssartan's therapy, a reliable reduction in the risk of cardiovascular mortality and incidence of 39% was noted. In addition, there was a decrease in the risk of primary or re-stroke by 40%, a decrease in the risk of hospitalization due to angina range by 65%, reducing the risk of hospitalization due to heart failure by 47% and reduced risk of developing aorta aneurysm by 81%.
An important positive property of the Bra is their ability to reduce the risk of developing new CD cases in patients with hypertension, surpassing other classes of antihypertensive drugs in this respect. This effect was demonstrated in separate RCCs, in particular, for Valsartan in the Value study and as part of clinical practice. A major meta-analysis of 22 RCCs, which included 143,53 patients with AG, who did not have at the time of inclusion in the studies of the SD, showed that the sconium reduces the risk of DE NOVO's Risk almost 2 times, surpassing all other classes of antihypertensive preparations, including IAPF. This property of the sconce seems very significant, since the steady increase in the number of patients of SD 2 type 2 throughout the world is an essential medical and social problem.
Saw is characterized by a favorable metabolic profile. It is shown, for example, that Valsartan improves the sensitivity of peripheral tissues to glucose in patients with ag. Therefore, the sconium is recommended for use in patients with ag on the background of metabolic syndrome.
Among the advantages of the Branch, it is necessary to note a positive impact on such a most important aspect of the quality of life, as a sexual function in men and women with AG. It was convincingly demonstrated for Valsartan. Perhaps this is one of the most significant factors explaining the maximum long-term preservation by patients of commitment to the prescribed treatment of sconces.
Thus, AT1-angiotensin receptor blockers have a pronounced antihypertensive effect, a complex of organophetic properties and proven influence on the most important endpoints. The magnificent profile of tolerance and safety in patients with metabolic syndrome and diabetes mellitus, as well as high rates of adherence to the treatment of sconium, can recommend to recommend wider use of drugs of this group, in particular, Valsartan, in the treatment of arterial Gi-Per-Tensia.
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In recent decades of the XIX century, convincing evidence was obtained that the increased activity of the renin-angiotensin system (races) in the bloodstream and especially in tissues plays an important role in the pathogenesis of not only renovascular hypertension and hypertension (GB), but also chronic heart failure (CHHN ) and diabetic nephropathy. According to some observations, the high activity of renin and elevated levels of angiotensin II in the blood plasma are indicators of an unfavorable forecast of both in patients with GB and in patients with HSN. In particular, according to M. Alderman et al., In patients with high rhenin activity in blood plasma, the risk of developing myocardial infarction is almost 4 times higher than in patients with low renin activity. E. Roig et al. It was shown that in patients with HSN, receiving inhibitors of angiotensin gluttering enzyme (IAPF), elevated levels of another marker of activation of RAS - angiotensin II - indicate an unfavorable forecast.
Until recently, 3 class of drugs were used to suppress the increased activity of the RAS with GB - sympatholyticity of the type of reserpine, the agonists of the central 2adrenoreceptors and BADRereGic receptor blockers.
In 1982, Japanese researchers Y.FURUKAWA and BASTA. It was shown that the derivatives of imidazole can act as an antagonists of the pressing effect of angiotensin II. In the late 80s - early 90s of the last century, drugs were synthesized, which provide a more selective and more specific impact on the effects of activation of races. These are Blockers of AT-Angiotenzine 1-type receptors, which act as angiotensin II antagonists with respect to AT1 receptors mediating the main cardiovascular and renal effects of the activation of races.
AT1-angiotensin receptor blockers have a number of important advantages over ACE inhibitors that make their use in the treatment of GB.
Castle, Blockers AT1-angiotensin receptors are more efficient than the IAPF, the cardiovascular and renal effects of activation of races are suppressed. Indeed, in contrast to the IAPF, which affect only one of the ways of forming the basic effector peptide of races of angiotensin II, they act as angiotensin antagonists II, regardless of how angiotensin II was formed.
Waiter, the effect of Blockers AT1-angiotensin receptors is more specific than the effect of the IAPF. Indeed, in contrast to the IAPF, AT1-angiotensin receptor blockers do not affect the activity of other neurohumoral systems, which are associated with such Side effects characteristic of the IAPF, like a dry cough and angioedema edema.
The first Blocker AT1-angiotensin receptors, effective when taking inside, is Lozartan, which was synthesized in 1988. In the 90s of the last century, other Blocators of AT1-angiotensin receptors were developed, which differ from losartan with a chemical structure, features of pharmacokinetics and most importantly prolonged action.
Mechanisms of action and pharmacological effects of blockers
AT1 angiotensin receptors
The basis of antihypertensive effects and other pharmacological effects of AT1-angiotensin receptor blockers are several mechanisms - one direct and at least two indirect (indirect).
The direct mechanism of the antihypertensive effect of AT1-angiotensin receptor blockers is associated with the weakening of angiotensin II effects, which are mediated by AT1-angiotensin receptors. Blocking AT1 receptors, AT1-angiotensin blockers reduce the caused by angiotensin II arterial vasoconstriction, reduce the increased hydraulic pressure in the renal gloms, and also reduce the secretion of such vasoconstrictor and anti-nodetic substances, like aldosterone, arginine-vasopressin, endothelin-1 and norepinephrine. With prolonged use, AT1-angiotensin receptor blockers weaken the proliferative effects of angiotensin II, as well as aldosterone, arginine-vasopressin, endothelin-1 and norepinephrine with respect to cardiomyocytes and smooth muscle cells of the vascular wall, as well as fibroblasts and mergangial cells.
Indirect mechanisms of pharmacological effects of Blockers of AT1-angiotensin receptors are associated with reactive hyperactivation of CAP in conditions of blockade of AT1 receptors, which leads, in particular, to the increased formation of angiotensin II and angiotensin- (1-7). These effector peptides of the CAP in the conditions of the blockade of AT1 receptors cause additional stimulation of AT2-, and ATC receptors. At hypertension, at least such effects of angiotensin II and angiotensin- (1-7), such as arterial vasodulation, sodium and antiproliferative effect, which are mediated by AT2 and ATH -ANGiotenzine receptors.
The effects of AT1-angiotensin receptor blockers are favorable in the kidneys, both with a blockade of AT1 receptors and with the stimulation of AT2 receptors. Thus, the blockade of AT1-angiotensin receptors in the efferent (submitting) armiones of the renal glomers leads to a decrease in hydraulic pressure in them, and the stimulation of AT2 receptors in afferent (bringing) and efferent (submitting) kidney gloms are accompanied by an increase in the effective renal plasmock.
AT1-angiotensin receptor blockers are capable of penetrating through the hematostephalic barrier and inhibit the activity of the presynaptic AT1-receptors of sympathetic neurons, which regulate the release of norepinephrine into the synaptic slot by a positive feedback mechanism.
This ability is largely determined by the lipophilic properties of AT1-blockers. For example, higher-vigorous AT1-blockers, candequartane and telmachantan, are easier to penetrate the hematorecephalic barrier than less lipophilic drugs like Lozartan and IrbeCartan. Due to the ability to penetrate into the brain, these AT1-blockers during systemic administration can weaken the pressing effect of angiotensin II entered into the ventricular brain. At the same time, these lipophily AT1-blockers indirectly enhance the stimulation of Angiotensin II Angiotensin Angiotensin II, which is formed in the brain in the brain in the conditions of the Blocade of AT1 receptors. It is assumed that the stimulation of AT2 receptors underlies the cerebroprotective action of AT1-angiotensin receptor blockers, which manifests itself in the experiment in ischemia.
Thus, AT1-angiotensin receptor blockers provide a variety of protest effects - with respect to the kidneys, heart, brain and vessels. These organoprotective effects of AT1 blockers are associated with both the blockade of AT1 receptors and the stimulation of AT2 receptors and ATC receptors.
Features of Pharmacokinetics Kandesartan
According to the chemical structure of Kandesartan, the cyractyl is as well as the first Blocator AT1-angiotensin receptors of Lozartan, is a biphenyl derivative of Tetrazole, but it has a higher lipophilicity. It is assumed that due to high lipophilicity, the Kandesartan can easily penetrate the tissue and weaken the effects of activation of not only circulating, but tissue (local) races.
Unlike Losartan Kandesartan, the cyractyl is a prodrug. After receiving inside the Kandesartan, the cyractyl (TCV-116) in the blood is practically not determined, since during suction in the gastrointestinal tract as a result of deesterification it is almost entirely turning into an active blockator of AT1-angiotensin receptors Kandesartan (CV-11974).
Kandesartan is a highly selective and strong Blocker of AT1-angiotensin receptors of long-acting. The indicator of AT1-selectivity in Kandesartan is more than 10,000: 1, which is more than Lozartan (1,000: 1), Telmsartan (3,000: 1) and irbesartan (\u003e 1 000: 1).
The affinity of the Kandesartan to AT1 receptors is about 80 times higher than that of losartan, 10 times higher than that of the active metabolite EXP-3174, and 250 times higher than that of the Candesartan cyractyl.
By the ability to exhibit angiotensin II due to AT1-receptors, Kandesartan also exceeds other AT1-angiotensin receptor blockers. Angiotensin II Power Power In various AT1-blockers decreases in such a sequence: Kandesartan\u003e EXP-3174\u003e Irbesartan\u003e Lozartan.
Kandesartan firmly binds to AT1 receptors and slowly dissociate from communication with them. An excess of angiotensin II cannot displace Kandesartan due to AT1 receptors. This gives reason to assume that Kandesartan, like Waltzartan and Irbesartan, causes an irreversible (insurmountable) blockade of AT1 receptors. Slow dissociation of candesartan due to receptors contributes to its accumulation in the environment and re-binding to AT1 receptors.
The strength of the binding of fundamentan with AT1-angiotensin receptors, its slow dissociation due to them and re-binding is explained why Kandesartan has a more pronounced and longer antihypertensive effect than Lozartan, Waltzartan and Irbesartan, which remains for 36-48 hours.
When taking inside, the bioavailability of the Kandesartan ranges from 34 to 56%, which averages 42%. The bioavailability of the Kandesartan does not change when co-administration with food and increases (by 20%) in combination with hydrochlorodiazide. Plasma concentrations of Kandesartan reach a maximum after 3-5 hours after taking the drug inside. More than 99% of Kandesartan circulates in blood due to proteins.
The half-life of Kandesartan in the blood plasma ranges on average 9 h. (From 8 to 13 hours), which is more than Lozartan and its active metabolite EHR-3174, as well as the Candesartan of Cyxetil (3.5-4 hours) . In the elderly, the half-life of Kandesartan is about 2-3 times more than that of young people. Nevertheless, the cumulation of Kandesartan in elderly people does not happen.
From the vascular wall, Kandesartan eliminates more slowly than from blood plasma, which is associated with its very high lipophilicity and connection strength with AT1 receptors. The persistence of the Kandesartan in the vascular wall is explained by its longer antihypertensive effect (more than 24-36 hours) than what could be expected, given the magnitude of his half-life in the blood plasma.
From the body, the Kandesartan is excreted mainly unchanged, most (60-70%) through the kidneys, and the rest (20-40%) - with biliary. The small part of the kandesartan is inactivated by cytochromic enzymes of cytochrome P-450 liver (2c9), as a result of which the inactive metabolite CV-15959 is formed, which is derived from urine and bile. Therefore, in contrast to losartan, the pharmacokinetics of the Kandesartan with long-term appointment does not change in most patients with cirrhosis of the liver, as well as with co-use with inductors or inhibitors of cytochromic hepatic enzymes. Only in patients with severe hepatic renal failure, the initial dose of Kandesartan is recommended to be reduced by half (up to 4 mg). In renal failure, Kandesartian clearance slows down, but it is necessary to reduce the dose of the drug only in patients with severe renal failure.
Side Effects and Portability of KandaCartan
In several placebo-controlled studies, the portability of the Kandesartan in a dose of 4 to 16 mg / day was assessed. in patients with GB According to summary data relating to 1724 patients with GB, the overall frequency of adverse events was the same in patients treated with candesarthane (34.9%), and patients receiving placebo (33.5%). The most frequent side effects were headache (10% on Candesartians and 10% on placebo), dizziness and weakness. The cough, which is the characteristic side effect of the JAPP, met with the same frequency in patients treated with Candesarthane (1.6%), and patients receiving placebo (1.1%). To stop the study due to side effects had a larger number of patients receiving placebo (2.6%), compared with patients treated with kandesarthane (2.4%). The abolition frequency of the Candesartan did not depend on its dose and was 1.6, 2.2 and 1.6%, respectively, when prescribing the drug in a dose of 4, 8 and 16 mg / day. This indicates that the portability of the Kandesartan is somewhat better than the placebo tolerance, which is explained by the fact that, in contrast to placebo, it has an antihypertensive effect.
In several comparative studies, it is shown that the tolerability of AT1-blockers is much better than that of antihypertensive drugs of other classes, and this concerns the low frequency of the occurrence of not only cough, but also other side effects. For example, in a 12-week comparative study, a lower frequency of side effects has been demonstrated in women with GB in the treatment of AT1-blocker with Kandesarthane than in the treatment of IAPF by Enalapril and diuretic hydrochlorosticide (Table 1). In particular, the cough met in the treatment of kandesarthane and hydrochlorostiazide significantly less often than in the treatment of enalapril (2 and 4%, respectively, against 13%; p<0,001). Гиперурикемия чаще сочеталась с лечением гидрохлортиазидом (p<0,001).
Therefore, in women with GB, the Blocator AT1 receptors Kandesartan on tolerance clearly exceeds both the ENALAPRIL EAPF and a thiazid diuretic hydrochlorosticia. In particular, the cough in the treatment of Kandesarthane is much less common than in the treatment of EAPF enalapril, and even with the treatment of hydrochlorosticia.
An important clinical value is the fact that Kandesartan, like other AT1-angiotensin receptor blockers, with the same antihypertensive efficiency is much better tolerated than the IAPF. Thus, in a placebo-controlled study, with comparison of the Kandesartan and Enalapril, there were no significant differences in the antihypertensive efficacy of drugs, but the side effects in the treatment of Kandesarthane met much less frequently than in the treatment of enalapril (11.3% against 23.5%), and unreliable less often, than when the placebo is prescribed (11.3% against 15.9%). Enalapril had to be canceled due to cough in 3.7% of patients, but none of the patients receiving Kandesartan.
When comparing the Candesarthane and antagonist, the calcium amlodipine did not detect significant differences in either antihypertensive efficiency or in the frequency of side effects.
Considering that in the treatment of IAPF, the cough occurs more often in women than in men, the obtained data gives reason to assume that in women for initial therapy AG, apparently, it is better to use Blockers AT1-angiotensin receptors, and not an AAPF or thiazide diuretics.
The use of Kandesartan, as well as other AT1-angiotensin receptor blockers, may be promising according to the same testimony, which is currently used by the IAPF, namely: CXN, diabetic nephropathy and non-biotegic diseases of the kidneys.
Experience in the use of Kandesartan in the treatment of GB
Along with the excellent portability of Kandesartan, like other Blockers AT1-angiotensin receptors, has high antihypertensive efficacy. In large placebo-controlled and comparative studies, it is shown that in patients with soft and moderate forms of GB Candesartan in a dose from 4 to 16 mg / day. When appropriate, systolic blood pressure (GARD) and diastolic blood pressure (DDA) significantly reduces as a monotherapy - on average by 6-16.9 / 4-10.3 mm Hg. Art. Compared to the initial level.
The antihypertensive effect of the Kandesartan is manifested after the first week of therapy and increases in the next week. Approximately 2/3 of the total antihypertensive effect of the drug is achieved during the 1st week of therapy, 80 and 90% - after 2 and 4 weeks. Treatment, respectively.
Unlike losartan and some other AT1-angiotensin receptor blockers, the severity of the antihypertensive action of Kandesartan clearly depends on the dose of the drug. In one study, it is shown that with amendment on the placebo effect, the DAD is reduced by an average of 4 mm RT. Art. After 24 hours after receiving the Kandesartan at a dose of 4 mg / day, by 6 mm Hg. Art. After taking the drug at a dose of 8 mg / day. And at 7.8 mm Hg. Art. In a dose of 16 mg / day.
An important advantage of Kandesartan is its ability when taking 1 time per day effectively reduce the hell for more than 24 hours and prevent the rise of blood pressure in the early morning watches. When taking the Candesartian inwards in a daily dose of 16 mg, its antihypertensive effect is preserved to 36-48 hours.
As is known, for an objective estimate of the duration and uniformity of the antihypertensive effect of drugs in recent years, the ratio of the residual (final) effect to the greatest (peak) effect is used. It is believed that the ratio of the residual effect to the greatest (OE / NE) for new antihypertensive drugs should be at least 50% (or 0.50). According to P. Meredith, ideally the value of the OE / NE ratio should exceed 60%. The closer the OE / NE ratio of 100% (or 1.00), the equality of the antihypertensive effect of the drug during the day, and therefore, less variability of blood pressure, which, as is known, is one of the risk factors for the development of cardiovascular complications.
According to the consolidated data of controlled studies, the average values \u200b\u200bof the OE / NE ratios for DDA at KandaCartan are approaching 100%, which is much larger than that of losartan (60-70%), Valcartan (65-70%), Irbesartan (55-77%) and Eporalartan (70-90%).
This indicates that the Kandesartan provides a more uniform decrease in the blood pressure over the day than Lozartan and most other AT1-angiotensin receptor blockers.
Kandesartan in the same extent reduces blood pressure in men and women, patients of middle and old age, as well as regardless of the presence or absence of diabetes in patients (SD) and obesity. In a daily dose of 8-16 mg, Kandesartan provides a good antihypertensive effect in 55-70% of patients. Tiazide diuretics and calcium antagonists enhance the antihypertensive effect of Kandesartan, as well as other Blockers AT1-angiotensin receptors.
With prolonged use, the Kandesartan causes the reverse development of the left ventricular hypertrophy (GLB) in patients with GB. The regression of the GLB is accompanied by an improvement in its diastolic function.
In a comparative randomized study, CATCH shows that the Blocator AT1-angiotensin receptors of Kandesartan and EAPF Enalapril to the same extent cause regression of the GLF in patients with GB. This gives the basis to consider Kandesartan with a preparation of the first row for long-term treatment of GB in patients with GLB.
In the early current century, several large controlled studies have been completed, which gave an unequivocal answer to the question, whether the AT1-angiotensin receptor blockers are capable of slowing down the occurrence of type 2. The most convincing evidence of the antidiabetogenic action of AT1-angiotensin receptor blockers was obtained in randomized studies Alpine (2003 ), Scope (2003), and Charm (2003), in which the lengthy effects of the Kandesartan were evaluated (Table 2).
In a small 1-year randomized study of Alpine 392 patients with GB (average age 55 years), either Kandesartan (± calcium antagonist) was obtained, or hydrochlorodiazide (± -adrenobloclocator Atenolol). There were no differences between groups in the severity of antihypertensive therapy. Nevertheless, 8 new cases of the SD developed in the group of patients who received a diuretic, but only 1 case among patients receiving kandesartan (p \u003d 0.030). The metabolic syndrome was diagnosed in 18 patients receiving a diuretic, but only 5 patients receiving candesartan (p \u003d 0.007) (see Table 2).
The encouraging results of the Alpine study were confirmed by the data obtained in 2 large randomized studies of Scope and Charm. For example, in a placeling-control-controlled SCOPE study in elderly patients with GB (average age 76 years), a significant, but statistically inaccurate decrease in the risk of type 2 diabetes (by 20%) in the treatment of Kandesarthane (at a dose of 8 mg / day) compared to control group. It can be assumed that this is due to the fact that the relatively low dose of Kandesartan was appointed or in the elderly patients the antidiabetogenic effect of Kandesartan is less pronounced. This assumption is consistent with the results of a placebo-controlled CHARM study.
In a large research program, Charm Kandesartan was compared with placebo in 7,599 patients with various forms of HSN (average age 66 years). Kandesartan was prescribed at a dose to 32 mg / day. The duration of the observation was more than 3 years. In patients without SD, the likelihood of its occurrence during the observation period (by 22%) decreased under the influence of Candesarthane treatment. Further analysis showed that the Kandesartan affected the frequency of new cases of the SD in various categories of patients with HSN, which received different therapy.
Thus, the antidiabetogenic effect of Kandesartan was not found in Charm-added, in which the Kandesartan or placebo was added to the IAPF therapy. This gives reason to assume that the Blockers of AT1-angiotensin receptors and the IAPF influence the same pathogenetic mechanisms of type 2. and therefore, the addition of Kandesartan to the IAPF does not reduce the likelihood of developing new CD cases in patients with CXN.
A other business is the cases where the Blockers of AT1-angiotensin receptors are prescribed by patients who do not receive the IAPF. In such cases, Kandesartan exhibits its antidiabetogenic effect, reducing the likelihood of SD development by 21% in the CHARM-Alternative study and 40% in the CHARM-Preserve study (see Table 2).
The results of the analysis of the influence of Kandesartan's influence on the risk of developing the SD in patients with HSN in the CHARM scientific and research program, depending on other factors. It turned out that the antidiabetogenic effect of Kandesartan weakens with age and practically not detected in patients aged 75 years and older. Kandesartan reduces the likelihood of the development of the SD in patients with the CXN II functional class (FC), but does not affect it in patients with HSN III FC. It is possible that this is due to the fact that patients with CXN III FC are more often obtained by IAPF and diuretics, which weaken the antidiabetogenic lifestyle of the Kandesartan.
Thus, there is evidence that the Blocator AT1angiotenzine receptors Kandesartan is capable of preventing the development of the CD (and possibly its progression) and therefore can be considered a preparation of the first row for prolonged treatment of hypertension in patients with metabolic syndrome or diabetes.
Kandesartan has a beneficial effect on the function of the kidneys, which is convincingly demonstrated in experimental studies. Despite the reduction of systemic blood pressure, the renal blood flow and the speed of glomerular filtration are not reduced or even increase in the treatment of cubezartan. In humans, the renoprotective effect of the drug is most pronounced in diabetic nephropathy.
In a randomized study, Calm was compared the kidney effects of the Kandesartan and Lisinopril in 197 patients with type 2 SD with microalbuminuria and AG. Within 12 weeks One half received Candesartan (16 mg / day), and the other half is leasing (20 mg / day). After 12 weeks. After the randomization of 1/3 of patients who received Kandesartan, licked, and 1/3 of patients who received lysine arrived, Kandesartan was added. As a result, from the 12th to 24th week, 1/3 of patients received Kandesartan (n \u003d 66), another third - leasedid (n \u003d 64) and the third third is a combination of cubezartan and leasing (n \u003d 67).
There were no significant differences in the antihypertensive and antalbuminuric effects of the Kandesartan and the Lisinopril appointed as a monotherapy. At the same time, the additivity of the antihypertensive and antalbuminuric effects of the Kandesartan and the lysine arrived in patients with diabetic nephropathy is revealed. For example, in patients who received a combination of kandesartan and lysinopril, Dad decreased by an average of 16.3 mm Hg. Art. against 10.4 mm Hg. Art. and 10.7 mm Hg. Art. In groups of patients who received Kandesartan and Lysinopril as a monotherapy. The average decrease in the excretion of albumin with urine was 50% after combined therapy against 24 and 39% after monotherapy of the Kandesarthane and the leased, respectively.
The results obtained indicate the same severity of the renoprotective effects of the Blockers of AT1-angiotensin receptors and the IAPF. For the first time in patients with CD, the additivity of the hemodynamic and renal effects of the Blocker of the AT1ANGiotenzine receptors of Kandesartan and the IAPF Lisinopril is demonstrated.
In a large randomized placebo-control-controlled SCOPE study, the ability of Kandesartan to prevent the development of stroke in elderly patients with GB is proved. As you know, 4,973 men and women aged 70 years old and older, half of which were appointed Kandesartan were included in the SCOPE study. Other antihypertensive drugs were used to control the level of blood pressure in all patients, in particular, for ethical considerations of 85% of patients from the placebo group had to add antihypertensive preparations (most often diuretics, -adrenoblastors or calcium antagonists). As a result, it turned out that the study of SCOPE was compared the effectiveness of therapy between patients with kandesartan, and the control group of patients receiving other antihypertensive drugs. After 3.7 years of observation in the group of patients receiving the Kandesartan, the frequency of basic cardiovascular events was unreliable (by 11%) less than in the group receiving placebo, and the frequency of the non-infamary stroke was reliably (28%) below (p \u003d 0 04). In addition, a significant, but statistically inaccurate decrease (by 20%) of new SD cases among patients receiving kandesartan (p \u003d 0.09) were noted.
In several controlled studies, the antihypertensive efficacy of Kandesartan and other antihypertensive drugs was compared. In these studies, it is shown that the antihypertensive effectiveness of the Kandesartan in a dose from 4 to 16 mg / day. Compare with hydrochlorodiazide (12.5-25 mg / day), enalapril (10-20 mg / day) and amlodipine (5 mg / day).
In a placebo-controlled comparative study, Candle shows that Kandesartan in a dose of 8 and 16 mg / day. It causes a reliable decline in blood pressure compared to placebo. The degree of reduction of DAD and the garden in the patient's position sitting after 24 hours after taking 16 mg of Kandesartan is statistically greater than after receiving 50 mg and 100 mg of losartan.
High antihypertensive efficacy of Kandesartan in women with GB has recently been demonstrated in a major comparative study. K. Malmquist et al. The antihypertensive efficacy and portability of the Kandesartan in comparison with Enalapril and hydrochlorostiazide in 429 women were evaluated. After randomization patients within 6 weeks. Candesartan 8 mg / day was obtained., Enalapril 10 mg / day. or hydrochlorostiazide 12.5 mg / day. At the end of the 6th week, the doses were allowed to increase twice. Therapy continued a total of 12 weeks. The antihypertensive effect of Kandesartan was more pronounced than the effects of enalapril and hydrochlorostiazide in both primary and twin doses (Table 3).
Thus, in women with GB, Kandesartan was not only better transferred than the EAPF Enalapril and a thiazid diuretic hydrochlorosticiazide, but also exceeded their antihypertensive efficacy. These data indicate that the Kandesartan and other Blockers of AT1-angiotensin receptors may be more promising for long-term treatment of AG in women than tiazide diuretics or IAPF.
R. Fogari et al. They compared the antihypertensive efficacy of four AT1-blockers - losartan, waltzartan, irbesartan and kandesartan in 40 patients with soft and moderate forms of GB. In the recommended initial dose of Walsartan (80 mg / day) and Irbesartan (150 mg / day) exceeded the efficiency of Lozartan (50 mg / day): decreased angle by an average of 13.8 / 9.8 and 14.1 / 9 , 9 mm Hg. Art. Against 9.9 / 6.9 mm Hg. Art. Reduced blood pressure on the background of treatment with candesarthane (8 mg / day) amounted to an average of 10.8 / 7.9 mm Hg. Art. And it was not reliably distinguished from other studied Blockers AT1-angiotensin receptors.
After doubling the initial dose, there were no significant differences in antihypertensive efficiency of 4 compared at1-blockers. As shown by calculations, the equipotent daoses of the Blockers of AT1-angiotensin receptors are: 80.2 mg for losartan, 115.5 mg for waltzartan, 216.6 mg for irbesartan and 13.7 mg for Kandesartan. Compared to a period of reception of placebo, the plasma activity of the renin was significantly increased in patients receiving AT1-blockers, and the levels of renin were the largest during the reception period of the Kandesartan and the smallest in the period of receiving losartan (248 ± 85 and 152 ± 53 pg / ml, respectively against 41 ± 16 pg / ml when receiving placebo).
Taking into account the fact that the severity of the reactive hyperreninee in the treatment of AT1-blockers reflects the degree of braking of the RAS activity, the obtained data indirectly confirms the results. Experimental studies that are shown that the Kandesartan is associated with AT1-angiotensin receptors, more stronger than Losartan, Waltzartan or Irbesartan.
Thus, the new Blocator of AT1-angiotensin receptors Kandesartan has a pronounced antihypertensive effect, which is preserved for more than 24-36 hours. And which does not depend on gender, age and body weight of patients. With long-term use, Kandesartan causes the reverse development of the GLF, has a renoprotective effect and warns the development of a brain stroke. Along with high antihypertensive efficacy, the Kandesartan is characterized by excellent portability, which serve as the basis for its widespread use in the treatment of arterial hypertension (AG). The results of the CALM study give rise to hope that the Kandesartan will be useful in the treatment of diabetic nephropathy.
Experience in the use of Kandesartan in the treatment of HSN
Treatment of CXN is another promising area of \u200b\u200bclinical use of Kandesartan and other AT1-angiotensin receptor blockers. The place of Kandesartan in modern CHHN therapy was determined in the course of 3 randomized placebo-controlled studies made in the framework of the major research program Charm, the results of which were recently published.
As is known, 3 independent placebo-controlled studies have been held within the framework of the Candesartan Cilexetil in Heart Failure Reduction in Mortality and Morbidity, 1999-2003): 1) CHARMADDED - 2548 patients with LV systolic dysfunction (emission fraction LV 40%) receiving the EAPP in an adequate dose; 2) the study of Charm-Alternative - 2048 patients with LV systolic dysfunction (LV 40% emission fraction), non-IAPF; 3) Research Charm-Preserve - 3023 patients with preserved systolic function of LV (emission fraction\u003e 40%).
Under the influence of the Kandesartan (32 mg / day), mortality of patients with CHF reliably decreased - on average by 10% (p \u003d 0.032). At the same time, mortality from cardiovascular causes decreased by 13% (p \u003d 0.006). It was especially significant to reduce overall mortality and mortality from cardiovascular causes among patients with systolic dysfunction of LV (a decrease of 12 and 16%, respectively).
The frequency of the primary endpoint (death from cardiovascular causes or hospitalization due to CHF) decreased in patients with CXN in the treatment of candacentom on average by 16% (p<0,0001), в том числе на 15% в исследовании CHARM-Added.
The analysis of the results of individual studies made within the framework of the Research Program Charm has practical importance. Thus, the data of the CHARM-Alternative research confirmed that the Kandesartan and other Blockers of AT1-angiotensin receptors can be considered as an alternative to the IAPP in patients with CXN and successfully used in the intolerance to the IAPF. The CHARM-PRESERVED study showed that the Kandesartan and other Blockers of AT1-angiotensin receptors can be useful in the treatment of HSN in patients with a preserved systolic function of LV (emission fraction\u003e 40%).
When analyzing the results of the study, Charmadded expressed the opinion that in patients with CXH, due to systolic dysfunction of LV, there would be no significant benefit from the addition of Kandesartan to the IAPF, if the maximum doses of the IAPF were used as basic therapy. In other words, it was assumed that the Blockers of AT1-angiotensin receptors cause further suppression of the activity of the RAS in cases where it cannot be adequately suppressed due to relatively small doses of IAPF.
Special analysis of the results of the research of Charm-Added showed that it is not. It turned out that in patients with HSN, due to systolic dysfunction of LV, the addition of Kandesartan leads to a decrease in the total number of deaths from cardiovascular causes and hospitalization due to CHN (primary endpoint) not only in general (by 15%), but also In patients receiving maximum recommended doses of IAPF (on average by 25%). The favorable effect of adding Candesartan to the IAPF for the course of CXN remained even in patients who additionally obtained B-adrenoblays.
Therefore, in patients with HSN, due to systolic dysfunction of the LV, receiving the IAPF and B-adrenobloclars, the addition of Candesartan (and, apparently, other AT1-angiotensin receptor blockers) is not only safe, but also has a beneficial effect on the course and outcomes of the disease.
Thus, within the framework of the Research project, Charm received indisputable evidence that the Blocator of AT1-angiotensin receptors of long-acting Candesartan improves the distant prognosis of life with CXH in patients with both disturbed and stored LV systolic function. Improving the forecast, apparently, does not depend on the floor and the age of patients, nor from the etiology of the CHF, or on the concomitant therapy.
So, the Blocator AT1-angiotensin receptors Kandesartan has a pronounced antihypertensive effect, which is preserved for more than 24-36 hours and does not depend on the floor, age and body weight of patients. With long-term use, the Kandesartan causes the reverse development of the GLF, has an antidiabetogenic and renoprotective effect and warns the development of a brain stroke. Along with the high antihypertensive efficiency, the Kandesartan is characterized by excellent tolerance, which serves as the basis for its wide use in the treatment of AG. The experience of clinical use of Kandesarthane indicates the prospect of its use not only with various forms of ag, but also at CHN, diabetic nephropathy and non-biotic diseases of the kidneys.
In 1998, the 100th anniversary of the opening of Renin Swedish physiologist R. Tigerstedt. Almost 50 years after that, in 1934, Goldblatt and co-authors on the reninine-dependent agricultural model were first proved the key role of this hormone in the level of blood pressure regulation. The synthesis of angiotensin II Brown Menendes (1939) and Page (1940) was another step towards the assessment of the physiological role of the renin-angiotens-new system. Development of the first inhibitors of the renin-angiotensin system in the 70s (heating, Saralazina, and then - captopril, Enalapril, etc.) for the first time, made it possible to influence the functions of this system. The following event was the creation of compounds selectively blocking angiotensin II receptors. Their electoral blockade is a fundamentally new approach to eliminating the negative effects of activation of the renin-angiotensin system. The creation of these drugs discovered new perspectives in the treatment of hypertension, heart failure, diabetic nephropathy.
In accordance with the classical ideas, the main effector hormone of the renin-angiotensin system angiotensin II is formed in systemic blood flow as a result of a cascade of biochemical reactions. In 1954, L. Skeggs and a group of specialists from Cleveland found that angiotensin is represented in circulating blood with two forms: in the form of a decapidide and octapeptide, subsequently called angiotensin I and angiotensin II.
Angiotensin I is formed as a result of its cleavage of angiotensinogen produced by the liver cells. The reaction is carried out under the action of renin. In the future, this inactive decaption is exposed to ACE and in the process of chemical transformation turns into an active octapeptide angiotensin II, which is a powerful vasoconstrictor factor.
In addition to angiotensin II, the physiological effects of the renin angiotensin system are carried out by several more biologically active substances. The most important of them is angiotensin (1-7), which is formed mainly from angiotensin I, as well as (to a lesser extent) - from angiotensin II. Heptapeptide (1-7) has a vasodilant and antiproliferative effect. For the secretion of aldosterone, he, in contrast to angiotensin II, does not affect.
Under the influence of proteinases from angiotensin II, several more active metabolites are formed - angiotensin III, or angiotensin (2-8) and angiotensin IV, or angiotensin (3-8). The processes contributing to the increase in blood pressure are associated with angiotensin III, - stimulation of angiotensin receptors and the formation of aldosterone.
Studies of the last two decades have shown that angiotensin II is formed not only in the systemic bloodstream, but also in various tissues, where all components of the Rhenin-angiotensin system (angiotensinogen, renin, APE, Angiotensin receptors) were found, and the expression of Renin and angiotensin genes II was detected . The value of the tissue system is due to its leading role in the pathogenetic mechanisms for the formation of diseases of the cardiovascular system at the organ level.
In accordance with the concept of two-componentness of the renin-angiotensin system, the system link is given a leading role in its short-term physiological effects. The tissue link of the renin angiotensin system provides a long-term effect on the function and structure of the organs. Vasoconstriction and the liberation of aldosterone in response to the stimulation of angiotensin are immediate responses arising within seconds, in accordance with their physiological role, which is to support blood circulation after bloodstures, dehydration or with orthostatic changes. Other effects - myocardial hypertrophy, heart failure - develop for a long period. For pathogenesis of chronic diseases of the cardiovascular system, slow responses carried out in the tissue level are more important than the rapid, realized by the systemile ring of the renin-angiotensin system.
In addition to the APE dependent transformation of angiotensin I in angiotensin II, alternative ways of its education are established. It was revealed that the accumulation of angiotensin II continues, despite the almost complete blockade of ACE with the help of its Enalapril inhibitor. Subsequently, it was found that at the level of the tissue link of the renin-angiotensin system, the formation of angiotensin II occurs without the participation of ACE. The transformation of angiotensin I in angiotensin II is carried out with the participation of other enzymes - Tonin, Himaz and Katpsin. These specific proteinases are capable not only to convert angiotensin I to angiotensin II, but also split angiotensin II directly from angiotensinogen without the participation of Renin. In organs and tissues, the leading place is occupied by an independent ECF path of the formation of angiotensin II. So, in myocardium, a person about 80% is formed without the participation of ACE.
Angiotensin II receptors
The main effects of angiotensin II are carried out through its interaction with specific cellular receptors. Currently there are several types and subtypes of angiotensin receptors: AT1, AT2, AT3 and AT4. The person was found only at1, - and AT2 receptors. The first type of receptors is divided into two subtypes - AT1A and AT1V. Earlier it was believed that AT1A- and AT2V-subtypes are available only in animals, but at present they are identified in humans. The functions of these isoforms are not completely clear. AT1A receptors prevail in smooth muscle cells of vessels, heart, lungs, ovaries and in the hypothalamus. The predominance of AT1A receptors in the smooth muscles of vessels indicates their role in vasoconstriction processes. Due to the fact that AT1B receptors prevail in adrenal glands, the uterus, the front share of the pituitary gland, one can assume that they are involved in the processes of hormonal regulation. It is assumed to have an AT1C - subtype of receptors in rodents, however, their exact localization is not established.
It is known that all cardiovascular, as well as the extracardial effects of angiotensin II are mediated mainly through AT1 -receptors.
They are found in heart fabrics, liver, brain, kidneys, adrenal glands, uterus, endothelial and smooth muscle cells, fibroblasts, macrophages, peripheral sympathetic nerves, in the conductive heart system.
About AT2 -receptors are known significantly less than about AT1 type receptors. AT2 -receptor was first cloned in 1993, its localization on the X-chromosome was established. In adulthood, AT2 receptors are presented in high concentrations in the brainstorming layer of adrenal glands, in the uterus and ovaries, they are also found in the vascular endothelium, the heart and various areas of the brain. In the embryonic tissues of AT2 receptors are presented much wider than in adults and are in them predominant. Shortly after the birth of AT2 receptor "turns off" and activated with certain pathological conditions, such as myocardial ischemia, heart failure, vessel damage. The fact that AT2 receptors are most widely represented in the fetal tissues and their concentration is dramatically reduced in the first weeks after birth, indicates their role in the processes related to cellular growth, differentiation and development.
AT2 receptors are considered to mediate apoptosis - the programmed cell death, which is a natural consequence of its differentiation and development processes. Due to this, the stimulation of AT2 receptors has an antiproliferative effect.
AT2 receptors consider physiological counterweight at1 receptors. Obviously, they control overweight, mediated through AT1 receptors or other growth factors, as well as balance the vasoconstrictor effect of the AT1 receptor stimulation.
It is believed that the main mechanism of vasodilation during the stimulation of AT2 receptors is the formation of nitrogen oxide (NO) endothelium of blood vessels.
Effects of angiotensin II.
A heart
The effect of angiotensin II on the heart is carried out both directly and indirectly - through an increase in the sympathetic activity and concentration of aldosterone in the blood, an increase in post-loading due to vasoconstrictions. The direct effect of angiotensin II on the heart is in the inotropic effect, as well as in strengthening the growth of cardiomyocytes and fibroblasts, which contributes to myocardial hypertrophy.
Angiotenzine II participates in the processes of heart failure progression, causing such adverse effects as an increase in the pre- and post-loading for myocardium as a result of venical constructions and narrowing the arterioles, followed by an increase in the venous blood return to the heart and an increase in systemic vascular resistance; aldosteron-dependent fluid delay in the body leading to an increase in the volume of circulating blood; Activation of the sympathetic and adrenal system and stimulation of processes of proliferation and fibroelastosis in myocardium.
Vessels
Interacting with AT, -receptors of vessels, angiotensin II has a vasoconstrictor action, leading to an increase in blood pressure.
An increase in OPS also contributes to hypertrophy and hyperplasia of smooth muscle cells, hyperproduction of collagen by the wall of blood vessels, stimulation of endothelin synthesis, as well as the inactivation of NO-due to vessel relaxation.
Vasoconstrictor effects of angiotensin II in various departments of the vascular bed of unequal. The most pronounced vasoconstriction due to its impact on AT, the receptors are observed in the vessels of the peritoneum, kidneys and skin. A less significant vasoconstrictor effect manifests itself in brain vessels, lungs, hearts and skeletal muscles.
Kidney
Renal effects of angiotensin II play a significant role in regulation of blood pressure. Activation of AT1 renal receptors contributes to sodium delay and, therefore, fluid in the body. This process is implemented by increasing the synthesis of aldosterone and the direct effect of angiotensin II to the proximal department of the downward tube of nephron.
Kidney vessels, especially efferent arterioles, are extremely sensitive to angiotensin II. Rising the resistance of afferent renal vessels, angiotensin II causes a decrease in the renal plasmock and reduce the glass filtration rate, and the narrowing of the efferent arteriol contributes to an increase in the glomerular pressure and the appearance of proteinuria.
Local formation of angiotensin II has a decisive effect on the regulation of the kidney function. It directly acts on the renal tubules, increasing the reabsorption of Na +, contributes to the reduction of merzangial cells, which reduces the total surface area of \u200b\u200bthe glomeruli.
Nervous system
The effects caused by the influence of angiotensin II on the CNS are manifested by central and peripheral reactions. The impact of angiotensin on the central structures causes an increase in blood pressure, stimulates the release of vasopressin and adrenocorticotropic hormone. Activation of angiotensin receptors of peripheral departments of the nervous system leads to the strengthening of sympathetic neurotransmission and the oppression of the reverse seizure of norepinephrine in the nerve endings.
Other vital effects of angiotensin II are stimulation of the synthesis and release of aldosterone in the glomerular zone of adrenal glands, participation in the processes of inflammation, atherogenesis, regeneration. All these reactions play an important role in the pathogenesis of diseases of the cardiovascular system.
Preparations blocking angiotensin II receptors
Attempts to achieve the blockade of the renin-angiotensin system at the receptor level have been made for a long time. In 1972, the peptide antagonist angiotensin II Saralazine was synthesized, but he did not find therapeutic use due to a short period of semi-exploration, partial agonistic activity and the need for intravenous administration. The basis for creating the first non-peptide blocker angiotensin receptors was the study of Japanese scientists, which in 1982 received data on the presence of imidazole derivatives to block AT1 receptors. In 1988, a non-peptide antagonist angiotensin II Losarytan, which became a prototype of a new group of antihypertensive agents, was synthesized by R. Timmermans Group. Used in the clinic since 1994
In the future, a number of AT1 receptor blockers were synthesized, but at present, only a few drugs found clinical use. They differ in each other by bioavailability, the level of absorption, distribution in tissues, the rate of elimination, the presence or absence of active metabolites.
The main effects of AT1 receptor blockers
The effects of angiotensin II antagonists are due to their ability to communicate with specific receptors of the latter. Having high specificity and preventing the effect of angiotensin II at the level of tissues, these drugs provide a more complete blockade of the renin angiotensin system compared to ACE inhibitors. The advantage of AT1 receptor blockers in front of ACE inhibitors is also the lack of increasing kinin levels when applying them. This avoids such unwanted adverse reactions caused by the accumulation of bradykinin as cough and angioedema edema.
The blockade of AT1 receptors of angiotensin II antagonists leads to the suppression of its main physiological effects:
- vasoconstrictions
- aldosterone synthesis
- liberation of catecholamines from adrenal glands and presynaptic membranes
- vasopressin isolation
- the slowdown in the process of hypertrophy and proliferation in the wall of vessels and myocardium
Hemodynamic effects
The main hemodynamic effect of AT1 receptor blockers is vasodulation and, therefore, decreased blood pressure.
The antihypertensive efficacy of drugs depends on the initial activity of the renin-angiotensin system: in patients with high activity of renin, they act more.
Mechanisms through which angiotensin II antagonists reduce vascular resistance, the following:
- suppression of vasoconstriction and hypertrophy of the vascular wall due to angiotensin II
- reducing reabsorption Na + due to the direct effect of angiotensin II on renal channels and through a decrease in the release of aldosterone
- elimination of sympathetic stimulation due to angiotensin II
- regulation of baroreceptor reflexes due to inhibition of the structures of the renin-angiotensin system in the brain tissue
- an increase in the content of angiotensin which stimulates the synthesis of vasodilative prostaglandins
- reducing the release of Vasopressin
- modulating Action on Vessel Endothelium
- strengthening the formation of nitrogen oxide by endothelium by activating AT2 receptors and bradykinin receptors with an increased level of circulating angiotensin II
All AT1 receptor blockers have a long antihypertensive effect, which continues within 24 hours. It manifests itself after 2-4 weeks of therapy and reaches a maximum of the 6-8th week of treatment. Most of the drugs have a dose-dependent decline in blood pressure. They do not disturb its normal daily rhythm. The existing clinical observations indicate that with long-term assignment of angiotensin receptor blockers (for 2 years or more), the resistance to their action does not develop. Cancellation of treatment does not lead to a "riccetic" increase of blood pressure. AT1 receptor blockers do not reduce the blood pressure level if it is within normal values.
When compared with antihypertensive preparations of other classes, it was noted that AT1 receptor blockers, providing a similar antihypertensive effect, cause fewer side effects and is better transferred to patients.
Action on myocardium
Reducing the level of blood pressure when using AT1 receptor blockers is not accompanied by an increase in heart rate. This may be due to both a decrease in peripheral sympathetic activity and the central action of drugs due to the oppression of the activity of the tissue link of the renin-angiotensin system at the level of the brain structures.
The blockade of activity of this system directly in myocardium and the vascular wall is particularly important, which contributes to the regression of myocardial hypertrophy and vascular wall. AT1 receptor blockers not only oppress growth factors, the action of which is mediated through the activation of AT1 receptors, but also affect the AT2 receptors. The suppression of AT1 receptors helps to increase the stimulation of AT2 receptors due to an increase in the content of angiotensin II in the blood plasma. The stimulation of AT2 receptors slows down the processes of growth and hyperplasia of the smooth muscles of vessels and endothelial cells, and also suppresses the synthesis of collagen with fibroblasts.
The effect of AT1 blockers -receptors on the processes of hypertrophy and myocardial remodeling has the therapeutic importance of an ischemic and hypertensive cardiomyopathy, as well as cardiosclerosis in patients with IHD. In experimental work, it is shown that the drugs of this class increase the coronary reserve. This is due to the fact that the oscillations of coronary blood flow depend on the tone of coronary vessels, diastolic perfusion pressure, of course-diastolic pressure in lz factors modulated by angiotensin II antagonists. AT1 receptor blockers also neutralize the participation of angiotensin II in atherogenesis processes, reducing the atherosclerotic lesion of the blood vessels.
Action on the kidneys
The kidneys is a target organ with AG, the function of which Blockers AT1 receptors have a significant effect. The blockade of AT1 receptors in the kidneys contributes to a decrease in the tone of efferent arterioles and an increase in the renal plasmock. At the same time, the speed of glomerular filtration does not change or increases.
AT1 receptor blockers, contributing to the dilatation of efferent renal arterioles and a decrease in intraccular pressure, as well as suppressing the renal effects of angiotensin II (an increase in sodium reabsorption, disruption of the function of mesangilation cells, activation of glomerular sclerothing processes), prevent the progression of renal failure. Due to the electoral decrease in the tone of the efferent arteriole and, consequently, a decrease in intraccurid pressure, preparations reduce proteinuria in patients with hypertensive and diabetic nephropathy.
However, it is necessary to remember that in patients with one-sided stenosis of the renal artery, AT1 receptor blockers can cause an increase in the level of creatinine in blood plasma and acute renal failure.
Blocade AT, -ReppecTors has a moderate sodium-reaction effect by direct suppression of sodium reabsorption in the proximal canal, as well as due to the oppression of the synthesis and release of aldosterone. The decrease in the conditioned aldosterone of sodium reabsorption in the distal tube contributes to some diuretic effect.
Losarytan, the only drug from AT1 receptor blockers, has a dose-dependent uricosuric effect. This effect does not depend on the activity of the renin-angiotensin system and the use of cook salt. The mechanism is still not finally clear.
Nervous system
AT blockers, -receptors slow down the neurotransmission, angry peripheral sympathetic activity by means of a blockade of presopriate adrenergic receptors. In experimental intracerebral administration of drugs, there is a suppression of central sympathetic responses at the level of paraventricular nuclei. As a result of the operation on the CNS, the release of vasopressin decreases, the feeling of thirst decreases.
Indications for the use of AT1 receptor blockers and side effects
Currently, the only indication to the use of AT1 receptor blockers is AG. The feasibility of their use in patients with GLB, chronic heart failure, diabetic nephropathy is specified in the process of clinical trials.
A distinctive feature of a new class of antihypertensive drugs is good, comparable with placebo, tolerability. Side effects when applying them are observed significantly less frequently than when used. Unlike the latter, the use of angiotensin II antagonists is not accompanied by bradykinine accumulation and the appearance of cough caused by this. Significantly less often an angioedema swelling is also observed.
Like the ACE inhibitors, these tools can cause a fairly rapid decrease in blood pressure under reninine-dependent forms of AG. In patients with bilateral narrowing of the renal arteries of kidney, it is possible to deteriorate the kidney function. In patients with CPN, there is a risk of developing hypercalemia in connection with the oppression of the release of aldosterone during the treatment.
The use of AT1 receptor blockers during pregnancy is contraindicated due to the possibility of disorders of the development of the fetus and his death.
Despite the aforementioned unwanted effects, AT1 receptor blockers are the most well-portable patient with a group of antihypertensive preparations with the lowest frequency of the development of adverse reactions.
AT1 receptor antagonists are well combined with almost all groups of antihypertensive agents. Especially effectively their combination with.
Losaryan
It is the first deficiencies Blocator AT1 receptors, which has become a prototype of this class of antihypertensive preparations. It is a benzylimidazole derivative, does not have agonistic activity to AT1 receptors, which blocks 30,000 times more active than AT2 receptors. The half-life of Losartan is short - 1.5- 2.5 hours. At the first passage through the Losarytan liver, the metabolism is subjected to metabolism to form an active metabolite for ~ fermentation, which is 15-30 times more active than Losartan and has a longer half-life - from 6 to 9 hours. Basic Losartan's biological effects are due to this metabolite. Like Losaryan, it is characterized by high selectivity to AT1 receptors and the absence of agonistic activity.
The bioavailability of Losartan when taking inside is only 33%. Its removal is carried out with bile (65%) and urine (35%). The disorder of the kidney function slightly affects the pharmacokinetics of the drug, whereas with the liver dysfunction, the clearance of both active agents decreases, and their concentration in the blood rises.
Some authors believe that the increase in the dose of the drug more than 50 mg per day does not give an additional antihypertensive effect, while others observed a more significant decrease in blood pressure when the dose is up to 100 mg / day. Further increase in the dose does not lead to an increase in the effectiveness of the drug.
High hopes associated with the use of Losardan in patients with chronic heart failure. The basis was the basis of the data of ELITE (1997), in which Losartan's therapy (50 mg / day) for 48 weeks contributed to a decrease in the risk of death by 46% in patients with chronic heart failure compared to the captive appointed by 50 mg 3 times a day. Since this study was conducted at a relatively small contingent (722) patients, a larger study of ELITE II (1992), which included 3152 patients was undertaken. The goal was to study the influence of Losartan on the forecast of patients with chronic heart failure. However, the results of this study did not confirm the optimistic forecast - the mortality rate of patients against the background of treatment with captoprot and Losartan was almost the same.
Irbesartan.
Irbesartan is a highly-specific AT1 receptor blocker. In the chemical structure, it refers to the derivative of imidazole. It has a high affinity for AT1 receptors, 10 times exceeding the selectivity of Losarytan.
When comparing the antihypertensive effect of irbesartan at a dose of 150-100 mg / day and Losardan at a dose of 50-100 mg / day, it was noted that after 24 hours after taking, Irbesartan significantly reduced DDA than Losarytan. After 4 weeks therapy, raise the dose to achieve the target level of DDA (<90 мм рт. ст.) потребовалось у 53% больных, получавших ирбесартан, и у 61% пациентов, получавших лосартан. Дополнительное назначение гидрохлоротиазида более значительно усилило антигипертензивный эффект ирбесартана, чем лосартана.
In numerous studies, it was established that the blockade of activity of the renin-angiotensin system has a protective effect on the kidneys in patients with ag, diabetic nephropathy and proteinuria. The basis of this effect is the inactivating effect of drugs on inside the renal and systemic effect of angiotensin II. Along with the systemic decrease in blood pressure, which in itself has a protective effect, neutralization of angiotensin II effects at an organ level contributes to a decrease in the resistance of efferent arterioles. This leads to a decrease in intraccurid pressure, followed by a decrease in proteinuria. It can be expected that the renoprotective effect of AT1 receptor blockers may turn out to be more significant than the effect of ACE inhibitors. AT1 receptor blockers selectively act at the level of the AT1 receptor, the renin-angiotensin system in the kidney tissue is more fully blocked, since it impede the effects of angiotensin II of any origin.
In several studies, the renoprotective effect of irbesartan in patients with AG and type II diabetes with proteinuria was studied. The drug reduced proteinuria and slowed down the processes of glomerulosclerosis.
Currently, clinical studies are underway to study the renoprotective effect of irbesartan in patients with diabetic nephropathy and ag. In one of them, IDNT, the comparative efficacy of irbesartan and amlodipine in patients with ag on the background of diabetic nephropathy is studied.
Telmisartan.
Teleminsartan has an inhibitory effect on AT1 receptors, 6 times superior to such Losartan. It is a lipophilic drug, thereby penetrating the tissue well.
Comparison of the antihypertensive efficacy of televisartan with other modern means shows that it is not inferior to any of them.
The effect of telemisartan is dose-dependent. Increased daily dose from 20 mg to 80 mg is accompanied by a double gain of action on the garden, as well as a more significant decrease in DDA. The increase in the dose of more than 80 mg per day does not give an additional decrease in blood pressure.
Valsartan.
The resistant decline in the garden and DDA occurs after 2-4 weeks of regular reception, as well as other AT1 receptor blockers. Effective effect is observed after 8 weeks. Daily monitoring of blood pressure testifies that Valsartan does not violate the normal circadian rhythm, and the indicator T / P is, according to various sources, 60-68%. Efficiency does not depend on gender, age and race. Valsartan is not inferior on antihypertensive efficacy of amlodipine, hydrochlorothiazid and lysinopril, surpassing them tolerability.
In the Value study, which has begun in 1999 and includes 14,400 patients with ag of 31 countries, a comparative assessment of the effectiveness of the effect of Valsartan and Amlodipine to endpoints will resolve the issue of their availability, as in relatively new drugs, advances Development of complications in patients with ag in comparison with diuretics and.
