Direct renin inhibitors mechanism of action. Treatment of arterial hypertension (hypertension) with a renin inhibitor. Direct renin inhibitors - a new class of antihypertensive drugs: potential opportunities and prospects

Content

High blood pressure can lead to even more dangerous consequences - the development of myocardial infarction or coronary disease. Those who suffer from hypertension (hypertension) should be constantly monitored by a doctor and undergo preventive treatment. Antihypertensive drugs are used to stabilize the pressure. They are selected taking into account the severity of the disease and the presence of concomitant health problems.

What is hypertension

Arterial hypertension (AH, hypertension) is one of the most common pathologies of the cardiovascular system, characterized by a stable increase in blood pressure to 140/90 mmHg or higher. The main symptoms of the disease are:

, which does not have a clear relationship with the time of day. Patients describe it as heaviness in the back of the head, a feeling of fullness of the skull.
heart pain, which equally occur at rest and in a state of stress.
Peripheral vision disorder. It is characterized by the appearance of a veil, eye fogging, "flies" before the eyes.
, swelling of the eyelids or face additional symptoms of hypertension.

An increase in blood pressure develops under the influence of external or internal environmental factors that provoke disruption of the vasomotor, cardiovascular systems and hormonal mechanisms responsible for controlling blood pressure. Primary factors include hereditary predisposition: if someone in the family suffered from hypertension, the risk of its development in relatives increases significantly.

Another reason for the development of the disease is frequent stress, nervous work, a sedentary lifestyle. Of the many provoking factors, WHO experts have identified those that often contribute to the development of hypertension:

metabolic disorders in the body and, as a result, the appearance of excess body weight;
prolonged depression, stress, nervous strain, experienced tragedies;
craniocerebral injuries - abrasions, bruises, accidents, hypothermia;
chronic diseases in the acute stage - atherosclerosis, diabetes mellitus, rheumatoid arthritis, gout;
consequences of viral and infectious diseases - meningitis, sinusitis, pharyngitis;
age-related changes in the structure of blood vessels;
the formation of cholesterol plaques on the walls of blood vessels;
climacteric condition in women after 40 years;
bad habits - smoking, drinking alcohol, unhealthy diet.

Treatment

For successful therapy, it is important to diagnose the disease in time and identify the cause of its occurrence. With a properly organized treatment regimen, dangerous complications can be avoided - thrombosis, aneurysm, deterioration or loss of vision, myocardial infarction, stroke, development of heart or kidney failure. If a slight increase in blood pressure is detected, the doctor will recommend establishing proper nutrition, exercising more, and giving up bad habits. Arterial hypertension of the second and third degree is treated with the addition of drug therapy.

The choice of drug is carried out in accordance with the patient's history. If he has inflammation of the prostate gland, alpha-blockers are preferred. For people with heart failure or left ventricular dysfunction, ACE inhibitors (angiotensin-converting enzyme inhibitors) and diuretics are often prescribed. In the presence of pain in the region of the heart, Nitroglycerin or Papazol may be prescribed. Only the attending physician is engaged in the choice of medicine.

Medicines for high blood pressure

Several mechanisms are responsible for the increase in blood pressure, so some patients require two or more medications at the same time to achieve stable control of blood pressure. In order to reduce the number of pills taken and reduce the risk of side effects, the latest generation of hypertension drugs has been created. There are only five groups of antihypertensive drugs. Classification is carried out according to the composition and principle of action of tablets on the body:

angiotensin II receptor antagonists;
diuretics (diuretic) drugs;
calcium antagonists;
beta - blockers;
angiotensin-converting enzyme inhibitors.

Beta blockers

This is a popular group of new generation hypertension drugs with high efficacy and versatility. Hypertension can occur from the effects of catecholamines (norepinephrine and adrenaline) on special receptors located in the heart - beta-adrenergic receptors. This effect causes the heart muscle to contract faster and the heart to beat faster, increasing blood pressure. Beta-blockers stop this mechanism, providing a persistent hypertensive effect.

The first beta-blocker was introduced to the world in 1964, and many doctors called the development one of the most important developments in medicine. Over time, other products with a similar principle of action began to be produced. Some of them affect the work of all types of beta-adrenergic receptors, others - on one of them. Depending on this, beta-blockers are usually divided into three groups:

First generation or non-selective drugs- block the beta-1 and beta-2 receptors. These include:, Sotalol, Timolol,.

Second generation or selective agents- block the work of only the beta-1 receptor. This group is represented by: Oxprenolol, Metoprolol, Bisoprolol, Esmolol, Atenolol, Betaxolol, Doxazosin, Candesartan,.

Third generation drugs with a neurogenic effect- affect the regulation of vascular tone. These include: Clonidine, Carvedilol, Labetalol, Nebivolol,

Diuretics

Diuretic drugs are one of the oldest groups of antihypertensive drugs. It was first used in the early 50s of the last century, but diuretics have not lost their popularity today. Today, diuretic drugs to lower blood pressure are prescribed in combination with other drugs (ACE inhibitors or sartans).

Diuretics help lower blood pressure by increasing the excretion of salt and fluids by the kidneys. This effect on the body leads to a decrease in the load on the vessels, contributes to their relaxation. Modern diuretics are used in very low dosages, which does not cause a significant diuretic effect, washing out a large amount of useful substances from the body. The hypotensive effect occurs 4-6 weeks after the start of treatment.

In pharmacology, there are up to four types of diuretic drugs, but only three of them are used to treat hypertension:

Thiazide and thiazide-like- refers to the means of prolonged action. They have a mild effect, almost no contraindications. The disadvantage of thiazides is that they can reduce the level of potassium in the blood, which is why it is necessary to evaluate the patient's condition every month after starting to take the pills. Thiazide diuretics: Hypothiazide, Apo-Hydro, Dichlothiazide, Arifon, Indapamide,

Loopback- are prescribed only when diagnosing highly resistant hypertension. They quickly lower blood pressure, but at the same time contribute to the loss of a significant amount of magnesium and sodium ions, increase the concentration of uric acid in the blood. Loop diuretics - Diuver, Torasemide, Furosemide.

Potassium-sparing- are used very rarely, because they increase the risk of developing hyperkalemia. These include: Veroshpiron, Spironolactone, Aldactone.

Sartans

Angiotensin II receptor blockers are one of the newest groups of antihypertensive drugs. According to the mechanism of action, they are similar to ACE inhibitors. The active components of sartans block the last level of the renin-angiotensin system, preventing the interaction of its receptors with the cells of the human body. As a result of this work, angiotensin does not constrict blood vessels, while the secretion of vasopressin and aldosterone (hormones that contribute to the accumulation of fluid in tissues) is reduced.

All sartans act for a long time, the hypotensive effect lasts for 24 hours. With regular use of angiotensin 2 blockers, the level of blood pressure does not decrease below acceptable values. It is worth knowing that these are not fast-acting high blood pressure pills. A steady decrease in blood pressure begins to appear 2-4 weeks after the start of treatment and intensifies by the 8th week of therapy. List of sartans:

(Dimethicone);
Olmesartan;
fimasartan;
Valsartan;
Aldosterone;
Cardosal.

ACE inhibitors

These are pharmaceuticals that are prescribed for high blood pressure against the background of heart failure, diabetes, kidney disease. Angiotensin-converting enzyme (ACE) inhibitors change the balance of biologically active blood components in favor of vasodilators, thereby reducing blood pressure.

The hypotensive effect of ACE inhibitors may decrease with the simultaneous use of non-steroidal anti-inflammatory drugs. According to the chemical structure, ACE inhibitors are divided into three groups:

Sulfhydryl- operate for a short period of time. These are ACE: Zofenopril, Captopril, Lotensin, Kapoten.

Carboxyl- differ in the average duration of action. This group includes:, Enalapril, Hortil, Quinapril, Perindopril.

phosphinyl- have a prolonged effect. This group includes: Fosinopril, Ramipril, Perindopril.

calcium inhibitors

Another name for these drugs is calcium channel blockers. This group is used mainly in the complex treatment of hypertension. They are suitable for those patients who have many contraindications to the use of other new generation hypertension drugs. Calcium inhibitors may be given to pregnant women, the elderly, and patients with heart failure.

The main principle of action of calcium channel blockers is vasodilation by creating obstacles for the penetration of calcium ions into muscle cells. Inhibitors are conditionally divided into three groups: nifedipine (dihydropyridines), diltiazem (benzothiazepines), verapamil (phenylalkylamines). To reduce blood pressure, the nifedipine group is more often prescribed. The medicines included in it are divided into subspecies:

First generation- Calcigard retard, Cordaflex retard, Nifecard, Nifedipine.

Second generation products-, Nicardipine, Plendil.

third class medicines-, Amlovas, Kalchek, Norvask.

fourth generation- Cilnidipine, Duocard (for hypertension, they are prescribed very rarely).

The latest generation of pressure medications

Most of the representatives of the above list are available in the form of tablets for oral use. The only exception is one beta-blocker - Labetalol, which comes on the shelves in the form of a powder or solution for intravenous administration. There are other medicines produced in the form of injections (for example, sodium nitroprusside, nitrates), but they do not belong to the category of modern medicines and are used exclusively to eliminate a hypertensive crisis.

Modern drugs for pressure in tablets will help get rid of not only changes in blood pressure, but also improve the functioning of the cardiovascular system, central nervous system and kidneys. Other benefits of the new drugs include:

Unlike systemic agents, modern antihypertensive pills can reduce left ventricular hypertrophy.
They have a selective effect on the body, due to which they are well tolerated by the elderly.
Do not reduce the efficiency and sexual activity of patients.
Gentle on the nervous system. Many products contain benzodiazepine, which helps fight depression, stress, and nervous disorders.

Calcium channel blockers

Calcigard retard is a new slow-release drug for hypertension. The drug has a high lipophilicity, due to which it has a long-term effect. The active ingredient in the tablets is nifedipine. Auxiliary components - starch, magnesium stearate, sodium lauryl sulfate, polyethylene glycol, stearic acid.

Calciguard retard acts very gently, due to which it can be used for the permanent treatment of hypertension, with stable angina pectoris, Raynaud's disease. The pharmacological properties of the tablets are slow vasodilation, due to which Calcigard has fewer side effects than pure Nifedipine. Negative reactions may include:

tachycardia;
peripheral edema;
headache;
dizziness;
drowsiness;
nausea;
constipation
allergic reaction;
myalgia;
hyperglycemia.

Calcigard retard is taken orally during or after a meal, the average dose is 1 tablet 2 times a day. With caution, this medicine is prescribed during pregnancy. Treatment with tablets is strictly prohibited for:

hypersensitivity to nifedipine;
arterial hypotension;
collapse;
unstable angina;
severe heart failure;
acute stage of myocardial infarction;
severe aortic stenosis.

Angiotensin-converting enzyme inhibitors

A bright representative of this group is the drug Diroton. The new generation hypertension drug is suitable even for the treatment of patients in whom high blood pressure is combined with liver diseases, the drug has a minimum of contraindications and side effects. The active substance of Diroton is lisinopril. Auxiliary components - magnesium stearate, talc, corn starch, calcium hydrogen phosphate dihydrate, mannitol.

The tool has a prolonged action, so it must be taken once a day in the morning before or after meals. The main indications for use are:

arterial hypertension (for monotherapy or combined treatment);
chronic heart failure;
acute myocardial infarction;
nephropathy due to diabetes.

With caution, Diroton is combined with potassium-containing diuretics and salt substitutes. Categorical contraindications: history of angioedema, age under 18 years, hypersensitivity to the components of the tablets, hereditary Quincke's edema. Side effects may include:

dizziness;
headache;
weakness;
diarrhea;
nausea with vomiting;
hypotension;
chest pain;
skin rash.

Beta blockers

One of the representatives of this group is the modern new generation pressure medicine Labetalol. The drug belongs to hybrid blockers, it simultaneously acts on beta and alpha receptors. Apply Labetalol for the permanent treatment of hypertension, pheochromocytoma, preeclampsia and for the relief of hypertensive crisis. Unlike selective drugs of the new generation, it gives an instant antihypertensive effect. The method of dosing and duration of treatment is selected individually. The average dosage is 100 mg 2-3 times a day with meals.

Of the drugs for hypertension of the new generation of selective action, Nebivolol can be distinguished separately. Produced in the form of tablets, coated with a soluble coating. In addition to the antihypertensive effect, the drug has vasodilating properties by increasing the production of nitric oxide in the walls of blood vessels. Nebivolol is taken orally at a dose of 5 mg once daily with or without food. The drug does not increase the level of glucose and lipids, practically does not affect the heart rate.

All beta-blockers are prescribed with caution to patients with diabetes mellitus, myasthenia gravis, bradycardia, and low blood pressure. Categorical contraindications - bronchial asthma, obstructive pulmonary disease, severe obliterating diseases of the blood arteries, unstable heart failure, atrioventricular blockade of 2 and 3 degrees. Of the side effects can be observed:

headache;
insomnia (as a result of insufficient production of melatonin);
erectile dysfunction;
bronchospasm;
dyspeptic phenomena;
increased fatigue;
swelling.

Angiotensin 2 receptor blockers

- a characteristic representative of the sartans group. The drug is produced in the form of round tablets of white or almost white color. The active ingredient is azilsartan medoxomil potassium. As auxiliary components in the composition of the drug are present: mannitol, sodium hydroxide, hyprolose, microcrystalline cellulose, fumaric acid, magnesium stearate.

The antihypertensive effect of azilsartan develops during the first days, reaching the highest degree of therapeutic action 30 days after the start of treatment. The decrease in blood pressure occurs within a few hours after ingestion of a single dose and persists throughout the day. Tablets can be taken at any time of the day, even on an empty stomach. The recommended starting dosage is 40 mg.

With caution, the drug is prescribed for arrhythmia, severe chronic cardiac, hepatic or renal failure, with bilateral renal artery stenosis, patients over 75 years of age. Absolute contraindications include:

pregnancy;
individual intolerance to the components;
age up to 18 years;
diabetes;
severe liver dysfunction.

Edarbi is indicated for the treatment of essential hypertension. The drug is well tolerated by patients, but in rare cases, side effects may occur:

cardiopalmus;
dizziness;
diarrhea;
rash;
increased fatigue;
swelling of soft tissues;
pronounced decrease in blood pressure;
increased activity of creatine kinase;
angioedema.

Direct renin inhibitors

Aliskiren is a new generation of little-known hypertension drug. The drug belongs to selective renin inhibitors with pronounced activity. Aliskiren inhibits the interaction of renin with angiotensinogen of the first and second groups, due to which a decrease in blood pressure is observed. The drug is never used for monotherapy, but only as a maintenance agent in the treatment of severe hypertension.

Aliskiren is prescribed with caution in renal artery stenosis, diabetes mellitus, after kidney transplantation. It is strictly forbidden to use this new generation medicine for people with hypersensitivity to the composition, with severe liver failure, with nephrotic syndrome, pregnancy or lactation, children under 18 years of age. The list of side effects includes:

dry cough;
skin rash;
diarrhea;
increased potassium levels;
headache.

Price

All drugs can be bought at a pharmacy, online store or ordered through a catalog from an official manufacturer. The cost of heart drugs for blood pressure will depend on your region of residence, the country of manufacture of the drug, and pharmacy pricing. Approximate prices for antihypertensive drugs in Moscow:

The name of the next generation drug	Estimated cost, rubles
ACE inhibitors:
Parnavel
Monopril

Renipril
Amprilan
Zocardis


Calcium channel blockers:

Kordafen


Angiotensin II receptor blockers:


Valsacor
Aprovel

How to choose new generation hypertension drugs

The active participation of the patient in the treatment process significantly increases the chances of recovery, especially if a person understands: what drugs are prescribed for him, how they work, why it is necessary to take pills. Competent treatment must necessarily take place under the supervision of a doctor, he must also be engaged in the selection of the best medicine for pressure of a new generation. You should not listen to what your neighbors say or rely entirely on user reviews on the global network. Self-medication can not only aggravate the situation, but also lead to the development of serious complications.

No Side Effects

There are no new generation drugs for hypertension that do not have a list of side effects in the instructions for use. It should be understood that not all patients may experience any negative reactions even after taking potent drugs. If you still decide to protect the body from side effects as much as possible, you should pay attention to herbal medicines, but you can’t expect instant results from them.

In medical practice, homeopathic medicines are prescribed only for complex treatment as biologically active food supplements. Some of them, in addition to the ability to lower blood pressure, have a number of other useful properties: they stimulate the immune system, cleanse the body of toxins and toxins, and are able to thin blood clots. Popular homeopathic remedies include:

Hyper stable;
Golubitoks;
Cardimap;
Normolife (Normalif).

Fast acting tablets

With sharp jumps in blood pressure, the load on the heart and blood vessels increases several times, there is an insufficient flow of oxygen and blood to the tissues of the internal organs, which worsens the patient's condition. Simple medicines will help to calm down - Valerian tincture, Motherwort. To normalize pressure, the following new-generation fast-acting drugs are used:

Captropil;

Weak pills

This group of drugs includes drugs that have the ability to gradually accumulate in the body and begin to act actively some time after the start of treatment. Veroshpiron is isolated from diuretics of weak action. It helps lower blood pressure, but it does not remove potassium from the body. Weak hypotensive properties have:

Lacidipine;
Lercanidipine;

Strong pills

The most potent drug for hypertension is Clonidine, but it is released only by prescription. Simple but effective drugs should not only normalize blood pressure, but also prevent the appearance of new jumps in blood pressure and prevent the development of complications. There are several such drugs that have proven themselves well, according to patient reviews:

Noliprel;
Methyldopa;

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)

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 SOLELY FOR INTRODUCTION WITH 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 THE 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” beneficial substances from the body, it has been proven to cause new cases of diabetes mellitus, atherosclerosis, and 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 doctor.

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))

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 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 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.

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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 RAS activity 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 has been established 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 their increase in 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, which 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, the 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 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 effectively reduces office and 24-hour BP, as do equivalent doses of other antihypertensive drugs, and it may be somewhat 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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