Treatment of arterial hypertension (essential hypertension) with a renin inhibitor. New and promising drugs blocking the renin-angiotensin-aldosterone system Renin inhibitors drugs names

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

Renin is synthesized by specialized smooth muscle cells in the wall of the renal glomerulus bringing arteriole (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 bloodstream, it breaks down the angiotensinogen synthesized in the liver to the decapeptide angiotensin I. ACE, in turn, converts angiotensin II into biologically active angiotensin II.

APF, circulating in plasma, is localized on the surface of endothelial cells. It is a nonspecific peptidase capable of cleaving C-terminal dipeptides from a variety of peptides (dipeptidyl carboxypeptidase). 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. Most meaningful actionwhich angiotensin II has on cardiovascular system, mediated by AT 1 -receptors. Angiotensin II increases blood pressure in various ways:
1) vasoconstriction of both arterial and venous beds;
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 sympathetic tone nervous system, and on the periphery - increased release and action of norepinephrine. Long-term elevations in angiotensin II levels can lead to hypertrophy of the muscle cells of the heart and arteries and an increase in the number connective tissue (fibrosis).

and) 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. It may also contribute to the weakening of the breakdown of kinins, which have a vasodilating effect.

When congestive heart failure after application, the cardiac output increases, since due to a drop in peripheral resistance, the afterload of the ventricles decreases. Decreases venous stasis (preload), decreases the secretion of aldosterone and the tone of the venous capacitive vessels.

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), use aCE inhibitors may initially cause an excessive drop in blood pressure. Quite often there is such side effect, like a dry cough (10%), which may be caused by a decrease in kinin inactivation in the bronchial mucosa.

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

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

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

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

The history of the study of the renin-angiotensin-aldosterone system (RAAS), which proved to be the most successful in terms of developing approaches to pharmacological modulation of its activity, allowing to prolong the life of patients with cardiovascular and renal diseases, began 110 years ago. When renin was identified as the first component. In the future, in experimental and clinical researchx managed to clarify the physiological role of renin and its importance 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.

At present, the first direct renin inhibitor Rasilez (aliskiren) is prescribed 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 capabilities of direct renin inhibitors in the protection of the target organs of hypertension, compared to other RAAS blockers, is that when using drugs blocking RAAS at other levels, according to the law of negative feedback there is both an increase in the concentration of prorenin and an increase in the plasma activity of renin. It is this circumstance that cancels the often noted decrease in the effectiveness of ACE inhibitors, including in terms of their ability to reduce elevated blood pressure. Back in the early 1990s, when many of the organoprotective effects of ACE inhibitors were not established as reliably as today, it was shown that as their dose increases, the plasma renin activity and the plasma concentration of angiotensin significantly increase. Along with IaEs and ARBs, thiazide and loop diuretics can also provoke an increase in plasma renin activity.

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

A pooled analysis of a clinical study that included a total of 8481 patients receiving monotherapy with aliskiren 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 decrease, 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 efficacy 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 versus -14.7 / -10.3 mm Hg; R< 0,001)

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

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers are today a fundamentally important component of the strategy for long-term management of patients with high and very high risk hypertension, as well as type 2 diabetes mellitus, chronic heart failure, and chronic kidney disease with proteinuria. The range of use of aldosterone antagonists is somewhat narrower - they are used to treat chronic heart failure and special variants of hypertension, in particular, arising in 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 RAAS at other levels.

■ Rasilesi

Synonym:Aliskiren.

Pharmachologic effect. Selective inhibitor of renin of non-peptide structure with pronounced activity. Renin secretion by the kidneys and 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 into active angiotensin II. Angiotensin II is a potent vasoconstrictor, stimulating the release of catecholamines, increasing the secretion of aldosterone and reabsorption of Na +, which leads to an increase in blood pressure. Long-term increase in angiotensin II stimulates the production of inflammatory and fibrosis mediators, which leads to damage to target organs. Angiotensin P reduces renin secretion by a negative feedback mechanism. Thus, rasilosis reduces plasma renin activity in contrast to ACE and angiotensin receptor antagonists. Aliskiren neutralizes the suppression of negative feedback, resulting in a decrease in renin activity (by 50-80% in patients with arterial hypertension), as well as the concentration of angiotensin I and angiotensin II. When taken in a dose of 150 mg and 300 mg once a day, there is a dose-dependent decrease in systolic and diastolic blood pressure within 24 hours. A stable 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 once a day. Monotherapy for diabetes mellitus allows you to achieve an effective and safe reduction in blood pressure; when combined with ramipril, it leads to a more pronounced decrease in blood pressure compared with monotherapy with each drug separately.

Indications for use.Arterial hypertension.

Contraindications.Hypersensitivity, a history of angioedema with the use of rasilez, severe hepatic failure, severe chronic renal failure, nephrotic syndrome, renovascular hypertension, hemodialysis, concomitant use of cyclosporine, pregnancy, lactation, childhood (up to 18 years).

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

Method of administration and dosage.Inside, regardless of food intake, the initial and maintenance dose is 150 mg once a day; if necessary, the dose is increased to 300 mg once a day.

Side effect.From the digestive system: often - diarrhea. From the side of the skin: infrequently - skin rash. Others: dry cough (0.9% versus 0.6% when taking placebo), angioedema.

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

O. BELOKONEVA, Candidate of Chemical Sciences.

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 out 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 capable of withstanding the dangerous action of a long-known substance.

Science and Life // Illustrations

Figure: 1. Liver cells constantly release the long peptide angiotensinogen into the bloodstream.

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

Figure: 3. A direct renin inhibitor (DIR) is incorporated into the active center of renin and prevents it from cleaving angiotensinogen.

In the early 1990s, the number of cardiovascular patients in Russia began to grow. And until now, in our country, the mortality rate among the working-age 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. The women turned out to be more resilient - they live on average 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 lining 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, no less important and most common cause of cardiovascular disease is hypertension, which is manifested by a sustained 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 disrupted. These changes are called vascular remodeling. All this leads to the fact that the vessel affected by atherosclerosis loses its elasticity, ceases to pulsate under the influence of blood flow. If healthy vessels can be compared to flexible rubber tubes that transmit a pulse wave and damp blood flow turbulence, then pathological vessels are like a metal pipeline. Vascular remodeling contributes to the progression of atherosclerosis.

Hypertension as a cause of heart attacks and strokes

Hypertension often proceeds imperceptibly. Patients do not know that they are sick, do not change their lifestyle, do not go to the doctor and do not take medicine. Meanwhile, hypertension by its destructive effect on the body can be called a "silent killer". If the disease develops quickly, then it leads to the progression of atherosclerosis and, ultimately, to heart attack, stroke, gangrene of the lower extremities. If the disease continues for a long time and the body manages to adapt to the 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? Biochemistry provides the answer to these questions.

Molecules that increase pressure

The role of biochemical disorders in the development of hypertension became known for a long time. In 1897, a professor of physiology at Karolinska University in Stockholm, Finnish by birth, Robert Tigerstedt, at an international conference in Moscow, announced his discovery. Together with his assistant Per Gustav Bergman, he discovered that intravenous administration of a kidney extract caused an increase in blood pressure in rabbits. The substance that increases the pressure, scientists called renin. Tigerstedt's report did not create a sensation, moreover, the study was considered small, insignificant, made for the sake of another publication. The frustrated professor gave up 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 symptoms of hypertension in dogs by clamping the renal artery and proceeded to release a 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 Goldblatt's first publication, in 1935, two research groups at once - from Buenos Aires led by Eduardo Mendez and the American led by Irving Page - independently from 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 of only eight amino acids. American researchers named it hypertensin, and Argentine researchers called it angiotonin. In 1958, during an informal meeting over a glass of martini, scientists compared the results of the 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 the pressure were discovered, only the connecting links in the mechanism of the development of hypertension were lacking. And they appeared. In the late 1950s, the concept of the functioning of the renin-angiotensin system (RAS) was formed.

The classic understanding of how the RAS works 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 receptors of the 1st and 2nd types. When angiotensin II interacts with type 1 receptors, the body responds with vasospasm and increased aldosterone production. Aldosterone is a hormone of the adrenal cortex responsible for fluid retention in the body, which also increases 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 inflammatory processes 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 vascular walls.

So, the renin-angiotensin system (RAS) plays a key role in both the increase in blood pressure and the development of atherosclerosis. Scientists have found that genes responsible for the functioning of proteins involved in ASD determine a person's predisposition to hypertension and cardiovascular disease. If certain genes are active, then the ASD is also hyperactivated, and the likelihood of developing hypertension and cardiovascular diseases 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 of searching for new drugs has developed in three main directions (see Fig. 1): the search for renin inhibitors; search for angiotensin-converting enzyme (ACE) inhibitors; search for angiotensin II receptor blockers type 1 (ARB).

The most attractive target for pharmacologists has been and remains the enzyme renin, since it is this which 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 the activity) of renin, developed back in the 60s of the last century, could not be put into practice due to unsatisfactory pharmacological properties and high synthesis costs. They were poorly absorbed in the gastrointestinal tract and had to be administered intravenously.

After the failure with renin, pharmacologists began looking for another molecular target. The poisonous snake Bothrops gararaca helped scientists find it, the bite of which leads to a prolonged and sometimes fatal drop in blood pressure. In 1960, the Brazilian Sergio Ferreiro started looking for a substance contained in the poison and causing "vascular paralysis." In 1968, it was discovered that the substance in question is 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 was introduced, the first synthetic ACE inhibitor that could be taken in pill form and whose effectiveness other ACE inhibitors could not surpass. It was a breakthrough and 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 on the appearance of a rash, itching, and a painful dry cough. In addition, even at maximum doses, ACE inhibitors cannot completely neutralize the destructive effect 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 forces 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 leading place in a new class of drugs - angiotensin receptor blockers (ARBs). Modern ARBs completely turn off the “harmful” type 1 receptors without affecting the “good” type 2 receptors. These drugs, the first of which was losartan, practically do not have the side effects characteristic of ACE inhibitors, in particular, do not cause dry cough. ARBs are in no way inferior to ACE inhibitors in reducing 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 help improve the condition of the vessels and myocardium affected by hypertension.

Curiously, while captopril is still not inferior in effectiveness to newer ACE inhibitors, ARBs are constantly being improved. New ARBs are more specific for type 1 receptors and remain active in the body for longer.

The last assault

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

A more complete blockade of the angiotensin II synthesis system was expected from renin inhibitors. The enzyme renin catalyzes the conversion of angiotensinogen, that is, in the biochemical cascade, it interacts with only one molecule (Fig. 3). This means that renin inhibitors should not have significant side effects, in contrast to ACE inhibitors, which act not only on ACE, but also on 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 (DIRs) have many benefits. They are easily tolerated by patients, slowly excreted from the body, they are good (better than ACE inhibitors) reduce blood pressure, do not cause a withdrawal effect when you stop taking them.

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 a 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 renin inhibitors can not only block its enzymatic activity, but also prevent the binding of renin to renin receptors. This possibility is now being actively studied. 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 this is 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 can reverse the horrific statistics of mortality from cardiovascular diseases. All this is due to scientific research and the implementation of the developments of scientists in 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 with sartan (valsartan, irbesartan, telmisartan). Direct renin inhibitors (DIRs) can be distinguished by the end of kiren (aliskiren, remikiren, enalkiren).

The non-commercial name should not be confused with the trademark. There are usually no rules and patterns in 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.

03.07.2012

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With arterial hypertension (hypertension), the amount of the enzyme Renin in the blood is increased. This leads to a persistent and long-term increase in the amount of protein Angiotensin 2 in the blood and body tissues. Angiotensin 2 has a vasoconstrictor 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 is a drug that enters into a compound with Renin, as a result of which Renin is neutralized and loses its enzymatic activity. This interconnected leads to a decrease in the level of angiotensin 2 in the blood and tissues - to a decrease in blood pressure.

AT2 has a vasoconstrictor effect, promotes sodium and water retention 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 together becomes the cause of an increase (BP) of 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 \u003d Angiotensin 1 + ACE \u003d Angiotensin 2, called Renin-Angiotensin System (RAS) or Renin-Angiotensin-Aldosterone System (RAAS)... Activation (increased activity) of RAS means 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 is interconnected leads to a decrease in the level of AT2 in the blood and tissues - to a decrease in blood pressure.

Renin inhibitor - a drug that enters into a compound 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 associated with a renin inhibitor loses the ability to break down angiotensinogen to AT1. At the same time, a decrease in the level of AT2 in the blood and tissues occurs - a decrease in blood pressure, a decrease in RAS activity, an improvement in blood flow, blood supply to organs and tissues of the body.

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

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

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

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