Medicines for hypertension of a new generation: a list of drugs. Treatment of arterial hypertension (hypertension) with a renin inhibitor How a direct renin inhibitor helps with hypertension

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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 and electrolyte balance. Studies of recent decades have shown the great importance of increasing the activity of the RAS in the formation and progression of arterial hypertension (AH), heart failure (HF), chronic kidney disease (CKD), and systemic atherosclerosis. In addition, 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. Angiotensin II is the main conductor that provides almost all known effects of RAS. The latter realizes its tonic effects through the 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, 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 was found that angiotensin II promotes the accumulation of collagen matrix, the production of cytokines, adhesive molecules, the activation of the intracellular signaling system (multiple intracellular signaling cascades) through the stimulation of mitogen-activated protein kinase (mitogen-activated protein), tyrosine kinase and various transcription factors.

Numerous studies have confirmed the involvement of RAS activation in the processes of cardiac remodeling. Thus, great importance is attached to the participation of angiotensin II in the formation of pathological left ventricular (LV) hypertrophy, 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 an increase in the 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 the mass of the left ventricle, followed by a decrease in the first 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, responsible for the intensity of intracellular protein synthesis. And although the role of activation of these genes is not completely clear, many researchers associate the increase in their expression with a violation of the intracellular signaling cascade and activation of the fetal type of metabolism.

It has been established that angiotensin II can also play a central role in the processes of arterial remodeling, intensification of oxidative stress, and apoptosis. In addition, angiotensin II can take part in the formation and progression of arterial hypertension, heart failure, atherosclerotic vascular damage, diabetic and non-diabetic nephropathies, angiopathy in diabetes mellitus, eclampsia of pregnant women, 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 involvement of most of the molecular and cellular mechanisms of ASD 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 has yet to be established.

Thus, angiotensin II seems to be the central link in a complex cascade of RAS activation that has a negative impact on the structural and functional characteristics of the cardiovascular system. At the same time, renin secretion is the first and most important step in increasing the synthesis of angiotensin I, angiotensin II, and other products of the RAS cascade as a whole. Moreover, the implementation of all subsequent effects of 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 the arteries, including the renal and coronary ones. Renin has a high affinity for the formation of a specific bond with its own receptors. Renin bound to the receptor induces a series of intracellular processes that result in increased angiotensin II production. It should be noted that the described type of receptors has the ability to bind prorenin with the subsequent implementation of the processes of activation of the synthesis of angiotensin II. It is now established that prorenin is a powerful predictor of the occurrence of microvascular complications in diabetes mellitus, although the mechanism underlying this process is not fully understood. In this regard, restriction of 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 RAS activity has been carried out in the direction of limiting the production of angiotensin II due to inhibition of the angiotensin-converting enzyme, blockade of angiotensin II and aldosterone receptors, and also due to the restriction of renin secretion, mainly through the use of beta-blockers. At the same time, numerous studies have shown that an adequate reduction in RAS activity is postulated rather than actually achieved. It has been established that the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor antagonists (ARAs) is often associated with the 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 ARA, 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 "ACE inhibitor + ARA", "ACE inhibitor + beta-blocker", "ACE inhibitor + spironolactone (eplerenone)". The emergence of direct renin inhibitors (RIRs), which reduce the secretion of the latter and limit the intensity of angiotensin II production, has been considered as a possible way to achieve more complete control over RAS activity and overcome the escape phenomenon.

Cyrenes are a new class of antihypertensive drugs

The first PIRs (enalkiren, remicren, 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. At the same time, 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 ACE inhibitors, and the end of the millennium - ARA. The first success for kirens came only after the synthesis of CGP 60536, a non-peptide low molecular weight renin inhibitor suitable for oral administration, called aliskiren. To date, the drug has passed all stages of clinical trials and since April 2007 it has been recommended for the treatment of hypertension in the USA and the countries of the European Union.

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, the peak plasma concentration is reached after 1-2 hours, the bioavailability is in the range of 16.3%, and the half-life is 2.3 hours. In healthy volunteers, the pharmacokinetic properties of the drug were evaluated in the dose range from 40 to 1800 mg/day. . It turned out that the plasma concentration of aliskiren increases progressively after administration of 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 administration. In addition, the researchers noted the ability of the drug to moderate cumulation 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. In addition, the drug has a comparable kinetic profile in representatives of different races and ethnic groups. Aliskiren moderately binds to plasma proteins, and the intensity of this interaction does not depend on its plasma concentration. Elimination of the drug is carried out unchanged mainly with bile, urinary excretion is less than 1%. The features of the drug are low competition with other drugs for the connection with blood plasma proteins and the absence of the need for degradation on the cytochromes of the P450 system. Aliskiren in a wide dose range 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). day) .

Aliskiren is a highly selective non-peptide inhibitor of renin synthesis, superior in this regard to other representatives of this class. The drug does not have an additional inhibitory effect on other aspartate peptidases, such as cathepsin D and pepsin, neither in experimental nor in clinical conditions. Moreover, aliskiren leads to a significant blockade of renin secretion even at relatively low doses and with limited bioavailability.

Early phase 1 and 2 studies have shown that the drug promotes effective blockade of the RAS and a dose-dependent reduction in systemic blood pressure. Thus, in healthy volunteers, the drug, when taken once, compared with placebo, leads to an almost 80% reduction in the initial concentration of angiotensin II, although the content of renin in plasma decreases by more than ten times. An increase in the observation time from one to eight days with continued continuous use of aliskiren contributed to the preservation of deep RAS blockade due to the reduction of the angiotensin II plasma pool 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 does the ACE inhibitor enalapril at a dose of 20 mg / day. In addition, at a dose of more than 80 mg / day, the drug contributes to a significant regression of the plasma aldosterone content (Nussberger et al., 2002).

In a cohort of patients with hypertension, during 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 blood plasma renin activity is accompanied by its gradual increase, which 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 realizing the phenomenon of "escape" of renin secretion from the influence of aliskiren led to the need to continue research in the direction of evaluating 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 is superior to valsartan at a dose of 160 mg / day in relation to the reduction of plasma renin activity. At the same time, the combination of aliskiren and valsartan at half daily doses was preferable compared to the isolated use of each of the drugs due to the ability to block the activity of the RAS. This resulted 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 had 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 to 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 able to carry out a rather 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 devoid of fundamentally negative qualities, primarily associated with the implementation of the phenomenon of "escape" of PAR, which in principle is typical for all drugs that mediate their pharmacodynamic effect by chronic blockade of the RAS. It has been established that theoretical concerns regarding a decrease in the effectiveness of aliskiren due to the restoration of renin secretion or the presence of a withdrawal syndrome after a sudden refusal of treatment are not confirmed by clinical observations.

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

Studies of the clinical efficacy of aliskiren were aimed at obtaining evidence of the existence of its advantages in terms of antihypertensive potential and the ability to realize a beneficial effect on target organs, compared with placebo, with other representatives of antihypertensive drugs, including ACE inhibitors 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 level of blood pressure 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) in order to achieve adequate control over the magnitude of hypertension in almost 45% of patients with mild and moderate blood pressure who received aliskiren at a daily dose of 150-300 mg, it became necessary to additionally prescribe a 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 Gradman et al. (2005), aliskiren at a dose of 150 mg/day was similar in efficacy and safety to irbesartan at the same dose. In a randomized controlled crossover 8-week study involving 1123 patients with mild to moderate hypertension, aliskiren monotherapy at ranged doses of 75, 150 and 300 mg per day was shown to be 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 BP reduction and exceeds the effectiveness of each component of this combination in the form of monotherapy.

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

In general, it should be noted that aliskiren is effective in reducing office and 24-hour BP, as are equivalent doses of other antihypertensive drugs, and it may be slightly more effective than routinely used doses of ACE inhibitors and ARBs. The latter circumstance may be due to the long half-life of aliskiren, due to which adequate control of blood pressure in the morning is achieved. This fact is likely to have a serious clinical significance in the prevention of cardio- and cerebrovascular events.

Organoprotective qualities of aliskiren

It has been established that chronic blockade of the RAS in patients with AH contributes to the improvement of 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 properties of antihypertensive drugs to the reduction of the global value of cardiovascular risk is widely discussed. It is believed that it is the implementation of control over the value of blood pressure that is the main determinant in the implementation of the organ-protective effects of antihypertensive therapy. However, PIRs have the potential to have beneficial effects on target organs and clinical outcomes. It is assumed that aliskiren may have an organ-protective effect through inhibition of specific renin receptors present in the mesangial tissue of the kidneys, in the subendothelium of the renal and coronary arteries. In addition, there is evidence of a beneficial effect of aliskiren on the activity of the local renal RAS.

The experiment proved the ability of aliskiren to induce vasodilation of the renal arteries and increase minute diuresis, lead to 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 has shown a positive effect on the reduction of albuminuria, the prevention of a decrease in glomerular filtration rate and an increase in plasma creatinine. Moreover, the nephroprotective activity of the drug was not inferior to ARA losartan. In addition, aliskiren is able to reduce the severity of pro-inflammatory and neurohumoral activation not only in the experiment, but also in the clinical setting. The possibility of reversing LV hypertrophy with long-term administration of aliskiren and the potentiation of this effect with the addition of losartan were shown.

Tolerability and safety of aliskiren in monotherapy and in combination administration

Aliskiren showed high safety both in healthy volunteers during the first phase trials and in patients with hypertension. The frequency of unwanted side effects or adverse reactions that led patients to refuse 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. In general, the tolerability of aliskiren is comparable to that of ARA and placebo.

Aliskiren is not only well tolerated by patients with hepatic impairment, but also has a pharmacokinetic profile independent of the severity of hepatic insufficiency. There are data on the safety of aliskiren in patients with renal insufficiency, diabetes mellitus, obesity, metabolic syndrome and heart failure, as well as in older age groups. However, there is a potential risk of deterioration in renal function against the background of the use of aliskiren in monotherapy or when combined with ARA in patients with renal artery stenosis, during parenteral anesthesia, as well as in a cohort of individuals receiving COX-2 inhibitors.

In conclusion, it should be noted that a new class of antihypertensive drugs certainly deserves attention. However, the clinical efficacy of PIR and aliskiren in particular requires more research to increase the amount 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 PIRs will take their rightful place among antihypertensive drugs.

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At present, 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 action 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. 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.

Renin-angiotensin-aldosterone system (RAAS) regulates blood pressure, as well as sodium and water homeostasis.

Renin synthesized by specialized smooth muscle cells in the wall of the afferent arteriole of the renal glomerulus (juxtaglomerular apparatus). Renin release may be due to a drop in renal perfusion pressure and sympathetic activation of p-adrenergic receptors in juxtaglomerular cells.

Once renin enters the blood, it breaks down angiotensinogen synthesized in the liver to angiotensin I decapeptide. ACE, in turn, converts angiotensin II into biologically active angiotensin II.

ACE, circulating in plasma, is localized on the surface of endothelial cells. It is a non-specific peptidase capable of cleaving C-terminal dipeptides from a variety of peptides (dipeptidylcarboxypeptidase). Thus, ACE helps to inactivate kinins such as bradykinin.

Angiotensin II can activate two different receptors (AT 1 and AT 2) associated with G-proteins. The most significant effect that angiotensin II has on the cardiovascular system is mediated by AT 1 receptors. Angiotensin II raises blood pressure in various ways:
1) vasoconstriction of both arterial and venous channels;
2) stimulation of aldosterone secretion, leading to an increase in renal reabsorption of NaCl and water, and consequently, to an increase in BCC;
3) a central increase in the tone of the sympathetic nervous system, and on the periphery - an increased release and action of norepinephrine. A prolonged increase in angiotensin II levels can lead to hypertrophy of the muscle cells of the heart and arteries and an increase in the amount of connective tissue (fibrosis).

a) ACE inhibitors, such as captopril and enalapril, occupy the active site of this enzyme, competitively inhibiting the breakdown of angiotensin I. These drugs are used for hypertension and chronic heart failure. The decrease in elevated blood pressure is mainly due to a decrease in the formation of angiotensin II. The weakening of the breakdown of kinins, which have a vasodilating effect, can also contribute.

At congestive heart failure after application, the minute volume of the heart increases, because due to the fall in peripheral resistance, the afterload of the ventricles decreases. Venous stasis (preload) decreases, aldosterone secretion and tone of venous capacitive vessels decrease.

Side effects. If the activation of the RAAS is due to the loss of electrolytes and water (as a result of treatment with diuretics, heart failure, or renal artery stenosis), the use of ACE inhibitors may initially cause an excessive fall in blood pressure. Quite often there is such a side effect as dry cough (10%), the cause of which may be a decrease in the inactivation of kinins in the bronchial mucosa.

Combination ACE inhibitors with potassium-sparing diuretics can lead to hyperkalemia. In most cases, ACE inhibitors are well tolerated and give a good therapeutic effect.

Towards new data analogues drugs include lisinopril, ramipril, quinapril, fosinopril, and benazepril.

b) Antagonists of AT 1 -receptors of angiotensin II (« sartans"). Blockade of AT 1 receptors by antagonists inhibits the activity of angiotensin II. Losartan was the first drug in the "sartans" group, analogues were soon developed. These include candesartan, eprosartan, olmensartan, telmesartan, and valsartan. The main (hypotensive) effects and side effects are the same as those of ACE inhibitors. However, "sartans" do not cause dry cough, because they do not inhibit the breakdown of kinins.

in) renin inhibitor. Since 2007, a direct renin inhibitor (aliskiren) has been on the market that can be used to treat hypertension. This drug is poorly absorbed after oral administration (bioavailability 3%) and is excreted very slowly (half-life 40 hours). Its spectrum of action is similar to AT 1 receptor antagonists.

The answer to this question is simple:

Point one: in order to meaningfully understand this issue, you need to finish medical school. After that, it can be theoretically assumed that drug A in patient X with one "bunch" of diseases will work better than drug B in patient Y with a different "bunch", however:

Point two: in each patient, the strength of the effect of any drug and the level of side effects are unpredictable and all theoretical discussions on this topic are meaningless.

Point three: drugs within the same class, subject to therapeutic doses, usually have approximately the same effect, but in some cases - see point two.

Point four: to the question "which is better - watermelon or pork cartilage?" different people will answer differently (There are no comrades for the taste and color). Also, different doctors will answer questions about drugs in different ways.

How good are the latest (new, modern) drugs for hypertension?

I publish the dates of registration in Russia of the "newest" drugs for hypertension:

Edarbi (Azilsartan) - February 2014

Rasilez (Aliskiren) - May 2008

The degree of "newest" evaluate yourself.

Unfortunately, all new drugs for hypertension (representatives of the ARA (ARB) and PIR classes) are not stronger than enalapril invented more than 30 years ago, the evidence base (the number of studies on patients) for new drugs is less, and the price is higher. Therefore, I cannot recommend "the latest drugs for hypertension" just because they are the latest.

Repeatedly, patients who wished to start treatment with "something newer" had to return to older drugs because of the ineffectiveness of new ones.

Where to buy cheap medicine for hypertension?

There is a simple answer to this question: look for a website - a pharmacy search engine in your city (region). To do this, type in Yandex or Google the phrase "pharmacy reference" and the name of your city.

A very good search engine aptekamos.ru works for Moscow.

Enter the name of the medicine in the search bar, choose the dosage of the drug and your place of residence - and the site gives out addresses, phone numbers, prices and the possibility of home delivery.

Can drug A be replaced by drug B? What can replace drug C?

These questions are often asked to search engines, so I launched a special site analogs-drugs.rf, and started filling it with cardiological drugs.

A brief reference page containing only the names of drugs and their classes is on this site. Come in!

If there is no exact replacement of the drug (or the drug is discontinued), you can try one of his "classmates" UNDER THE CONTROL OF THE DOCTOR. Read the "Classes of Hypertension Drugs" section.

What is the difference between drug A and drug B?

To answer this question, first go to the page of analogues of drugs (here) and find out (or rather write down) which active substances from which classes contain both drugs. Often the answer lies on the surface (for example, a diuretic is simply added to one of the two).

If drugs belong to different classes, read the descriptions of those classes.

And in order to absolutely accurately and adequately understand the comparison of each pair of drugs, you still need to graduate from the medical institute.

Introduction

This article was written for two reasons.

The first is the prevalence of hypertension (the most common cardiac pathology - hence the mass of questions on treatment).

The second is the fact that instructions for preparations are available on the Internet. Despite the huge number of warnings about the impossibility of self-prescribing drugs, the patient's stormy research thought makes him read information about drugs and draw his own, far from always correct, conclusions. It is impossible to stop this process, so I stated my view on the issue.

THIS ARTICLE IS INTENDED EXCLUSIVELY TO INTRODUCE THE CLASSES OF ANTIHYPERTENSIVE DRUGS AND CANNOT BE A GUIDE TO INDEPENDENT TREATMENT!

THE APPOINTMENT AND CORRECTION OF THE TREATMENT OF HYPERTENSION SHOULD BE CARRIED OUT ONLY UNDER THE FULL-TIME SUPERVISION OF A DOCTOR!!!

There are a lot of recommendations on the Internet for limiting the consumption of table salt (sodium chloride) for hypertension. Studies have shown that even a fairly severe restriction of salt intake leads to a decrease in blood pressure numbers by no more than 4-6 units, so I personally am quite skeptical about such recommendations.

Yes, in the case of severe hypertension, all means are good, when hypertension is combined with heart failure, salt restriction is also absolutely necessary, but with low and non-severe hypertension, it can be a pity to look at patients who poison their lives by restricting salt intake.

I think that for patients with "average" hypertension, the recommendation "do not eat pickles (or analogues) in three-liter jars" will be sufficient.

With the ineffectiveness or insufficient effectiveness of non-drug treatment, pharmacological therapy is prescribed.

What is the strategy for selecting antihypertensive therapy?

When a patient with hypertension first visits a doctor, a certain amount of research is carried out, depending on the equipment of the clinic and the financial capabilities of the patient.

A fairly complete examination includes:

• Laboratory methods:
  • General blood analysis.
  • Urinalysis to exclude renal origin of hypertension.
  • Blood glucose, glycosylated hemoglobin for the purpose of screening for diabetes mellitus.
  • Creatinine, blood urea to assess kidney function.
  • Total cholesterol, high and low density lipoprotein cholesterol, triglycerides in order to assess the degree of atherosclerotic process.
  • AST, ALT in order to assess liver function if it is possible to prescribe cholesterol-lowering drugs (statins).
  • T3 free, T4 free and TSH to assess thyroid function.
  • It's good to look at uric acid - gout and hypertension often go together.
• Hardware methods:
  • ABPM (24-hour blood pressure monitoring) to assess daily fluctuations.
  • Echocardiography (ultrasound of the heart) to assess the thickness of the left ventricular myocardium (if there is hypertrophy or not).
  • Duplex scanning of the vessels of the neck (commonly called MAG or BCA) to assess the presence and severity of atherosclerosis.
• Expert advice:
  • Optometrist (in order to assess the condition of the fundus vessels, which are often affected in hypertension).
  • Endocrinologist-nutritionist (in case of increased patient weight and deviations in thyroid hormone tests).
• Self examination:
  • BPMS (Blood Pressure Self-Control) - measurement and recording of pressure and pulse numbers on both hands (or on the one where the pressure is higher) in the morning and evening in a sitting position after 5 minutes of quiet sitting. The results of the SCAD recording after 1-2 weeks are presented to the doctor.

The results obtained during the examination may affect the treatment tactics of the doctor.

Now about the algorithm for selecting drug treatment (pharmacotherapy).

Adequate treatment should lead to a decrease in pressure to the so-called target values ​​(140/90 mm Hg, with diabetes - 130/80). If the numbers are higher, the treatment is wrong. THE PRESENCE OF HYPERTENSION CRISES IS ALSO A PROOF OF INADEQUATE TREATMENT.

Drug treatment for hypertension SHOULD CONTINUE FOR LIFE, so the decision to start it must be strongly justified.

With low pressure figures (150-160), a competent doctor usually first prescribes one drug in a small dose, the patient leaves for 1-2 weeks to record the SCAD. If the target levels have been established at the initial therapy, the patient continues to take the treatment for a long time and the reason for meetings with the doctor is only an increase in blood pressure above the target, which requires adjustment of the treatment.

ALL STATEMENTS OF DRUG ADDICTIVITY AND THE NEED TO REPLACE THEM, SIMPLY BECAUSE OF THE LONG TIME OF USE, ARE FICTIONAL. SUITABLE DRUGS ARE TAKEN FOR YEARS, AND THE ONLY REASONS FOR REPLACING THE DRUG ARE ONLY INTOLERANCE AND INEFFICIENCY.

If the patient's pressure on the background of the prescribed therapy remains above the target, the doctor can increase the dose or add a second and, in severe cases, a third or even a fourth drug.

Original drugs or generics (generics) - how to make a choice?

Before moving on to a story about drugs, I will touch on a very important issue that significantly affects the wallet of each patient.

Creating new drugs requires a lot of money - at present, at least a BILLION dollars is spent on the development of one drug. In this regard, the development company, under international law, has the so-called patent protection period (from 5 to 12 years), during which other manufacturers do not have the right to bring copies of a new drug to the market. During this period, the developer company has a chance to return the money invested in the development and get the maximum profit.

If a new drug has proved to be effective and in demand, at the end of the patent protection period, other pharmaceutical companies acquire the full right to produce copies, the so-called generics (or generics). And they actively use this right.

Accordingly, drugs that are of little interest to patients are not copied. I prefer not to use "old" original preparations that do not have copies. As Winnie the Pooh said, this "zhzhzh" is not without reason.

Often, generic manufacturers offer a wider range of doses than the original drug manufacturers (for example, Enap produced by KRKA). This additionally attracts potential consumers (the procedure for breaking tablets makes few people happy).

Generic drugs are cheaper than brand-name drugs, but because they are produced by companies with LESS financial resources, the production technologies of generic factories may well be less efficient.

Nevertheless, generic companies are doing quite well in the markets, and the poorer the country, the greater the percentage of generics in the total pharmaceutical market.

Statistics show that in Russia the share of generic drugs in the pharmaceutical market reaches up to 95%. This indicator in other countries: Canada - more than 60%, Italy - 60%, England - more than 50%, France - about 50%, Germany and Japan - 30% each, USA - less than 15%.

Therefore, the patient in relation to generics faces two questions:

• What to buy - original drug or generic?
• If a choice is made in favor of a generic, which manufacturer should be preferred?

• If there is a financial opportunity to buy the original drug, it is better to buy the original.
• If there is a choice between several generics, it is better to buy a drug from a well-known, "old" and European manufacturer than from an unknown, new and Asian one.
• Drugs costing less than 50-100 rubles, as a rule, work extremely poorly.

And the last recommendation. In the treatment of severe forms of hypertension, when 3-4 drugs are combined, taking cheap generics is generally impossible, since the doctor is counting on the work of a drug that has no real effect. A doctor can combine and increase doses without effect, and sometimes simply replacing a low-quality generic with a good drug removes all questions.

When talking about a drug, I will first indicate its international name, then the original brand name, then the names of trustworthy generics. The absence of a generic name in the list indicates my lack of experience with it or my unwillingness, for one reason or another, to recommend it to the general public.

What classes of drugs for hypertension are there?

There are 7 classes of drugs:

Angiotensin-converting enzyme inhibitors (ACE inhibitors)

These are drugs that at one time revolutionized the treatment of hypertension.

In 1975, captopril (Capoten) was synthesized, which is currently used to relieve crises (its use in the permanent treatment of hypertension is undesirable due to the short period of action of the drug).

In 1980, Merck synthesized enalapril (Renitec), which remains one of the most prescribed drugs in the world today, despite the intensive work of pharmaceutical companies to create new drugs. Currently, more than 30 factories produce enalapril analogues, and this indicates its good qualities (bad drugs are not copied).

The rest of the group's drugs do not differ significantly from each other, so I'll tell you a little about enalapril and give the names of other representatives of the class.

Unfortunately, the reliable duration of enalapril is less than 24 hours, so it is better to take it 2 times a day - in the morning and in the evening.

The essence of the action of the first three groups of drugs - ACE inhibitors, ARA and PIR - blocking the production of one of the most powerful vasoconstrictor substances in the body - angiotensin 2. All drugs of these groups reduce systolic and diastolic pressure without affecting the pulse rate.

The most common side effect of ACE inhibitors is the appearance of a dry cough a month or more after the start of treatment. If a cough appears, the drug must be replaced. Usually they are exchanged for representatives of the newer and more expensive ARA group (ARA).

The full effect of the use of ACE inhibitors is achieved by the end of the first - second week of administration, therefore, all earlier blood pressure figures do not reflect the degree of effect of the drug.

All representatives of ACE inhibitors with prices and forms of release.

Angiotensin receptor antagonists (blockers) (sartans or ARAs or ARBs)

This class of drugs was created for patients who had cough as a side effect of ACE inhibitors.

To date, none of the ARB companies claims that the effect of these drugs is stronger than that of ACE inhibitors. This is confirmed by the results of large studies. Therefore, the appointment of an ARB as the first drug, without trying to prescribe an ACE inhibitor, I personally regard as a sign of a positive assessment by the doctor of the thickness of the patient's wallet. Prices for a month of admission have not yet fallen significantly below a thousand rubles for any of the original sartans.

ARBs reach their full effect by the end of the second to fourth week of use, so the assessment of the effect of the drug is possible only after two or more weeks have passed.

Class members:

• Losartan (Cozaar (50mg), Lozap (12.5mg, 50mg, 100mg), Lorista (12.5mg, 25mg, 50mg, 100mg), Vasotens (50mg, 100mg))
• Eprosartan (Teveten (600mg))
• Valsartan (Diovan (40mg, 80mg, 160mg), Valsacor, Valz (40mg, 80mg, 160mg), Nortivan (80mg), Valsafors (80mg, 160mg))
• Irbesartan (Aprovel (150mg, 300mg))
• Candesartan (Atakand (80mg, 160mg, 320mg))
• Telmisartan (Micardis (40mg, 80mg))
• Olmesartan (Cardosal (10mg, 20mg, 40mg))
• Azilsartan (Edarbi (40mg, 80mg))

Direct renin inhibitors (DRIs)

This class so far consists of only one representative, and even the manufacturer admits that it cannot be used as the only remedy for the treatment of hypertension, but only in combination with other drugs. In combination with the high price (at least one and a half thousand rubles for a month of admission), I do not consider this drug very attractive to the patient.

• Aliskiren (Rasilez (150mg, 300mg))

For the development of this class of drugs, the creators received the Nobel Prize - the first case for "industrial" scientists. The main effects of beta-blockers are slowing the heart rate and lowering blood pressure. Therefore, they are used mainly in hypertensive patients with a frequent pulse and in the combination of hypertension with angina pectoris. In addition, beta-blockers have a good antiarrhythmic effect, so their appointment is justified with concomitant extrasystoles and tachyarrhythmias.

The use of beta-blockers in young men is undesirable, since all representatives of this class negatively affect potency (fortunately, not in all patients).

In the annotations to all BBs, bronchial asthma and diabetes mellitus appear as contraindications, but experience shows that quite often patients with asthma and diabetes get along well with beta-blockers.

Old representatives of the class (propranolol (obzidan, anaprilin), atenolol) are unsuitable for the treatment of hypertension due to the short duration of action.

Short-acting forms of metoprolol I do not give here for the same reason.

Members of the beta-blocker class:

• Metoprolol (Betaloc ZOK (25mg, 50mg, 100mg), Egiloc retard (100mg, 200mg), Vasocardin retard (200mg), Metocard retard (200mg))
• Bisoprolol (Concor (2.5mg, 5mg, 10mg), Coronal (5mg, 10mg), Biol (5mg, 10mg), Bisogamma (5mg, 10mg), Cordinorm (5mg, 10mg), Niperten (2.5mg; 5mg; 10mg ), Biprol (5mg, 10mg), Bidop (5mg, 10mg), Aritel (5mg, 10mg))
• Nebivolol (Nebilet (5mg), Binelol (5mg))
• Betaxolol (Locren (20mg))
• Carvedilol (Carvetrend (6.25mg, 12.5mg, 25mg), Coriol (6.25mg, 12.5mg, 25mg), Talliton (6.25mg, 12.5mg, 25mg), Dilatrend (6.25mg, 12.5mg , 25mg), Acridiol (12.5mg, 25mg))

Calcium antagonists, pulse-lowering (AKP)

The action is similar to beta-blockers (slow down the pulse, reduce pressure), only the mechanism is different. Officially allowed the use of this group in bronchial asthma.

I give only "long-playing" forms of the representatives of the group.

• Verapamil (Isoptin SR (240mg), Verogalide EP (240mg))
• Diltiazem (Altiazem RR (180mg))

Dihydropyridine calcium antagonists (AKD)

The era of ACD began with the drug, which is familiar to everyone, but modern recommendations do not recommend taking it, to put it mildly, even with hypertensive crises.

It is necessary to firmly refuse to take this drug: nifedipine (adalat, cordaflex, cordafen, cordipin, corinfar, nifecard, fenigidin).

More modern dihydropyridine calcium antagonists have firmly taken their place in the arsenal of antihypertensive drugs. They increase the pulse much less (unlike nifedipine), reduce pressure well, and are applied once a day.

There is evidence that long-term use of drugs in this group has a preventive effect on Alzheimer's disease.

Amlodipine, in terms of the number of factories producing it, is comparable to the "king" of the ACE inhibitor enalapril. I repeat, bad drugs are not copied, only very cheap copies cannot be bought.

At the beginning of taking this group of drugs can give swelling of the legs and hands, but usually it disappears within a week. If it does not pass, the drug is canceled or replaced with a "cunning" form of Es Cordi Cor, which almost does not have this effect.

The fact is that the "ordinary" amlodipine of most manufacturers contains a mixture of "right" and "left" molecules (they differ from each other, like the right and left hands - they consist of the same elements, but are organized differently). The "right" version of the molecule generates most of the side effects, and the "left" provides the main therapeutic effect. The manufacturer Es Cordi Core left only the useful "left" molecule in the medicine, so the dose of the drug in one tablet is halved, and there are fewer side effects.

Group representatives:

• Amlodipine (Norvasc (5mg, 10mg), Normodipin (5mg, 10mg), Tenox (5mg, 10mg), Cordi Cor (5mg, 10mg), Es Cordi Cor (2.5mg, 5mg), Cardilopin (5mg, 10mg), Kalchek (5mg, 10mg), Amlotop (5mg, 10mg), Omelar cardio (5mg, 10mg), Amlovas (5mg))
• Felodipine (Plendil (2.5mg, 5mg, 10mg), Felodipine (2.5mg, 5mg, 10mg))
• Nimodipine (Nimotop (30mg))
• Lacidipine (Lacipil (2mg, 4mg), Sakur (2mg, 4mg))
• Lercanidipine (Lerkamen (20mg))

Centrally acting drugs (application point - the brain)

The history of this group began with clonidine, which "reigned" until the advent of the era of ACE inhibitors. Clonidine greatly reduced the pressure (in case of overdoses - to coma), which was subsequently actively used by the criminal part of the country's population (clopheline thefts). Clonidine also caused a terrible dry mouth, but this had to be put up with, since other drugs at that time were weaker. Fortunately, the glorious history of clonidine is coming to an end, and you can buy it only with a prescription in a very small number of pharmacies.

Later drugs of this group are devoid of the side effects of clonidine, but their "power" is significantly lower.

They are usually used as part of complex therapy in excitable patients and in the evening with nocturnal crises.

Dopegyt is also used to treat hypertension in pregnant women, since most classes of drugs (ACE inhibitors, sartans, beta-blockers) have a negative effect on the fetus and cannot be used during pregnancy.

• Moxonidine (Physiotens (0.2mg, 0.4mg), Moxonitex (0.4mg), Moxogamma (0.2mg, 0.3mg, 0.4mg))
• Rilmenidine (Albarel (1mg)
• Methyldopa (Dopegyt (250 mg)

Diuretics (diuretics)

In the middle of the 20th century, diuretics were widely used in the treatment of hypertension, but time revealed their shortcomings (any diuretics eventually "wash out" useful substances from the body, it has been proven to cause the appearance of new cases of diabetes, atherosclerosis, gout).

Therefore, in modern literature there are only 2 indications for the use of diuretics:

• Treatment of hypertension in elderly patients (over 70 years).
• As a third or fourth drug with insufficient effect of two or three already prescribed.

In the treatment of hypertension, only two drugs are usually used, and most often in the composition of "factory" (fixed) combined tablets.

The appointment of fast-acting diuretics (furosemide, torasemide (Diuver)) is highly undesirable. Veroshpiron is used to treat severe cases of hypertension and only under the strict full-time supervision of a physician.

• Hydrochlorothiazide (Hypothiazide (25mg, 100mg)) - very widely used as part of combined preparations
• Indapamide (Potassium-sparing) - (Arifon retard (1.5mg), Ravel SR (1.5mg), Indapamide MV (1.5mg), Indap (2.5mg), Ionic retard (1.5mg), Acripamide retard (1.5mg) 5mg))

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 treated with 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 (R<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)