Renin inhibitors drugs names. New and promising drugs that block the renin-angiotensin-aldosterone system. Cyrenes - a new class of antihypertensive drugs

The renin-angiotensin-aldosterone system plays a key role in regulating blood pressure and water-electrolyte balance. A direct renin inhibitor, aliskiren, reduces plasma renin activity and has cardio- and nephroprotective effects. The antihypertensive effect does not depend on gender, race, age, or body mass index. The antihypertensive effect of aliskiren and angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium antagonists is comparable. Aliskiren is effective in patients with obesity, diabetes mellitus, impaired renal function and metabolic syndrome.

Direct renin inhibitors - aliskiren in the treatment of arterial hypertension

The Renin-angiotensin-aldosterone system plays a key role in the regulation of blood pressure and fluid and electrolyte balance. Direct renin inhibitor - aliskiren, decreasing plasma renin activity, providing cardio- and nephroprotective effects. Antihypertensive effect is independent of gender, race, age, body mass index. Antihypertensive effect of aliskiren and the angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, calcium antagonists is comparable. Aliskiren is effective in patients with obesity, diabetes, renal dysfunction and metabolic syndrome.

In the course of studying the renin-angiotensin-aldosterone system (RAAS), approaches have been developed to regulate its pharmacological activity. The first component of the RAAS, renin, was identified 110 years ago. Subsequently, its importance in the regulation of RAAS activity in pathological conditions was demonstrated, which became the basis for the development of direct renin inhibitors (DRIs). The RAAS plays a key role in regulating blood pressure (BP) and water and electrolyte balance. Increased activity of the RAAS plays a major role in the formation and progression of arterial hypertension (AH), chronic heart failure (CHF), chronic kidney disease, and systemic atherosclerosis. The RAAS is directly involved in the processes of tissue growth and differentiation, modulation of inflammation and apoptosis, as well as potentiation of the synthesis and secretion of a number of neurohumoral substances. The main effects of the RAAS are realized through angiotensin II (ATII) through stimulation of specific receptors. Activation of angiotensin receptor subtype 1 (AT1) leads to vasoconstriction and stimulates the release of vasopressin, aldosterone, endothelin, and norepinephrine. The physiological role of other angiotensin receptor subtypes (AT3, AT4 and ATx) continues to be studied. ATII promotes the accumulation of collagen matrix, the production of cytokines, adhesive molecules, activation of the intracellular signaling system, increased expression of fetal phenotype genes, plays a major role in myocardial remodeling and left ventricular (LV) hypertrophy, ATII is involved in the processes of arterial remodeling, intensification of oxidative stress and apoptosis, promotes the formation and progression of hypertension, CHF, atherosclerotic vascular damage, diabetic and non-diabetic nephropathy, angiopathy in diabetes mellitus (DM), eclampsia in pregnant women, Alzheimer's disease. The progression of cardiovascular diseases does not depend on the vasopressor effect of ATII.

Renin secretion is the first step in increasing the synthesis of ATI, ATII and other products of the RAAS cascade. The implementation of subsequent effects of the RAAS is modulated by the influence of renin on specific receptors, inducing an increase in ATII.

Until recently, the following RAAS inhibitors existed - angiotensin-converting enzyme inhibitors (ACEIs) and ATII receptor blockers (ARBs). The mechanism of action of ACE inhibitors is as follows: the activity of ACE is suppressed, which leads to a decrease in the effects of ATII and a slowdown in the degradation of vasopressors (bradykinin and prostaglandin E 2). ARBs competitively inhibit ATII receptors and reduce the effects of ATII. Receptors for renin and prorenin are located on the cell surface. Activation of the cellular signaling pathway by renin leads to fibrosis and cellular hypertrophy. In recent years, control of the activity of the RAAS has been carried out by limiting the production of ATII, blocking ATII and aldosterone receptors, by limiting the secretion of renin, mainly through the use of β-blockers. Numerous studies have shown that adequate reduction of RAAS activity with the help of ACE inhibitors, ARBs or aldosterone is more postulated than actually achieved, since the phenomenon of “escape” of the antihypertensive and organoprotective effects of RAAS blockers with their long-term use develops. To overcome this phenomenon, combinations of ACEI + ARB, ACEI + β-blocker, ACEI + spironolactone are used. The emergence of PIR is considered as a way to achieve more complete control of RAAS activity and overcome the “escape” phenomenon.

The first PIRs were synthesized in the 70s of the twentieth century, but the first drug suitable for oral administration was aliskiren (A). A., by binding to the active part of the target molecule, prevents its interaction with angiotensinogen. By reducing plasma renin activity (PRA), A. has cardio- and nephroprotective effects. RAAS inhibitors stimulate ARP, resulting in the following effects: vasoconstriction in the glomerulus, inflammation, fibrosis (kidneys); hypertrophy, fibrosis, vasoconstriction (heart); hyperplasia, hypertrophy, inflammation, lipid oxidation, fibrosis (vascular); vasoconstriction (brain). A. acts at the point of activation of the RAAS and reduces ARP. Unlike ACE inhibitors and ARBs, A reduces the level of ATI, AII and ARP. Renin has enzymatic as well as receptor-mediated activity.

Pharmacokinetics A. Clinical studies have shown that the tolerability of A is comparable to placebo. The duration of action of this drug exceeds 24 hours, and renal vasodilation may persist for up to 48 hours. The half-life of A is approximately 40 hours, which allows for once daily dosing. The recommended starting dose A is 150 mg with a further increase to 300 mg. The pharmacokinetic characteristics of A do not depend on fasting glycemia and the concentration of glycosylated hemoglobin in the blood plasma. Elimination of the drug is carried out unchanged in bile, excretion in urine is<1%. Исследования первой и второй фазы показали, что препарат способствует эффективной блокаде РААС и дозозависимому предотвращению повышения уровня АД . Полный антигипертензивный эффект наступает через 2 недели и не зависит от пола, расы, возраста, индекса массы тела. А обладает минимальным риском лекарственных взаимодействий, не требует коррекции дозы при хронической почечной недостаточности (ХПН), при поражении печени. Добавление А к ловастатину, атенололу, варфарину, фуросемиду, дигоксину, целекоксибу, гидрохлоротиазиду (ГХТЗ), рамиприлу, валсартану, метформину и амлодипину не приводило к клинически значимому увеличению экспозиции А. Совместное его применение с аторвастатином приводило к 50% увеличению Cmax (максимальная концентрацию препарата) и AUC (площадь под кривой «концентрация - время») после приема нескольких доз. Совместное применение 200 мг кетоконазола 2 раза в день с А приводило к 80% увеличению уровня А в плазме. При совместном применении А с фуросемидом AUC и Cmax фуросемида снижались на 30 и 50% соответственно . Не требуется коррекции дозы А у пациентов с ХПН. У пациентов с ХПН отмечается умеренное (~двухкратное) увеличение экспозиции А, но оно не коррелировало с тяжестью поражения почек и клиренсом креатинина. Клиренс А составлял 60–70 % у здоровых. Почечный клиренс А уменьшался с увеличением тяжести поражения почек. Поскольку поражение почек оказывает только умеренное влияние на экспозицию А, то коррекция дозы А, скорее всего, не требуется у пациентов с гипертензией и поражением почек. Не требуется коррекции дозы А и у пациентов поражением печени. Не было отмечено достоверной корреляции между экспозицией А и тяжестью поражения печени. А способен осуществлять блокаду РААС, что приводит к снижению сосудистого тонуса и системного АД. Однако препарат не лишен и негативных качеств, связанных с феноменом «ускользания», что характерно для всех лекарственных средств, блокирующих активность РААС. Снижение эффективности А вследствие восстановления секреции ренина или наличия синдрома отмены не подтверждается клиническими наблюдениями .

Antihypertensive efficacy A. ARP is an indicator necessary not only for the diagnosis of rare secondary forms of hypertension (renovascular). The clinical and prognostic significance of ARP is as follows: the indicator increases with hypertension in combination with other risk factors (male gender, smoking, type 2 diabetes, obesity, metabolic syndrome) and in the presence of target organ damage (TOD) ( persistent decrease in glomerular filtration rate); the increase in renin ARP can be iatrogenic, provoked by ACE inhibitors and/or diuretics (loop, thiazide), causing renal sodium loss: in this case, further activation of the RAAS is observed, which leads to loss of control over blood pressure and progression of CHF; an increase in ARP always predisposes to worsening POM and potentially fatal cardiovascular complications (CVD) and renal complications; Increased ARP is an independent factor for the pharmacological effects of PIR, which makes it possible to achieve a decrease in blood pressure and inhibit the progression of POM. A. can claim to be an effective antihypertensive drug in monotherapy and in combination with other drugs. Indications for the use of PIR are: hyperrenin variants of hypertension, normorenin hypertension, in which prorenin and indirect activation of prorenin receptors leads to tissue destruction. PIR is indicated not only for renovascular hypertension and CHF, but also for increased plasma concentrations of prorenin (hypertension with hyperactivation of the sympathetic nervous system, metabolic syndrome, type 2 diabetes, menopause).

Monotherapy A. provides a dose-dependent reduction in diastolic blood pressure (DBP) and systolic blood pressure (SBP) in patients with mild and moderate hypertension. An assessment of the effectiveness and safety of A. in 672 patients with stage I-II hypertension in an 8-week placebo-controlled study revealed a dose-dependent decrease in SBP and DBP. The antihypertensive effect of A persisted for two weeks after its discontinuation; A was well tolerated; the incidence of adverse events did not differ from placebo. A - trade name rasilez (P) - at a dose of 150 mg reduces SBP by 13 mm Hg. Art., and DBP by 10.3 mm Hg. Art., and at a dose of 300 mg reduces SBP from 15 to 22 mm Hg. Art. (depending on the level of hypertension), and DBP - by 11 mm Hg. Art. And provides blood pressure control in the early morning. After canceling A, the “rebound” phenomenon does not occur. Pooled analysis of clinical trials including 8481 patients. receiving monotherapy A or placebo, showed that a single dose of A at a dose of 150 or 300 mg/day caused a decrease in SBP by 12.5 and 15.2 mm Hg. Art. respectively, compared with a decrease of 5.9 mm Hg. Art. in patients receiving placebo (p<0,0001). ДАД снижалось на 10,1 (на дозе 150 мг) и 11,8 мм рт. ст. (на дозе 300 мг) соответственно (в группе плацебо - на 6,2 мм рт. ст., р<0,0001). Различий в антигипертензивном эффекте А у мужчин и женщин, а также у лиц старше и моложе 65 лет не выявлено. При применении иАПФ увеличиваются концентрации проренина и АРП (снижается эффективность иАПФ). При увеличении дозы иАПФ достоверно нарастает АРП и плазменная концентрация АТI . Исследование А в сравнении с иАПФ у пациентов с мягкой и умеренной АГ установило следующее: А достоверно больше снижает ДАД и САД, чем рамиприл через 12 недель лечения (монотерапия). А ± гидрохлортиазид (ГХТЗ) достоверно больше снижает ДАД и САД, чем рамиприл ± ГХТЗ через 26 недель лечения. А достоверно больше снижает ДАД и САД, чем рамиприл через 12 недель лечения (монотерапия) у пациентов с АГ II ст. Терапия А обеспечивает достоверно лучший контроль АД по сравнению с рамиприлом. САД и ДАД возвращаются к исходному уровню более быстро после отмены рамиприла, чем после отмены А. Сравнение гипотензивной эффективности А, ирбесартана и рамиприла после пропущенной дозы показало следующее: после пропущенной дозы достигнутое снижение АД было достоверно больше в группе А., чем в группе рамиприла . Достоверно больший процент снижения АД поддерживается после пропущенной дозы А по сравнению с ирбесартаном или рамиприлом. Возвращение к исходному АД происходит более плавно после отмены А., чем рамиприла. А. и эналаприл почти в равной степени уменьшают плазменную концентрацию АТП, но в отличие от А прием эналаприла приводил к более чем 15-кратному росту АРП. В условиях низкосолевой диеты индуцированная А органная (в частности, почечная) вазодилатация может сохраняться до 48 часов. Провоцировать подъем АРП могут препараты, стимулирующие натрийурез (тиазидовые и петлевые диуретики). Назначение А. в этой ситуации один из наиболее действенных подходов к устранению реактивного повышения АРП при комбинации с иАПФ и тиазидовым диуретиком.

In 2009, the results of a multicenter controlled clinical trial were published, in which the effectiveness of A and HCTZ (initial antihypertensive therapy) was compared in 1124 patients with hypertension; if necessary, amlodipine was added to these drugs. By the end of the monotherapy period (week 12), it became clear that A leads to a more pronounced decrease in blood pressure than HCTZ (-17.4/-12.2 mmHg versus -14.7/-10.3 mmHg Hg, p<0,001). Эти результаты важны, поскольку большинство пациентов, страдающих АГ, исходно нуждаются в комбинированной антигипертензивной терапии. Оптимизация комбинированной антигипертензивной терапии важна у пациентов с Ож. при этом у А имеются дополнительные преимущества . Больные с Ож, у которых полная (25 мг/сут) доза ГХТЗ не приводила к снижению АД, были рандомизированы на группы, которым назначали амлодипин + ГХТЗ (10/25 мг/сут), ирбесартан + ГХТЗ (300/25 мг/сут) и А. + ГХТЗ (300/25 мг/сут). По мере нарастания ст. Ож антигипертензивная эффективность схем лечения (БРА + ГХТЗ, антагонист кальция + ГХТЗ) снижается. В группе с Ож. III ст. (ИМТ≥40 кг/м 2) только у 50% удалось достичь целевого АД с помощью ирбесартана + ГХТЗ, у 43,8% - с помощью амлодипина + ГХТЗ и лишь у 16,7% - с помощью ГХТЗ. При менее выраженном (I–II ст.) Ож более чем у 40% пациентов, получавших БРА + ГХТЗ или амлодипин + ГХТЗ, и более чем у 60% больных, принимавших только ГХТЗ, целевое АД не было достигнуто. В группе пациентов с Ож. I-II ст., получавших А. + ГХТЗ, целевого АД достигли 56,7% больных, а с Ож. III ст. - 68,8%. АГ, сочетающаяся с Ож, часто ассоциируется с увеличением активности РААС и трудно корригируется, поэтому в таких случаях может быть назначен А.

A.'s ability to lower blood pressure and reduce albuminuria has been established. In the AVOID study, the effect of a combination of maximum doses of losartan and A on albuminuria (measured by urine albumin/creatinine ratio) was assessed in 599 patients with diabetic nephropathy with hypertension. The addition of A (300 mg/day) to losartan (100 mg/day) was accompanied by a significant decrease in the urine albumin/creatinine ratio by 20% in the group as a whole (100%), and in 24.7% - by 50% or more. In the losartan + placebo group, a decrease in urine albumin/creatinine ratio by 50% or more was achieved only in 12.5% of patients (p<0,001). ПИР могут уменьшить альбуминурию как в режиме монотерапии, так и при комбинации с БРА, позволяющей достичь оптимальной ст. блокады РААС, обеспечивающей устранение генерализованной и локально-почечной дисфункции эндотелия.

And with combination therapy of hypertension. In patients with mild and moderate hypertension without and with obesity. A. + HCTZ provide a significant reduction in DBP and SBP. More patients achieve BP control with the A + HCTZ combination than with other HCTZ combinations. In patients with hypertension and diabetes, A + ramipril significantly lowers blood pressure than both components of monotherapy. A provides significantly better blood pressure control than ramipril. In patients with mild and moderate hypertension, A + valsartan significantly reduces blood pressure better than both components of monotherapy. A significantly reduces blood pressure when combined with amlodipine at a dose of 5 mg/day. A increases the level of blood pressure control compared to amlodipine at a dose of 5 mg/day. A. ± HCTZ are effective in long-term therapy of hypertension. A + valsartan ± HCTZ provide long-term antihypertensive efficacy (interim analysis 6 months of therapy).

In 2009, the design of the ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) study was published (part of the ASPIRE HIGHER program), which studied the effect of double blockade of the RAAS using a combination of A and standard therapy (ACEIs or ARBs) in patients with diabetes. Type 2 with a high risk of cardiovascular complications and renal complications, partly due to an increase in ARP. The primary objective of this study is to evaluate the effectiveness of adding A to standard therapy on the effect on the composite endpoint (cardiovascular death and complications: successful resuscitation, non-fatal MI, non-fatal stroke, unplanned hospitalization due to CHF; development of end-stage renal failure, doubling of serum creatinine, death from causes related to kidney damage). This study should last about 4 years, and its results are intended to justify the use of a combination of A. with an ACE inhibitor or ARB to inhibit the progression of cardiorenal syndrome in type 2 diabetes. The greatest effectiveness of A can be expected in those variants of hypertension in which there is a tendency to increase ARP (forming essential hypertension, obesity, metabolic syndrome, type 2 diabetes, chronic renal failure). The vast majority of patients with hypertension require combination antihypertensive therapy already at the first stage of treatment and, as shown in one of the recently published clinical studies, as part of combinations A, it retains its activity regardless of the initial ARP. The increase in ARP in patients with hypertension is considered as a diagnostic marker and as an independent risk factor for potentially fatal cardiovascular events. Pharmacological modulation of ARP is one of the most promising approaches to managing the risk of cardiovascular events in patients with hypertension combined with kidney damage, metabolic syndrome and obesity. . The AVOID (Aliskiren in the eValuation of prOteinuria In Diabetes) study (part of the ASPIRE HIGHER program) was designed to evaluate the potential of a specific antihypertensive drug in protecting end organs in various situations characterized by a very high risk of potentially fatal complications (LV hypertrophy, type 2 diabetes , CHF). Interim results suggest that direct renin blockade with A is one of the most accessible strategies to improve long-term prognosis. In the ALLAY study (The Aliskiren Left Ventricular Assessment of Hypertrophy), A caused a decrease in the LV myocardial mass index, reflecting regression of its hypertrophy, in patients with hypertension and excess body weight. The combination of A and losartan provided a further reduction in LV myocardial mass index by an additional 20% compared with losartan monotherapy, but this difference did not reach a statistically significant value. According to the results of the ALOFT study (ALiskiren Observation of heart Failure Treatment study), the addition of A to the standard treatment regimen for CHF with signs of an unfavorable prognosis (persistent increase in plasma concentration of natriuretic peptide) and hypertension made it possible to further improve the ratio of the magnitude of mitral regurgitation to the area of the mitral orifice and transmitral blood flow . Thanks to A, it was possible to achieve a decrease in the concentration of markers of maladaptive neurohumoral activation (plasma levels of brain natriuretic peptide and its N-aminoterminal precursor (NT-pro BNP), urinary aldosterone concentration, ARP). Prospects for the use of A for the purpose of inhibiting the development of kidney damage are determined by its high safety, obviously significantly superior to other RAAS blockers (ACE inhibitors, ARBs and aldosterone antagonists) due to the lower risk of increasing creatininemia and kalemia. Excreted primarily in bile rather than urine, A retains its antihypertensive effect, but does not lead to deterioration of renal function in patients with a persistent decrease in glomerular filtration rate. It is in nephrology that aggressive blockade of the RAAS using simultaneously used several classes of drugs may be effective in preventing terminal chronic renal failure. A reduces albuminuria (significantly superior to monotherapy with each drug) and the likelihood of irreversible deterioration of renal function in the group of patients (with proteinuria >1 g/day), as shown in the COOPERATE study (COcombination treatment of angiOtensin-II recePtor blockEr and angiotensin-conveRting-enzyme inhibitor in non-diAbeTic rEnal disease). The ONTARGET study (OngoiNg Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) showed that the combination of ACEIs and ARBs is associated with a greater likelihood of arterial hypotension and hyperkalemia, and, compared with monotherapy with these drugs, is associated with an increase in the rate of initiation of program hemodialysis and a doubling of creatininemia in patients at high risk and POM. The following clinical situations can be objects for demonstrating the nephroprotective properties of A.: hypertension/metabolic syndrome or type 2 diabetes with albuminuria; Hypertension associated with a persistent decrease in glomerular filtration rate; Hypertension in chronic kidney diseases with and without proteinuria (including nephrotic) (for example, tubulointerstitial nephropathies); renovascular hypertension of various origins; patients who, for various reasons, have experienced an increase in creatininemia or hyperkalemia when using ACE inhibitors or ARBs; terminal chronic renal failure, including those treated with program hemodialysis or continuous ambulatory peritoneal dialysis; kidney transplant recipients.

A new class of antihypertensive drugs (ADMs) requires additional research to increase the body of evidence regarding slowing the progression of POM.

And, obviously, it is indicated for the majority of categories of patients suffering from hypertension, and this circumstance is reflected in the Russian recommendations on hypertension for the diagnosis and treatment of hypertension (fourth revision, 2010) as an additional class of antihypertensive drugs for combination therapy. With the development of kidney damage, A may be effective in preventing terminal chronic renal failure and improving the prognosis of these patients.

ON THE. Andreichev, Z.M. Galeeva

Kazan State Medical University

Andreichev Nail Aleksandrovich - Candidate of Medical Sciences, Associate Professor of the Department of Faculty Therapy and Cardiology

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24. Solomon S.D., Appelbaum E., Manning W.J. et al. Effect of the Direct Renin Inhibitor Aliskiren, Either Alone or in Combination With Losartan, Compared to Losartan, on Left Ventricular Mass in Patients With Hypertension and Left Ventricular Hypertrophy // The Aliskiren Left Ventricular Assessment of Hypertrophy (ALLAY) Trial. Presented at the American College of Cardiology. 57th Annual Scientific Session, March 31, 2008.
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30. Diagnosis and treatment of arterial hypertension: Russian recommendations // Systemic hypertension. - 2010. - No. 3. - P. 5-26.

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Direct renin inhibitors - a new class of antihypertensive drugs: potential opportunities and prospects

According to classical concepts, the renin-angiotensin system (RAS) plays a key role in the regulation of blood pressure and water-electrolyte balance. Research in recent decades has shown the great importance of increased RAS activity in the formation and progression of arterial hypertension (AH), heart failure (HF), chronic kidney disease (CKD), and systemic atherosclerosis. In addition, the RAS is directly involved in the processes of tissue growth and differentiation, modulation of inflammation and apoptosis, as well as potentiation of the synthesis and secretion of a number of neurohumoral substances. The main conductor that provides almost all known effects of RAS is angiotensin II. The latter realizes its tonic influences through stimulation of specific receptors. It has been established that activation of AT 1 and AT 2 receptors leads to opposite results. AT 1 receptors cause a vasoconstrictor effect, stimulate the release of vasopressin, aldosterone, endothelin, norepinephrine, and corticotropin-releasing factor. The physiological role of AT 3 -, AT 4 - and AT x receptors continues to be studied.

In research in vitro And in vivo It has been established that angiotensin II promotes the accumulation of collagen matrix, the production of cytokines, adhesion molecules, activation of the intracellular signaling system (multiple intracellular signaling cascades) through stimulation of mitogen-activated protein kinase, tyrosine kinase and various transcription factors.

Numerous studies have confirmed the involvement of RAS activation in cardiac remodeling processes. Thus, great importance is attached to the participation of angiotensin II in the formation of pathological hypertrophy of the left ventricle (LV), which is associated not only with an increase in myocardial mass, but is also associated with qualitative changes in the cardiomyocyte and the accumulation of extracellular collagen matrix. Angiotensin II directly promotes increased expression of fetal phenotype genes, such as genes for β-myosin heavy chains, skeletal α-actin, and atrial natriuretic factor. An increase in the expression of fetal isoforms of contractile proteins leads to an increase in LV mass with a subsequent decrease in the relaxation and then the total pumping function of the heart. In addition, angiotensin II promotes the expression of immediate-early or fetal genes, such as jun B, βgr-1, c-myc, c-fos, c-jun, which are responsible for the intensity of intracellular protein synthesis. And although the role of activation of these genes is not completely clear, many researchers associate an increase in their expression with a disruption of the intracellular signaling cascade and activation of the fetal type of metabolism.

It has been established that angiotensin II can play a central role in the processes of arterial remodeling, intensification of oxidative stress and apoptosis. In addition, angiotensin II may be involved in the formation and progression of arterial hypertension, heart failure, atherosclerotic vascular damage, diabetic and non-diabetic nephropathy, angiopathy in diabetes mellitus, eclampsia in pregnancy, Alzheimer's disease and many other diseases.

It should be noted that the adverse effect of angiotensin II on the progression of cardiovascular diseases is independent of its vasopressor effect. However, the participation of most molecular and cellular mechanisms of RAS in the progression of cardiovascular diseases has been confirmed in experimental studies, or in vitro. In this regard, the clinical and prognostic significance of many of them remains to be established.

Thus, angiotensin II appears to be a central link in a complex cascade of RAS activation, which has a negative impact on the structural and functional characteristics of the cardiovascular system. However, the secretion of renin is the first and most important step in increasing the synthesis of angiotensin I, angiotensin II and other products of the RAS cascade in general. Moreover, the implementation of all subsequent effects of the RAS is modulated by the influence of renin on specific receptors. The latter are present not only in the mesangial tissue of the kidneys, as previously assumed, but also in the subendothelium of arteries, including renal and coronary ones. Renin has a high affinity for forming a specific bond with its own receptors. Renin bound to the receptor induces a series of intracellular processes, the result of which is an increase in the formation of angiotensin II. It should be noted that the described type of receptor has the ability to bind prorenin with the subsequent implementation of processes of activation of angiotensin II synthesis. It has now been established that prorenin is a powerful predictor of microvascular complications in diabetes mellitus, although the mechanism underlying this process is not completely clear. In this regard, limiting the activity of RAS components is considered as an effective method of drug intervention in the progression of cardiovascular diseases.

It should be noted that in recent years, pharmacological control of the activity of the RAS has been carried out in the direction of limiting the production of angiotensin II through inhibition of angiotensin-converting enzyme, blockade of angiotensin II and aldosterone receptors, as well as by limiting renin secretion, mainly through the use of beta-blockers. At the same time, numerous studies have shown that adequate reduction in RAS activity is postulated rather than actually achieved. It has been found that the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor antagonists (ARAs) is often associated with activation of alternative pathways of RAS activation. Thus, for ACE inhibitors this is associated with an increase in the activity of tissue chymases and proteases, as well as the secretion of renin and aldosterone, and for ARAs - with an increase in the synthesis of angiotensin II and aldosterone without a corresponding increase in the pool of endogenous bradykinin. In a clinical sense, this phenomenon manifests itself in the so-called escape phenomenon of the antihypertensive and organoprotective effects of RAS blockers during their long-term use. Attempts to overcome this phenomenon include the use of combinations “ACEI + ARA”, “ACEI + beta-blocker”, “ACEI + spironolactone (eplerenone)”. The emergence of direct renin inhibitors (DRIs), which help reduce the secretion of the latter and limit the intensity of angiotensin II production, began to be considered as a possible way to achieve more complete control over the activity of the RAS and overcome the escape phenomenon.

Cyrenes - a new class of antihypertensive drugs

The first PIRs (enalkiren, remikiren, zankiren) were synthesized in the mid-70s of the last century, and clinical results regarding their use in healthy volunteers and patients with hypertension have become available since the late 80s. However, researchers encountered a number of difficulties, mainly associated with the extremely low bioavailability of PIR in the gastrointestinal tract (less than 2), short half-life and low stability of the components in tablet form, which significantly limited the potential therapeutic potential of cyrenes in general. In this regard, for quite a long time, cyrenes were not considered as a promising class of antihypertensive drugs, especially since the 90s of the last century were the heyday of ACEIs, and the end of the millennium - ARAs. The first success for kirens came only after the synthesis of CGP 60536, a non-peptide small-molecule renin inhibitor suitable for oral administration, called aliskiren. To date, the drug has passed all stages of clinical trials and since April 2007 has been recommended for the treatment of hypertension in the USA and European Union countries.

Pharmacokinetic and pharmacodynamic effects of aliskiren

Aliskiren has favorable physicochemical properties, including high solubility (> 350 mg/ml at pH = 7.4) and hydrophilicity, which significantly improves the bioavailability of the drug. Under experimental conditions, it was found that after taking the first dose, peak plasma concentration is reached after 1-2 hours, bioavailability is within 16.3%, and the half-life is 2.3 hours. In healthy volunteers, the pharmacokinetic properties of the drug were assessed in a dose range from 40 to 1800 mg/day. . It turned out that the plasma concentration of aliskiren increases progressively after taking ranged doses of 40-640 mg/day, reaching a maximum after 3-6 hours. The average half-life is 23.7 hours. Moreover, the stability of the plasma content of aliskiren is observed after 5-8 days of continuous use. In addition, the researchers noted the drug’s ability to moderately accumulate when used in high doses, as well as the presence of a direct dependence of the level of bioavailability on food intake. It should be noted that the pharmacokinetic characteristics of aliskiren do not depend on fasting glycemia and plasma concentration of glycosylated hemoglobin. Additionally, the drug has a comparable kinetic profile across different races and ethnicities. Aliskiren binds moderately to plasma proteins, and the intensity of this interaction does not depend on its plasma concentration. Elimination of the drug is carried out unchanged in the bile, excretion in urine is less than 1%. The peculiarities of the drug are low competition with other drugs for binding to blood plasma proteins and the absence of the need for degradation on cytochromes of the P450 system. Aliskiren over a wide range of doses does not have a clinically significant effect on the metabolism of warfarin, lovastatin, atenolol, celecoxib, cimetidine and digoxin. In addition, the drug at a daily dose of 300 mg orally does not change the pharmacokinetic profile of other antihypertensive drugs, such as ramipril (10 mg/day), amlodipine (10 mg/day), valsartan (320 mg/day), hydrochlorothiazide (25 mg/day). days).

Aliskiren is a highly selective non-peptide inhibitor of renin synthesis, superior in this regard to other members of its class. The drug does not have additional inhibitory effects on other aspartate peptidases, such as cathepsin D and pepsin, either experimentally or clinically. Moreover, aliskiren leads to a significant blockade of renin secretion even in relatively low doses and with limited bioavailability.

Early phase 1 and 2 studies have shown that the drug provides effective blockade of the RAS and a dose-dependent reduction in systemic blood pressure. Thus, in healthy volunteers, the drug, when administered once compared to placebo, leads to an almost 80% reduction in the initial concentration of angiotensin II, although the plasma renin content decreases more than tenfold. Increasing the observation time from one to eight days while continuing constant administration of aliskiren contributed to the maintenance of deep blockade of the RAS due to a reduction in the plasma pool of angiotensin II by 75% of the initial level. At a dose of 160 mg/day, aliskiren has the same depressant effect on the plasma concentration of angiotensin II as the ACE inhibitor enalapril at a dose of 20 mg/day. In addition, at a dose of more than 80 mg/day, the drug promotes a significant regression of plasma aldosterone levels (Nussberger et al., 2002).

In a cohort of patients with hypertension, over four weeks of therapy, aliskiren at a dose of 75 mg/day led to a reduction in plasma renin activity (PAR) by 34 ± 7% of the initial level; after increasing the dose to 150 mg/day, the drug contributed to a decrease in PAR by 27 ± 6% by the end of the eighth week of continuous use. It should be noted that the initial significant decrease in plasma renin activity is accompanied by a gradual increase that does not reach the initial level. It is important that this phenomenon is not accompanied by a loss of the antihypertensive effect of the drug. Nevertheless, the possibility of the phenomenon of “escaping” renin secretion from the influence of aliskiren has led to the need to continue research in the direction of assessing the prospects for the effectiveness of the combination of PIR and ARA, which are also capable of reducing plasma renin activity. Thus, in a small pilot crossover study, it was found that aliskiren at a dose of 300 mg/day was superior to valsartan at a dose of 160 mg/day in terms of reducing plasma renin activity. However, the combination of aliskiren and valsartan in half daily doses turned out to be preferable compared to the isolated use of each drug in terms of its ability to block RAS activity. This was reflected in a deeper decrease not only in PAR, but also in the levels of angiotensin II and angiotensin II. The researchers concluded that both drugs have a synergistic effect on RAS activity. Similar data were obtained by O'Brien et al. (2007) when using aliskiren (150 mg/day) in combination with hydrochlorothiazide, ramipril or irbesartan in patients with mild and moderate hypertension. It turned out that aliskiren contributed to a significant reduction in PAR by 65% (p< 0,0001) от исходного уровня, тогда как рамиприл и ирбесартан в монотерапии приводили к 90% и 175% снижению ПАР соответственно. Добавление алискирена к антигипертензивным лекарственным средствам не отражалось на дополнительном снижении ПАР, но приводило к достижению более эффективного контроля за величиной офисного АД и суточным профилем АД .

Thus, aliskiren is capable of quite serious blockade of the RAS, which is accompanied by the expected clinical effects in the form of a reduction in vascular tone and a decrease in systemic blood pressure. However, the drug is not without fundamentally negative qualities, primarily associated with the implementation of the phenomenon of “evasion” of PAR, which is, in principle, characteristic of all drugs that mediate their pharmacodynamic effect through chronic blockade of the RAS. It has been established that theoretical concerns regarding a decrease in the effectiveness of aliskiren due to restoration of renin secretion or the presence of withdrawal syndrome after sudden cessation of treatment are not supported by clinical observations.

Results of major clinical studies on the use of aliskiren in patients with arterial hypertension

Studies of the clinical effectiveness of aliskiren were aimed at obtaining evidence of the existence of its advantages regarding antihypertensive potential and the ability to realize a beneficial effect on target organs, compared with placebo, with other representatives of antihypertensive drugs, including ACEIs and ARBs.

When comparing the therapeutic potential of aliskiren with other representatives of antihypertensive drugs, it turned out that the drug in ranged doses of 75, 150, 300 mg per day is as effective as hydrochlorothiazide in doses of 6.25; 12.5 and 25 mg per day. At the same time, in patients with mild and moderate hypertension, the frequency of achieving the target blood pressure level when using aliskiren at a dose of 75 mg/day was 51.9%, and when the daily dose was increased to 300 mg - 63.9%. According to Sica et al. (2006) to achieve adequate control of hypertension in almost 45% of patients with mild and moderate blood pressure who received aliskiren at a daily dose of 150-300 mg, there was a need for an additional diuretic. It has been established that aliskiren in ranged doses (37.5; 75; 150; 300 mg orally once) exhibits the ability to dose-dependently reduce systemic blood pressure. At the same time, the severity of the antihypertensive effect of aliskiren in the dose range of 75-300 mg/day was equivalent to 100 mg/day of losartan. According to a study by Gradman et al. (2005), aliskiren at a dose of 150 mg/day had similar efficacy and was comparable in safety to irbesartan at the same dose. In a randomized, controlled, crossover, 8-week study involving 1123 patients with mild to moderate hypertension, it was shown that aliskiren monotherapy at ranged doses of 75, 150 and 300 mg per day was as effective as valsartan monotherapy at doses of 80, 160 and 320 mg per day. At the same time, the combined use of aliskiren and valsartan has a synergistic effect on the degree of blood pressure reduction and exceeds the effectiveness of each component of this combination as monotherapy.

Weir et al. (2006), in a meta-analysis of eight RCTs (n = 8570), found that among patients with mild and moderate hypertension, monotherapy with aliskiren (75-600 mg/day) leads to a dose-dependent decrease in blood pressure, regardless of the age and gender of patients.

Overall, it should be noted that aliskiren is as effective in reducing office and 24-hour BP as equivalent doses of other antihypertensive drugs, and may be somewhat more effective than routinely used doses of ACEIs and ARBs. The latter circumstance may be associated with the long half-life of aliskiren, which ensures adequate control of blood pressure in the morning. This fact is likely to have important clinical implications in the prevention of cardiovascular and cerebrovascular events.

Organoprotective qualities of aliskiren

It has been established that chronic blockade of the RAS in patients with hypertension improves clinical outcomes not only due to the reduction of blood pressure, but also, possibly, due to effective organ protection. At the same time, the contribution of the intrinsic qualities of antihypertensive drugs to the reduction of global cardiovascular risk is widely debated. It is believed that it is the control of blood pressure that is the main determinant in the implementation of the organoprotective effects of antihypertensive therapy. However, PIRs may potentially have beneficial effects on end organs and clinical outcomes. It is assumed that aliskiren may have an organoprotective effect by inhibiting specific renin receptors present in the mesangial tissue of the kidneys and in the subendothelium of the renal and coronary arteries. In addition, there is evidence of a beneficial effect of aliskiren on the activity of local renal RAS.

The experiment proved the ability of aliskiren to induce vasodilation of the renal arteries and promote an increase in minute diuresis, lead to the reversal of albuminuria, and also contribute to the reduction of LV hypertrophy. At the same time, the reno- and cardioprotective qualities of aliskiren were comparable to those of valsartan.

In clinical studies, aliskiren demonstrated a positive effect in reducing albuminuria, preventing a decrease in glomerular filtration rate and increasing plasma creatinine. Moreover, the nephroprotective activity of the drug was not inferior to the ARA losartan. In addition, aliskiren is able to reduce the severity of pro-inflammatory and neurohumoral activation not only in experiments, but also in clinical settings. The possibility of reversing LV hypertrophy with long-term administration of aliskiren and potentiation of this effect with the addition of losartan have been shown.

Tolerability and safety of aliskiren in monotherapy and in combination

Aliskiren showed high safety both in healthy volunteers during phase 1 trials and in patients with hypertension. The incidence of adverse side effects or adverse reactions leading to patient refusal to continue the study was comparable to that in the placebo groups. The most commonly reported side effects were fatigue, headache, dizziness and diarrhea. It should be noted that the incidence of side effects depends on the dose of the drug. It is important that aliskiren does not affect the metabolism of endogenous bradykinin and substance P, so the drug does not lead to the manifestation of cough and angioedema as often as ACE inhibitors. Overall, tolerability of aliskiren is comparable to that of ARBs and placebo.

Aliskiren is not only well tolerated by patients with impaired liver function, but also has a pharmacokinetic profile that is independent of the severity of liver failure. There is data on the safety of aliskiren in patients with renal failure, diabetes mellitus, obesity, metabolic syndrome and heart failure, as well as in older age groups. However, there is a potential danger of deterioration in renal function when using aliskiren in monotherapy or when combining it with ARA in patients with renal artery stenosis, during parenteral anesthesia, as well as in a cohort of people receiving COX-2 inhibitors.

In conclusion, it should be noted that the new class of antihypertensive drugs certainly deserves attention. However, regarding the clinical efficacy of PIR and aliskiren in particular, additional research is required to increase the body of evidence regarding possible beneficial effects on target organs. The amount of existing data regarding the prospects for the use of PIR in the treatment of not only hypertension, but also HF and diabetes mellitus is currently limited. However, high safety, good tolerability, favorable therapeutic profile, and the possibility of wide combination with various drugs allow us to hope that PIR will take its rightful place among antihypertensive drugs.

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The history of studying the renin-angiotensinaldosterone system (RAAS), which turned out to be the most successful in terms of developing approaches to pharmacological modulation of its activity, allowing to prolong the life of patients with cardiovascular and renal diseases, began 110 years ago. When renin, the first component, was identified. Subsequently, in experimental and clinical studies, it was possible to clarify the physiological role of renin and its significance in the regulation of RAAS activity in various pathological conditions, which became the basis for the development of a highly effective therapeutic strategy - direct renin inhibitors.

Currently, the first direct renin inhibitor Rasilez (aliskiren) is justified even in situations where other RAAS blockers - ACE inhibitors and ARBs are not indicated or their use is difficult due to the development of adverse events.

Another circumstance that allows us to count on the additional capabilities of direct renin inhibitors in protecting the target organs of hypertension compared to other RAAS blockers is that when using drugs that block the RAAS at other levels, according to the law of negative feedback, an increase in the concentration of prorenin occurs, and an increase in plasma renin activity. It is this circumstance that cancels the often noted decrease in the effectiveness of ACE inhibitors, including from the point of view of their capabilities in reducing high blood pressure. Back in the early 1990s, when many of the organoprotective effects of ACE inhibitors were not established as reliably as they are today, it was shown that as their dose increases, plasma renin activity and plasma angiotensin concentration significantly increase. Along with ACE inhibitors and ARBs, thiazide and loop diuretics can also provoke an increase in plasma renin activity.

The first direct renin inhibitor, the effectiveness of which was confirmed in controlled clinical trials of phase III, has a sufficient duration of action and reduces high blood pressure even in monotherapy, was aliskiren, and its use today can be considered as an innovative approach to the treatment of hypertension. Comparisons were made of its effect on the plasma concentration and activity of individual components of the RAAS with ACE inhibitors and ARBs. It turned out that aliskiren and enalapril almost equally reduce the plasma concentration of angiotensin II, but unlike aliskiren, taking enalapril led to a more than 15-fold increase in renin activity in the blood plasma. The ability of aliskiren to prevent negative changes in the balance of activity of the RAAS components was also demonstrated when compared with ARBs.

A pooled analysis of clinical studies that included a total of 8481 patients receiving aliskiren monotherapy or placebo showed that a single dose of aliskiren at a dose of 150 mg/day. or 300 mg/day. caused a decrease in SBP by 12.5 and 15.2 mmHg. respectively, compared with a decrease of 5.9 mmHg, placebo (P<0,0001). Диастолическое АД снижалось на 10,1 и 11,8 мм рт.ст. соответственно (в группе, принимавшей плацебо – на 6,2 мм рт.ст.; Р < 0,0001). Различий в антигипертензивном эффекте алискирена у мужчин и женщин, а также у лиц старше и моложе 65 лет не выявлено.

In 2009, the results of a multicenter controlled clinical trial were published, in which the effectiveness of aliskiren and hydrochlorothiazide was compared in 1124 patients with hypertension. If necessary, amlodipine was added to these drugs. Already at the end of the monotherapy period, it became clear that aliskiren leads to a more pronounced decrease in blood pressure than hydrochlorothiazide (-17.4/-12.2 mmHg versus -14.7/-10.3 mmHg; R< 0,001)

Pharmacokinetics

When alisicrene is taken orally, the bioavailability of the drug is 2.6%, protein binding is 47-51%, and the constant half-life of the drug in the blood plasma is 40 hours, which allows us to calculate that the duration of its antihypertensive effect may exceed 24 hours. In this case, there is no cumulation of the drug in the body and equilibrium concentration of aliskiren in the blood plasma is achieved between 5 and 7 days when taken once a day. It is excreted unchanged by the intestines (91%). Used at a dose of 150 mg/day, if necessary, increase the dose after 2 weeks to 300 mg 1 time/day.

The indication for prescribing aliskiren is hypertension.

Contraindications:

· hypersensitivity;

· severe chronic renal failure;

· nephrotic syndrome;

· renovascular hypertension;

· program hemodialysis;

· severe liver failure;

· under 18 years of age;

· pregnant women.

Side effects:

· diarrhea;

· skin rash;

angioedema;

Cautions:

· bilateral renal artery stenosis;

· stenosis of the artery of a single kidney;

kidney transplantation;

· diabetes;

· decrease in BCC;

hyponatremia;

· hyperkalemia.

An overdose can cause a pronounced decrease in blood pressure.

Interaction

The likelihood of interaction with other drugs is low. Does not have a significant effect on the pharmacokinetics of atorvastatin, valsartan, metformin, amlodipine. Caution should be prescribed together with potassium salts and potassium-sparing diuretics.

Aliskiren combines well with antihypertensive drugs of other classes - ARBs, ACE inhibitors, AK, β-AB, diuretics, and the effects of the drugs are mutually enhanced. In patients with diabetes mellitus, when taking aliskiren in combination with an ACE inhibitor, the incidence of hyperkalemia increases (5.5%).

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Currently, a significant number of folic acid antagonists have been obtained. Depending on their structure, they are divided into competitive and non-competitive inhibitors.

Effect of activators and inhibitors on enzyme activity

Evidence of the effect of various angiotensin-converting enzyme inhibitors in various diseases

Interest in the direct pharmacological blockade of active renin is determined by the need to eliminate its hemodynamic and tissue effects, which are realized largely through interaction with prorenin receptors. Control of renin activity allows us to count on the effective management of most components of the renin-angitensin-aldosterone system. In this regard, the direct renin inhibitor aliskiren, the effectiveness of which has been demonstrated in large controlled clinical trials, may be particularly effective in preventing renal damage in patients with arterial hypertension.

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers are today a fundamentally important component of the long-term management strategy for patients with high and very high risk hypertension, as well as type 2 diabetes mellitus, chronic heart failure and chronic kidney disease with proteinuria. The range of use of aldosterone antagonists is somewhat narrower - they are used for the treatment of chronic heart failure and special variants of hypertension, in particular, arising from primary hyperaldosteronism, and also not inferior to standard combinations of antihypertensive drugs. Currently, 110 years after the discovery of renin, it can be argued that direct blockade of its effects has acquired the status of an independent approach to antihypertensive therapy, which has a number of properties that are not typical for drugs that block the RAAS at other levels.

■ RASILESI (Rasilesi)

Synonym: Aliskiren.

Pharmachologic effect. A selective renin inhibitor of non-peptide structure with pronounced activity. Secretion of renin by the kidneys and activation of the RAAS occurs with a decrease in blood volume and renal blood flow. Renin acts on angiotensinogen, resulting in the formation of angiotensin I, which is converted by ACE into active angiotensin II. Angiotensin II is a powerful vasoconstrictor, stimulating the release of catecholamines, enhancing aldosterone secretion and Na + reabsorption, which leads to an increase in blood pressure. A prolonged increase in angiotensin II stimulates the production of mediators of inflammation and fibrosis, which leads to target organ damage. Angiotensin P reduces renin secretion via a negative feedback mechanism. Thus, rasilosis reduces plasma renin activity, in contrast to ACE and angiotensin receptor antagonists. Aliskiren neutralizes the suppression of negative feedback, resulting in a decrease in renin activity (by 50-80% in patients with arterial hypertension), as well as the concentration of angiotensin I and angiotensin II. When taken at a dose of 150 mg and 300 mg 1 time per day, a dose-dependent decrease in systolic and diastolic blood pressure is observed within 24 hours. A sustained hypotensive clinical effect (reduction in blood pressure by 85-90% of the maximum) is achieved 2 weeks after the start of therapy at a dose of 150 mg 1 time per day. Monotherapy for diabetes mellitus allows you to achieve an effective and safe reduction in blood pressure; when combined with ramipril, it leads to a more pronounced decrease in blood pressure compared to monotherapy with each drug separately.

Indications for use. Arterial hypertension.

Contraindications. Hypersensitivity, history of angioedema when using rasilez, severe liver failure, severe chronic renal failure, nephrotic syndrome, renovascular hypertension, hemodialysis, concomitant use of cyclosporine, pregnancy, lactation, children (up to 18 years).

Carefully. Unilateral or bilateral stenosis of the renal arteries, stenosis of the artery of a single kidney, diabetes mellitus, decreased blood volume, hyponatremia, hyperkalemia, condition after kidney transplantation.

Method of administration and dose. Orally, regardless of food intake, the initial and maintenance dose is 150 mg 1 time per day; if necessary, the dose is increased to 300 mg 1 time per day.

Side effect. From the digestive system: often - diarrhea. From the skin: infrequently - skin rash. Other: dry cough (0.9% compared to 0.6% with placebo), angioedema.

Release form: tablets of 150 mg and 300 mg No. 28.