Treatment of arterial hypertension (hypertension) with a renin inhibitor. New drugs to inhibit the renin-angiotensin-aldosterone system Molecules that increase blood pressure

The renin-angiotensin-aldosterone system plays a key role in the regulation of blood pressure and fluid and electrolyte balance. A direct inhibitor of renin - aliskiren, by reducing the activity of plasma renin, has cardio- and nephroprotective effects. The antihypertensive effect does not depend on gender, race, age, 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. The 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. Later, its importance in the regulation of RAAS activity in pathological conditions was shown, which became the basis for the development of direct renin inhibitors (DRIs). The RAAS plays a key role in the regulation of blood pressure (BP) and fluid and electrolyte balance. An increase in RAAS activity plays an important role in the formation and progression of arterial hypertension (AH), chronic heart failure (CHF), chronic kidney disease, and systemic atherosclerosis. 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 RAAS are realized through angiotensin II (ATII) through stimulation of specific receptors. Activation of angiotensin receptor subtype 1 (AT1) leads to vasoconstriction, stimulates the release of vasopressin, aldosterone, endothelin, norepinephrine. The physiological role of other angiotensin receptor subtypes (AT3, AT4 and ATx) continues to be studied. ATII contributes to the accumulation of collagen matrix, production of cytokines, adhesive molecules, activation of the intracellular signaling system, increased expression of fetal phenotype genes, plays an important role in myocardial remodeling and left ventricular (LV) hypertrophy, ATII participates in the processes of arterial remodeling, intensification of oxidative stress and apoptosis, contributes to the formation and progression of hypertension, CHF, atherosclerotic vascular damage, diabetic and non-diabetic nephropathy, angiopathy in diabetes mellitus (DM), eclampsia of 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 the subsequent effects of 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 (ACE inhibitors) and ATII receptor blockers (ARBs). The mechanism of action of ACE inhibitors is as follows: ACE activity 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. The 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, RAAS activity has been controlled by limiting the production of ATII, blockade of ATII and aldosterone receptors, due to the restriction of renin secretion, mainly through the use of β-blockers. Numerous studies have shown that an adequate decrease in RAAS activity with the help of ACE inhibitors, ARBs or aldosterone is postulated rather than actually achieved, since the phenomenon of "escape" of the antihypertensive and organoprotective effects of RAAS blockers develops during their long-term use. To overcome this phenomenon, combinations of ACE inhibitor + ARB, ACE inhibitor + β-blocker, ACE inhibitor + spironolactone are used. The emergence of PIR is seen as a way to achieve more complete control of RAAS activity and overcome the "escape" phenomenon.

The first PIRs were synthesized in the 1970s, 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 the activity of plasma renin (ARP), 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 (vessels); vasoconstriction (brain). A. acts at the point of activation of the RAAS and reduces the ARP. Unlike ACE inhibitors and ARBs, A reduces levels of ATI, AII, and ARP. Renin has enzymatic as well as receptor-mediated activity.

Pharmacokinetics A. Clinical studies have shown A tolerability 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 provides a single dose per day. The recommended starting dose A is 150 mg with a further increase to 300 mg. Pharmacokinetic characteristics of A do not depend on fasting glycemia and plasma concentrations of glycosylated hemoglobin. Elimination of the drug is carried out unchanged in the bile, excretion in the 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 (Ob.), metabolic syndrome) and in the presence of target organ damage (TOM) ( persistent decrease in glomerular filtration rate); an increase in renin ARP can be iatrogenic, provoked by ACE inhibitors and / or diuretics (loop, thiazide), causing renal sodium loss: 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 exacerbation of POM and potentially fatal cardiovascular (CV) and renal complications; increased ARP is an independent factor for the pharmacological effect of PIR, which makes it possible to achieve a decrease in blood pressure and inhibition of the progression of POM. A. can claim the role of 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 mediated activation of prorenin receptors leads to tissue destruction. PIR is indicated not only for renovascular hypertension and CHF, but also for increased plasma concentration 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 to moderate hypertension. Evaluation of the efficacy and safety of A. in 672 patients with hypertension of I-II degrees (st.) 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 withdrawal; A was well tolerated; the frequency 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 art. AG), and DBP - by 11 mm Hg. Art. A provides control of blood pressure in the early morning period. After the cancellation of A, there is no "rebound" phenomenon. Pooled analysis of clinical trials including 8481 patients. treated with A monotherapy 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 efficacy of A and HCTZ (initial antihypertensive therapy) was compared in 1124 hypertensive patients; 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 mm Hg vs. -14.7/-10.3 mm Hg Hg, r<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.

The ability of A. to reduce blood pressure and reduce albuminuria has been established. In the AVOID study in 599 patients with diabetic nephropathy with hypertension, the effect of the combination of the maximum doses of losartan and A on albuminuria (by the ratio of albumin/urine creatinine) was evaluated. 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 the urinary albumin/creatinine ratio of 50% or more was achieved in only 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 combined therapy of hypertension. In patients with mild to moderate hypertension without and with 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 DM, A + ramipril significantly better reduce blood pressure than both components of monotherapy. A provides significantly better blood pressure control than ramipril. In patients with mild to moderate hypertension, A + valsartan lowers blood pressure significantly 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 with 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 of 6 months of therapy).

In 2009, the design of the ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) study (part of the ASPIRE HIGHER program) was published, which studies the effect of dual blockade of the RAAS using a combination of A and standard therapy (ACE inhibitor or ARB) in patients with diabetes Type 2 with a high risk of CVC and renal complications, partly due to the increase in RDA. The primary goal of this study is to evaluate the effectiveness of adding A to standard therapy on the effect on the combined end point (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 designed 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 efficiency of A can be expected in those variants of hypertension, in which there is a tendency to increase ARP (emerging essential hypertension, obj., metabolic syndrome, type 2 diabetes, chronic renal failure). The vast majority of patients with hypertension already at the first stage of treatment require combined antihypertensive therapy and, as shown in one of the recently published clinical trials, as part of combinations, A retains its activity regardless of the initial ARP. The increase in ARP in hypertensive patients is considered as a diagnostic marker and as an independent risk factor for potentially fatal CV events. Pharmacological modulation of ARP is one of the most promising approaches to managing the risk of CVD in patients with AH associated with kidney damage, metabolic syndrome, and obesity. . The AVOID study (Aliskiren in the eValuation of prOteinuria In Diabetes) (part of the ASPIRE HIGHER program) is designed to evaluate the potential of a particular antihypertensive drug in target organ protection in a variety of situations characterized by a very high risk of potentially fatal complications (LV hypertrophy, type 2 DM). , HSN). Interim results suggest that direct A-blockade of renin is one of the most available strategies for improving long-term prognosis. In the ALLAY (The Aliskiren Left Ventricular Assessment of Hypertrophy) study, A caused a decrease in the mass index of the LV myocardium, reflecting the regression of its hypertrophy, in patients with hypertension and overweight. The combination of A and losartan provided a further decrease in the mass index of the LV myocardium by an additional 20% compared with losartan alone, 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 poor prognosis (persistent increase in plasma concentration of natriuretic peptide) and hypertension further improved 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 a lower risk of increasing creatininemia and potassium. Excreted predominantly in bile rather than urine, A retains its antihypertensive effect but does not impair renal function in patients with a persistent decrease in glomerular filtration rate. It is in nephrology that aggressive blockade of the RAAS with the help of several classes of drugs used simultaneously can be effective in terms of preventing end-stage renal failure. A reduces albuminuria (significantly superior to monotherapy with each of the drugs) and the likelihood of an irreversible deterioration in kidney function in a group of patients (with proteinuria> 1 g / day), as shown in the COOPERATE study (COMbination 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 ACE inhibitors 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 frequency of initiation of program hemodialysis and a doubling of creatininemia in high-risk patients with POM. The objects of demonstration of nephroprotective properties of A. may be the following clinical situations: hypertension / metabolic syndrome or type 2 diabetes with albuminuria; AH associated with a persistent decrease in glomerular filtration rate; Hypertension in chronic kidney disease with proteinuria (including nephrotic) and without it (for example, tubulo-interstitial nephropathy); renovascular hypertension of various origins; patients who, for various reasons, have an increase in creatininemia or hyperkalemia when using ACE inhibitors or ARBs; terminal chronic renal failure, including those treated with program hemodialysis or permanent outpatient peritoneal dialysis; kidney transplant recipients.

A new class of antihypertensive drugs (AIDs) requires more research to increase the amount of evidence to slow the progression of POM.

A, obviously, is indicated for most 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 end-stage renal failure and improving the prognosis of these patients.

ON THE. Andreichev, Z.M. Galeeva

Kazan State Medical University

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

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23. Mukhin N. A., Fomin V. V. Plasma renin activity - a risk factor and an independent target of antihypertensive therapy: the role of aliskiren // Consilium Medicum. - T. 11. - 2009. - No. 10. - S. 3-6.

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 al the American College of Cardiology. 57th Annual Scientific Session, March 31, 2008.

25. Mc. Murray J.V., Pitt B., Latini R. et al. Effects of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failure // Circulation-Heart Failure. - 2008. - Vol. 1. - S. 17-24.

26. Nakao N., Yoshimura A., Morita H. et al. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomized controlled trial // Lancet. - 2003. - Vol. 361(9352). - S. 117-124.

27. Mann I.F., Schmieder R. E., Mc.Queen M. et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial // Lancet. - 2008. - Vol. 372 (9638). - S. 547-553.

28. Chazova I.E., Fomin V.V., Paltseva E.M. Direct renin inhibitor aliskiren - new possibilities for protecting the kidneys in arterial hypertension // Clinical Nephrology. - No. 1. - 2009. - C. 44-49.

29. Chazova I.E., Fomin V.V. Direct renin inhibitor aliskiren: possibilities of correction of cardio-renal syndrome // Systemic hypertension. - 2009. - No. 4. - C. 53-58.

30. Diagnosis and treatment of arterial hypertension: Russian recommendations // Systemic hypertension. - 2010. - No. 3. - C. 5-26.

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. The control of renin activity makes it possible to rely on the effective control of most components of the renin-angitensin-aldosterone system. In this regard, the direct renin inhibitor aliskiren, which has been shown to be effective in large controlled clinical trials, may be particularly effective in preventing renal damage in hypertensive patients.

Angiotensin converting enzyme inhibitors (ACE inhibitors) 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 application of aldosterone antagonists is somewhat narrower - they are used to treat chronic heart failure and special types of hypertension, in particular, arising from primary hyperaldosteronism, and also not inferior to standard combinations of antihypertensive drugs. At present, 110 years after the discovery of renin, it can be argued that the 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 characteristic of drugs that block the RAAS at other levels.

■ RASILEZ (Rasilesi)

Synonym: Aliskiren.

Pharmachologic effect. Selective renin inhibitor of non-peptide structure with pronounced activity. The secretion of renin by the kidneys and the activation of the RAAS occurs with a decrease in BCC and renal blood flow. Renin acts on angiotensinogen, resulting in the formation of angiotensin I, which is converted by ACE to active angiotensin II. Angiotensin II is a powerful vasoconstrictor, stimulating the release of catecholamines, increases 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 damage to target organs. Angiotensin II reduces renin secretion by a negative feedback mechanism. Thus, rasilez 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, there is a dose-dependent decrease in systolic and diastolic blood pressure within 24 hours. Sustained hypotensive clinical effect (decrease 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 in diabetes mellitus allows 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 with monotherapy with each drug separately.

Indications for use. Arterial hypertension.

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

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

Method of application and dose. Inside, regardless of the meal, the initial and maintenance dose - 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. On the part of the skin: infrequently - skin rash. Others: dry cough (0.9% compared with 0.6% when taking placebo), angioedema.

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

The history of the study of the renin-angiotensin-aldosterone system (RAAS), which turned out to be the most successful in terms of developing approaches to the pharmacological modulation of its activity, allowing to prolong the life of patients with cardiovascular and renal diseases, began 110 years ago. When was renin identified - the first component. Later, 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 makes it possible to count on the additional possibilities 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, there is an increase in the concentration of prorenin, 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 ability to reduce elevated blood pressure. Back in the early 1990s, when many 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.

Aliskiren was the first direct renin inhibitor, the effectiveness of which was confirmed in controlled phase III clinical trials, which has a sufficient duration of action and reduces elevated blood pressure even in monotherapy, and its prescription can now be considered as an innovative approach to the treatment of hypertension. Comparisons were made of its effect on 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, enalapril administration led to a more than 15-fold increase in plasma renin activity. The ability of aliskiren to prevent negative changes in the balance of activity of RAAS components was also demonstrated when compared with ARBs.

A pooled analysis of a clinical study that included a total of 8481 patients who received 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 mm Hg. respectively, compared with a 5.9 mmHg reduction, 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 hypertensive patients. If necessary, amlodipine was added to these drugs. By 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 mm Hg vs. -14.7/-10.3 mm Hg; R< 0,001)

03.07.2012

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With arterial hypertension (hypertension), the amount of Renin enzyme in the blood is increased. This leads to a persistent and prolonged increase in the amount of Angiotensin 2 protein in the blood and tissues of the body. Angiotensin 2 has a vasoconstrictive effect, promotes sodium and water retention in the body, which leads to an increase in blood pressure. A high level of angiotensin 2 in the blood and tissues for a long time causes a persistent increase in blood pressure, that is, arterial hypertension. Renin inhibitor - a drug that combines with Renin, as a result of which Renin is neutralized and loses enzymatic activity. This interconnectedly leads to a decrease in the level of angiotensin 2 in the blood and tissues - to a decrease in blood pressure.

AT2 has a vasoconstrictive effect, promotes the retention of sodium and water in the body. This leads to an increase and an increase in the volume of circulating blood. Secondarily, there is an increase in the strength of heart contractions. All this in total causes an increase in (BP) both systolic (upper) and diastolic (lower). The higher the level of Renin in the blood, the higher the level of AT2 in the blood, the higher the blood pressure.

The sequence of enzymatic transformations: Renin + Angiotensinogen = Angiotensin 1 + ACE = Angiotensin 2, is called Renin-Angiotensin System (RAS) or Renin-Angiotensin-Aldosterone System (RAAS). By activation (increased activity) of the RAS is meant an increase in the blood level of Renin, AT2.

A high level of Renin in the blood leads to an increase in the level of AT2 in the blood and tissues. A high level of AT2 in the blood and tissues for a long time causes a persistent increase in blood pressure, that is -.

A decrease in the level of Renin in the blood leads to a decrease in the level of AT2 in the blood and tissues - to a decrease in blood pressure.

Renin inhibitor- a medicinal substance that enters into combination with Renin, as a result of which Renin is neutralized, loses its enzymatic activity, and the enzymatic activity of Renin in the blood decreases. Renin bound to a renin inhibitor loses its ability to cleave angiotensinogen to AT1. At the same time, there is an interconnected decrease in the level of AT2 in the blood and tissues - a decrease in blood pressure, a decrease in the activity of the RAS, an improvement in blood flow, blood supply to organs and tissues of the body.

Aliskiren is currently the first and only Renin inhibitor with which all stages of clinical trials have been carried out and which has been recommended for the treatment of arterial hypertension since 2007.

medicinal substance Aliskiren produced by the pharmaceutical industry under trade (commercial) names:

1. Rasilez in the form of a simple drug that contains only one drug substance - Aliskiren;
2. Ko Rasilez in the form of a combined (complex) drug that contains two drugs: the renin inhibitor Aliskiren and the diuretic drug Hydrochlorothiazide (saluretic, thiazide diuretic).

You can place your feedback and comments on the use of the renin inhibitor Aliskiren for the treatment of arterial hypertension below.

Candidate of Chemical Sciences O. BELOKONEVA.

Perhaps today there is no more common chronic disease than hypertension (high blood pressure). Even its slow and seemingly imperceptible course eventually leads to fatal consequences - heart attacks, strokes, heart failure, kidney damage. Back in the century before last, scientists found that the kidneys produce a protein - renin, which causes an increase in blood pressure in the vessels. But only 110 years later, through the joint efforts of biochemists and pharmacologists, it was possible to find an effective remedy that could withstand the dangerous action of a long-known substance.

Science and life // Illustrations

Rice. 1. Liver cells constantly release a long peptide angiotensinogen into the bloodstream.

Rice. 2. Cardiovascular continuum: the path from hypertension to damage to the heart, blood vessels, kidneys and other organs.

Rice. 3. A direct renin inhibitor (DRI) is built into the active center of renin and prevents it from splitting angiotensinogen.

In the early 1990s, the number of cardiovascular patients began to grow in Russia. And so far in our country, the mortality rate among the working population exceeds European indicators. Representatives of the male half of the population turned out to be especially unstable to social cataclysms. According to the World Health Organization, the life expectancy of men in our country is only 59 years. Women turned out to be more resilient - they live an average of 72 years. Every second citizen of our country dies from cardiovascular diseases and their consequences - heart attacks, strokes, heart failure, etc.

One of the main causes of cardiovascular disease is atherosclerotic vascular disease. With atherosclerosis, the inner shell of the vessel thickens, so-called plaques are formed, which narrow or completely clog the lumen of the artery, which disrupts the blood supply to vital organs. The main cause of atherosclerotic vascular lesions is a violation of fat metabolism, mainly an increase in cholesterol.

Another equally important and most common cause of cardiovascular disease is hypertension, which is manifested by a steady increase in blood pressure. An increase in blood pressure also leads to vascular damage. Namely, the lumen of the vessel narrows, its wall thickens (hypertrophy of the muscle layer develops), the integrity of the inner lining of the vessel, the endothelium, is violated. Such changes are called vascular remodeling. All this leads to the fact that the vessel affected by atherosclerosis loses elasticity, ceases to pulsate under the influence of blood flow. If healthy vessels can be compared with flexible rubber tubes that transmit a pulse wave and dampen blood flow turbulence, then pathological vessels are similar to a metal pipeline. Vascular remodeling contributes to the progression of atherosclerosis.

Hypertension as a cause of heart attacks and strokes

Hypertension often goes unnoticed. Patients do not know that they are sick, do not change their lifestyle, do not go to the doctor and do not take medication. Meanwhile, due to its destructive effect on the body, hypertension can be called a “silent killer”. If the disease develops quickly, then it leads to the progression of atherosclerosis and, ultimately, to a heart attack, stroke, gangrene of the lower extremities. If the disease proceeds for a long time and the body has time to adapt to blockage of blood vessels, damage to the heart muscle develops (first hypertrophy, and then myocardial atrophy, which leads to chronic heart failure), kidneys (albuminuria - loss of protein in the urine, impaired renal function and, as a result, - renal failure) and metabolic disorders (glucose intolerance, and then diabetes mellitus).

The causes of hypertension are not fully understood, although research in this direction has been going on for more than a century. How does hypertension occur and why does it cause such deadly complications? The answer to these questions is given by biochemistry.

Molecules that increase blood pressure

The role of biochemical disorders in the development of hypertension has been known for a long time. In 1897, Robert Tigerstedt, professor of physiology at Karolinska University in Stockholm, a Finn by birth, announced his discovery at an international conference in Moscow. Together with his assistant, Per Gustav Bergman, he discovered that intravenous administration of kidney extract caused an increase in blood pressure in rabbits. The substance that increases blood pressure is called renin. Tigerstedt's report did not cause a sensation, moreover, the study was considered small, insignificant, made for the sake of another publication. The disillusioned professor stopped his research and returned to Helsinki in 1900. Bergman took up medical practice, and the scientific world forgot about the pioneering work of Scandinavian physiologists for 40 years.

In 1934, a Canadian scientist working in California, Harry Goldblatt, caused the symptoms of arterial hypertension in dogs by clamping the renal artery and proceeded to release the protein substance - renin from the kidney tissue. This was the beginning of discoveries in the field of the mechanism of regulation of blood pressure. True, Goldblatt managed to obtain a preparation of pure renin only after 30 years.

Literally a year after the first publication of Goldblatt, in 1935, two research groups at once - from Buenos Aires under the leadership of Eduardo Mendez and the American under the leadership of Irving Page - independently of each other, also using the technique of clamping the renal artery, isolated another substance that increases arterial pressure. Unlike the large protein molecule renin, it was a small peptide consisting of only eight amino acids. American researchers called it hypertensin, and Argentine researchers called it angiotonin. In 1958, during an informal meeting over a glass of martini, scientists compared the results of their studies, realized that they were dealing with the same compound, and came to a compromise agreement on the chimeric name of the peptide they had discovered - angiotensin.

So, the main compounds that increase pressure were discovered, only the connecting links in the mechanism of the development of hypertension were missing. And they appeared. In the late 1950s, the concept of the functioning of the renin-angiotensin system (RAS) was formed.

The classic idea of ​​how the RAS functions is shown in Fig. one.

It is angiotensin II, acting on certain receptors, that leads to an increase in blood pressure, and with prolonged activation of the RAS, to dramatic consequences in the form of damage to the heart, blood vessels, kidneys, and ultimately to death (Fig. 2).

Several types of angiotensin II receptors have been found, the most studied of which are type 1 and type 2 receptors. When angiotensin II interacts with type 1 receptors, the body responds with vasospasm and increased production of aldosterone. Aldosterone is a hormone of the adrenal cortex that is responsible for fluid retention in the body, which also contributes to an increase in blood pressure. So type 1 receptors are responsible for the "harmful" action of angiotensin II, that is, for an increase in blood pressure. The interaction of angiotensin II with type 2 receptors, on the contrary, leads to a beneficial effect in the form of vasodilation.

As it turned out, the destructive effect of angiotensin II is not limited to an increase in pressure. Recent studies show that the binding of angiotensin II to type 1 receptors contributes to the development of atherosclerosis. It turned out that angiotensin II causes inflammation in the walls of blood vessels, promotes the formation of reactive oxygen species and, as a result, disrupts the structure and function of the endothelium - the cells lining the walls of blood vessels. Dysfunction of the endothelium leads to the development of atherosclerosis and remodeling of the vessel walls.

So, the renin-angiotensin system (RAS) plays a key role both in increasing pressure and in the development of atherosclerosis. Scientists have found that the genes responsible for the functioning of proteins involved in the ASD determine a person's predisposition to hypertension and cardiovascular disease. If certain genes are active, then the RAS is also hyperactivated, and the likelihood of developing hypertension and cardiovascular disease increases several times.

Search for drugs for hypertension. Three targets in a molecular chain

As soon as the concept of the renin-angiotensin system (RAS) was formed, three molecular targets were immediately identified in it, with the help of which it was possible to prevent the development of hypertension. Therefore, the strategy for the search for new drugs has developed along three main lines (see Fig. 1): the search for renin inhibitors; search for angiotensin-converting enzyme (ACE) inhibitors; search for type 1 angiotensin II receptor blockers (ARBs).

The enzyme renin has been and remains the most attractive target for pharmacologists, since it is the key molecule of the RAS. If there is no renin, angiotensin II is not produced either. However, the first inhibitors (substances that block activity) of renin, developed back in the 60s of the last century, could not be put into practice due to unsatisfactory pharmacological properties and the high cost of synthesis. They were poorly absorbed from the gastrointestinal tract and had to be administered intravenously.

After the failure of renin, pharmacologists began looking for another molecular target. The poisonous snake Bothrops gararaca helped scientists find it, the bite of which leads to a long and sometimes fatal drop in blood pressure. In 1960, the Brazilian Sergio Ferreiro began searching for the substance contained in the poison and causing "vascular paralysis." In 1968, they found that the substance was found to be an inhibitor of an enzyme that converts angiotensin I to angiotensin II. This is how the angiotensin-converting enzyme (ACE) was discovered. In 1975, captopril appeared, the first synthetic ACE inhibitor that could be taken in tablet form and whose effectiveness other ACE inhibitors could not surpass. It was a breakthrough and a real success in the treatment of hypertension. Now the number of ACE inhibitors is very large, there are more than 30 of them.

Along with the successes, data appeared on the side effects of captopril and other ACE inhibitors, in particular, the appearance of a rash, itching, and a painful dry cough. In addition, even at maximum doses, ACE inhibitors cannot completely neutralize the harmful effects of angiotensin II. In addition, the formation of angiotensin II during treatment with ACE inhibitors is very quickly restored due to alternative mechanisms. This is the so-called escape effect, which causes doctors to increase the dose or change the drug.

In Europe and the United States, over the past 10 years, ACE inhibitors have given way to a new class of drugs - angiotensin receptor blockers (ARBs). Modern ARBs completely turn off the "bad" type 1 receptors without affecting the "beneficial" type 2 receptors. These drugs, the first of which was losartan, have practically no side effects characteristic of ACE inhibitors, in particular, they do not cause a dry cough. ARBs are as good as ACE inhibitors in lowering blood pressure and more. Recent studies show that ACE inhibitors and angiotensin receptor blockers (ARBs) prevent damage to the heart and blood vessels and even improve the condition of blood vessels and myocardium affected by hypertension.

Curiously, if captopril is still as effective as newer ACE inhibitors, ARBs are constantly being improved. The newer ARBs are more specific for type 1 receptors and remain active in the body longer.

Last Assault

Despite the success of ACE inhibitors and ARBs, pharmacologists have not given up hope of "overcoming" the substance that plays a key role in hypertension, renin. The goal is very attractive - to turn off the molecule that "triggers" the biochemical cascade of the RAS.

A more complete blockade of the angiotensin II synthesis system was expected from renin inhibitors. The renin enzyme catalyses the process of angiotensinogen conversion, that is, it interacts with only one molecule in the biochemical cascade (Fig. 3). This means that renin inhibitors should not have significant side effects, unlike ACE inhibitors, which affect not only ACE, but also other regulatory systems.

A long-term search for renin inhibitors resulted in the synthesis of several molecules, one of which, aliskiren, already appeared in the arsenal of American doctors in 2007. Direct renin inhibitors (RDIs) have many advantages. They are easily tolerated by patients, are slowly excreted from the body, well (better than ACE inhibitors) reduce pressure, do not cause a withdrawal effect upon discontinuation.

So, our story began with renin, and it will end with it. The development of science has finally given scientists the opportunity to "approach" the protein, discovered 110 years ago, at a completely new molecular level. But perhaps the new drug is just the beginning. It turned out that renin is not only an enzyme, but also a hormone that interacts with special receptors discovered in 2002. It is likely that inhibitors of renin can not only block its enzymatic activity, but also prevent the binding of renin to renin receptors. This possibility is being actively explored. The next step in the search for new drugs for the treatment of hypertension may be the synthesis of renin receptor blockers or even therapy at the gene level. The development of inhibitors of enzymes for the synthesis of aldosterone and other enzymes - endopeptidases is also promising. But that's a topic for another article.

In any case, in the near future, patients will have access to drugs that are far superior to all known today and that can reverse the horrendous statistics of mortality from cardiovascular diseases. All this is due to scientific research and the introduction of the developments of scientists into medical practice.

By the non-commercial name of the drug for hypertension, one can conclude about the mechanism of its action. Angiotensin-converting enzyme (ACE) inhibitors have the ending -pril in their name (enalapril, lisinopril, ramipril). Angiotensin receptor blockers (ARBs) - ending sartan (valsartan, irbesartan, telmisartan). Direct renin inhibitors (DRIs) can be distinguished by the ending kiren (aliskiren, remikiren, enalkiren).

A non-commercial name should not be confused with a trademark. There are usually no rules and patterns in the names of brand names of original drugs.

Glossary for the article

Blockers are substances that block the interaction of physiologically active substances with receptors.

Inhibitors are substances that block the activity of enzymes.

Receptors are protein molecules on the surface of the cell membrane. The interaction of other molecules with them leads to the launch of a chain of reactions inside the cell.

Enzymes are protein molecules that catalyze processes in a living cell.