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.

As soon as 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 action, which angiotensin II has on the cardiovascular system, is 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 the tone of the sympathetic nervous system, and on the periphery - increased release and action of norepinephrine. Long-term elevations in angiotensin II levels can lead to hypertrophy of muscle cells in the heart and arteries and an increase in the amount of 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 minute volume of the heart 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 a side effect as a dry cough (10%), which may be caused by a decrease in the inactivation of kinins in the bronchial mucosa.

Combination aCE inhibitors with potassium-sparing diuretics can lead to hyperkalemia. In most cases, ACE inhibitors are well tolerated and 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 effects are the same as those of 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 answer to this question is simple:

Point one: in order to meaningfully understand this issue, you need to graduate from the medical institute. After that, we can theoretically assume that drug A in patient X with one "bouquet" of diseases will work better than drug B in patient C with a different "bouquet", however:

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

Point three: drugs within the same class, subject to the observation of 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 they will answer in different ways (There are no comrades for the taste and color). Also, different doctors will give different answers to questions about drugs.

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

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

Edarbi (Azilsartan) - February 2014

Rasilez (Aliskiren) - May 2008

Assess the degree of "newness" 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 "newest drugs for hypertension" just because they are newest.

Repeatedly there were patients who wished to start treatment with "something newer", 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 into the search box, choose the dosage of the medicine and your place of residence - and the site gives out addresses, phone numbers, prices and the possibility of home delivery.

Can you replace drug A with drug B? What can replace drug C?

These questions are very often asked in the address of search engines, so I launched a special site analogs- drugs.rf, and began filling it out with cardiac drugs.

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

If there is no exact replacement of the drug (or the drug is discontinued), you can try one of his "classmates" UNDER THE DOCTOR'S CONTROL. Read the section "Classes of drugs for hypertension".

What is the difference between drug A and drug B?

To answer this question, first go to the page of drug analogues (here) and find out (or better 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 the drugs are in different classes, read the descriptions for 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 there are instructions for drugs on the Internet. Despite a huge number of warnings about the impossibility of self-prescribing drugs, the patient's violent 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 presented my view on the question.

THIS ARTICLE IS INTENDED ONLY FOR KNOWING THE CLASSES OF ANTIHYPERTENSIVE DRUGS AND CANNOT SERVE A GUIDE TO THE INDEPENDENT PURPOSE OF TREATMENT!

THE APPOINTMENT AND CORRECTION OF TREATMENT OF HYPERTENSION SHOULD BE CARRIED OUT ONLY UNDER THE VERY CONTROL OF A DOCTOR !!!

There are a lot of recommendations on the Internet for limiting the consumption of table salt (sodium chloride) for hypertension. Studies have shown that even a fairly strict restriction of table salt intake leads to a decrease in blood pressure numbers by no more than 4-6 units, so I personally am rather skeptical of 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 mild hypertension it is a pity to look at patients who poison their lives by restricting salt intake.

I think that for patients with "moderate" hypertension, the recommendation "do not eat pickles (or analogs) in three-liter cans."

If ineffective or insufficiently effective, do not 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 patient's financial capabilities.

A fairly complete examination includes:

• Laboratory methods:
  • General analysis blood.
  • General urinalysis to exclude renal origin of hypertension.
  • Blood glucose, glycosylated hemoglobin for the purpose of screening for diabetes mellitus.
  • Creatinine, blood urea for the assessment of renal 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).
  • Free T3, free T4 and TSH to assess thyroid function.
  • It's a good idea 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 (hypertrophy or not).
  • Duplex scanning of the vessels of the neck (usually called MAG or BCA) to assess the presence and severity of atherosclerosis.
• Expert advice:
  • Oculist (in order to assess the state of the vessels of the fundus, which are often affected in hypertension).
  • Endocrinologist-dietitian (in case of an overweight patient and deviations in the tests for thyroid hormones).
• Self-examination:
  • SCAD (Self-Control of Blood Pressure) - measurement and recording of pressure and pulse numbers on two 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 can affect treatment tactics doctor.

Now about the algorithm for the selection of drug treatment (pharmacotherapy).

Adequate treatment should lead to a decrease in pressure to the so-called target values \u200b\u200b(140/90 mm Hg, with diabetes mellitus - 130/80). If the numbers are higher, the treatment is wrong. THE PRESENCE OF HYPERTONIC CRISES IS ALSO PROOF OF INAPPROPRIATE TREATMENT.

Drug treatment for hypertension MUST LAST LIFETIME, so the decision to initiate it must be strictly justified.

With low pressure values \u200b\u200b(150-160), a competent doctor usually first prescribes one drug in a small dose, the patient takes 1-2 weeks to record the SCAD. If the target levels are set during the initial therapy, the patient continues to take treatment for a long time and the reason for seeing a doctor is only an increase in blood pressure above the target, which requires adjustment of treatment.

ALL STATEMENTS ABOUT ADDICTION TO DRUGS AND THE NECESSITY OF THEIR REPLACEMENT SIMPLY DUE TO THE LONG TIME OF ADMISSION ARE Fiction. SUITABLE DRUGS TAKE FOR YEARS, AND THE ONLY REASONS FOR REPLACING THE DRUG ARE ONLY INTOLEXIBILITY AND INEFFICIENCY.

If the patient's pressure remains above the target during the prescribed therapy, 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 the story about drugs, I will touch on a very important issue that perceptibly concerns the wallet of each patient.

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

If a new drug proved to be effective and in demand, after the expiration 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, do not copy drugs that are of little interest to patients. I prefer not to use "old" original drugs that do not have copies. As Winnie-the-Pooh said, this is "LJJ" for a reason.

Generic manufacturers often offer a wider dose range than the originator brand (eg, Enap from KRKA). This additionally attracts potential consumers (very few people are happy with the tablet breaking procedure).

Generics are cheaper than original drugs, but since they are produced by companies with LESS financial capabilities, the production technologies of generic factories may well be less effective.

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 on 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, the USA - less than 15%.

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

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

• If you have the financial ability 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 of a well-known, "old" and European manufacturer than an unknown, new and Asian one.
• Drugs costing less than 50-100 rubles usually work extremely poorly.

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

Talking about the drug, I will first indicate it international name, then the original brand name, then the names of credible generics. The absence of the name of the generic in the list indicates that I have no experience of communicating with it or that I do not want to recommend it to the general public for one reason or another.

What classes of drugs for hypertension are there?

There are 7 classes of drugs:

Angiotensin-converting enzyme (ACE) inhibitors

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

In 1975, captopril (kapoten) was synthesized, which is still 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, analogues of enalapril are produced by more than 30 factories, and this indicates its good qualities (bad drugs do not copy).

The rest of the group's devices do not differ significantly from each other, so I will 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 a dry cough after a month or more after starting. If a cough occurs, the drug must be replaced. Usually they change to representatives of the newer and more expensive group of the ARA (ARA).

The full effect of the use of an ACE inhibitor is achieved by the end of the first - second week of admission, therefore, all earlier BP figures do not reflect the degree of the drug's effect.

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

Angiotensin receptor antagonists (blockers) (sartans or ARA or ARB)

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

To date, none of the ARB firms claim to be more effective than ACE inhibitors. This is confirmed by the results of large studies. Therefore, the appointment of ARBs as the first drug, without trying to prescribe an ACE inhibitor, I personally regard as a sign of a positive doctor's assessment of the thickness of the patient's wallet. Prices for a month of admission to none of the original sartans have yet dropped significantly below a thousand rubles.

ARBs reach their full effect by the end of the second - fourth week of administration, so the assessment of the drug's effect is possible only after two or more weeks.

Class representatives:

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

Direct renin inhibitors (PIRs)

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 (not less than one and a half thousand rubles per month of admission), I do not consider this drug very attractive for 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 heart rate and lowering blood pressure. Therefore, they are used mainly in hypertensive patients with frequent pulse and in combination with hypertension with angina pectoris. In addition, beta-blockers have a good antiarrhythmic effect, so their appointment is justified in case of concomitant extrasystole and tachyarrhythmias.

The use of beta-blockers in young men is undesirable, since all representatives of this class have a negative effect on potency (fortunately, not in all patients).

In the annotations to all BBs, there are contraindications bronchial asthma and diabetes mellitus, 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 their short duration of action.

Short-acting forms of metoprolol are not listed here for the same reason.

Beta-blocker class members:

• Metoprolol (Betaloc ZOK (25mg, 50mg, 100mg), Egilok retard (100mg, 200mg), Vasokardin 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 (Lokren (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, pulsating (ACP)

In action, they are similar to beta-blockers (they slow down the pulse, lower the pressure), only the mechanism is different. The use of this group is officially allowed for bronchial asthma.

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

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

Dihydropyridine calcium antagonists (ACD)

The era of AKD began with the device, which is familiar to everyone, however, modern recommendations, to put it mildly, are not recommended even for hypertensive crises.

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

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

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

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

At the beginning of taking drugs in this group can give swelling of the legs and hands, but usually it goes away within a week. If it does not go away, the drug is canceled or replaced with the "cunning" form of Es Cordi Cor, which has almost no such effect.

The fact is that "ordinary" amlodipine of most manufacturers contains a mixture of "right" and "left" molecules (they differ from each other, like the right and left hand - they consist of the same elements, but are organized in different ways). The "right" type of the molecule produces most of the side effects, while the "left" one provides most curative action... The manufacturer Es Cordi Cor has left only a useful "left" molecule in the drug, 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), Felodip (2.5mg, 5mg, 10mg))
• Nimodipine (Nimotop (30mg))
• Lacidipine (Lazipil (2mg, 4mg), Sakur (2mg, 4mg))
• Lercanidipine (Lerkamen (20mg))

Drugs central action (application point - brain)

The history of this group began with clonidine, which "reigned" before the era of ACE inhibitors. Clonidine greatly reduced blood pressure (in case of overdose - to coma), which was subsequently actively used by the criminal part of the country's population (clonidine thefts). Clonidine also caused terrifying dry mouth, but this had to be tolerated as other drugs were weaker at the time. Fortunately, the glorious history of clonidine is ending, and it is only available with a prescription from a very small number of pharmacies.

Later drugs in this group lack side effects clonidine, but the "power" of it is significantly lower.

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

Dopegit 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 (Dopegit (250 mg)

Diuretics (diuretics)

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

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

• Treatment of hypertension in elderly patients (over 70 years old).
• 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 as part of "factory" (fixed) combination 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 supervision of a physician.

• Hydrochlorothiazide (Hypothiazide (25mg, 100mg)) - very widely used in combination drugs
• Indapamide (Potassium-sparing) - (Arifon retard (1.5mg), Ravel SR (1.5mg), Indapamide MV (1.5mg), Indapamide (2.5mg), Ionic retard (1.5mg), Acripamide retard (1, 5mg))

LECTURE 2 CLINICAL PHARMACOLOGY OF ARTERIAL HYPERTENSION TREATMENTS

LECTURE 2 CLINICAL PHARMACOLOGY OF ARTERIAL HYPERTENSION TREATMENTS

Arterial hypertension is a pathological condition characterized by a long-term sustained increase in blood pressure. The reason for the persistent increase in blood pressure in about 90% of patients remains unclear. In this case, they speak of essential hypertension or hypertension. Experts European Society by arterial hypertension (EOAG) and the European Society of Cardiology (EOC) in 2003 proposed a classification of blood pressure levels in adults (over 18 years of age), which has not undergone fundamental changes until now (Table 2.1).

Table 2.1.Definition and classification of blood pressure levels (EOAG-EOC Recommendations 2003 and 2007, National guidelines for the prevention, diagnosis and treatment of arterial hypertension, second revision, 2004)

From the classification of blood pressure it follows that there is no discrete "threshold" blood pressure separating hypertension from normotension, and the indications for treatment and the degree of the planned decrease in blood pressure are determined by the aggregate risk of cardiovascular diseases and complications in a particular patient. Thus, the decision on pharmacotherapy in patients with hypertension should be made not only on the basis of the blood pressure level, but also taking into account the identified risk factors, pathological conditions or concomitant diseases (Table 2.2).

2.1. MAIN FACTORS INFLUENCING THE PREDICTION OF A PATIENT WITH ARTERIAL HYPERTENSION (RECOMMENDATIONS EOAG-EOK, 2007)

I.Risk factors

Levels of systolic blood pressure (BP) and diastolic blood pressure (BP) I-III degree.

Pulse blood pressure (in the elderly).

Age: men\u003e 55; women\u003e 65 years.

Smoking.

Dyslipidemia:

Total cholesterol\u003e 5.0 mmol / L, or

LDL cholesterol\u003e 3.0 mmol / L, or

HDL cholesterol: in men<1,0 ммоль/л; у женщин <1,2 ммоль/л, или

Triglycerides\u003e 1.7 mmol / L.

Fasting plasma glucose - 5.6-6.9 mmol / l.

Abdominal obesity: waist circumference in men\u003e 102 cm; in women\u003e 88 cm.

Family history of early manifestations of cardiovascular pathology (stroke or heart attack in men under the age of 55, in women under 65).

II.Subclinical organ damage

Signs of LV hypertrophy.

ECG (Sokolov-Lyon test\u003e 38 mm; Cornell test\u003e 2440 mm-ms) or echocardiography (LMMI in men\u003e 125 g / m2; in women\u003e 110 g / m2). *

Thickening of the mediintimal layer\u003e 0.9 mm or atherosclerotic plaque in the carotid artery.

Pulse wave velocity (carotid arteries - femoral arteries)\u003e 12 m / s.

Ankle-brachial BP index<0,9.

Mild increase in plasma creatinine:

Men - 115-133 μmol / L;

* - the greatest risk in concentric left ventricular hypertrophy (if the ratio of LV wall thickness to its radius in diastole is\u003e 0.42);

Women - 107-124 μmol / l.

Decreased glomerular filtration rate (<60 мл/мин на 1,73 м 2)** или клиренса креатинина (<60 мл/мин).***

Microalbuminuria (30-300 mg per 24 hours) or the ratio "albumin / creatinine": in men\u003e 22 mg / g; in women\u003e 31 mg / g creatinine.

III.Diabetes

Fasting plasma glucose ≥7.0 mmol / L on repeat measurements.

Plasma glucose after exercise\u003e 11 mmol / L.

IV.Diseases of cardio-vascular system or kidneys

Cerebrovascular diseases: ischemic stroke, hemorrhagic stroke, transient ischemic attack.

Heart disease: myocardial infarction, angina pectoris, coronary revascularization, heart failure.

Kidney disease: diabetic nephropathy, renal failure (plasma creatinine in men\u003e 133 μmol / L; in women\u003e 124 μmol / L).

Peripheral artery disease.

Severe retinopathy: hemorrhages or exudates, swelling of the nipple optic nerve.

The cumulative effect of several risk factors and pathological conditions on the prognosis can be assessed semi-quantitatively by stratifying risk into four categories (low additional risk, moderate additional risk, high and very high additional risk), while the term “additional” means a risk that exceeds the average ( see table 2.2).

The degree of risk of cardiovascular disease and complications determines the nature and urgency treatment measures, among which pharmacotherapy occupies a central place (Table 2.3). Thus, the definition of hypertension may vary depending on the severity of the overall cardiovascular risk.

An important postulate of the treatment of hypertension is not to be limited only to drug therapy. For many patients, the most important conditions for effective treatment are: adherence to diet (limiting the consumption of table salt, alcohol, saturated fat and cholesterol, increasing the consumption of fruits and vegetables), avoiding

** - according to the Cockroft-Gault formula; *** - according to the MDRD formula.

Table 2.2.Risk stratification of cardiovascular diseases and complications (Recommendations EOAG-EOK, 2007)

Note:FR - risk factors; STR - subclinical organ damage; MS - metabolic syndrome (presence of at least 3 out of 5 possible RFs: abdominal obesity, increased fasting glucose, blood pressure ≥ 130/85 mm Hg; low HDL cholesterol, increased triglycerides); DM - diabetes mellitus; CCC - cardiovascular system; ABP - systolic blood pressure; BPd - diastolic BP.

Table 2.3.Initiation and nature of antihypertensive treatment depending on risk stratification (EOAG-EOK Recommendations, 2007)

Note:FR - risk factors; STR - subclinical organ damage; MS - metabolic syndrome (presence of at least 3 out of 5 possible RFs: abdominal obesity, increased fasting glucose, blood pressure ≥130/85 mm Hg; low HDL cholesterol, increased triglycerides); DM - diabetes mellitus; CCC - cardiovascular system; ABP - systolic blood pressure; BPd - diastolic BP; MOF - lifestyle modification.

smoking, weight loss, regular physical exercise... Non-pharmacological intervention should be accessible to the hypertensive patient and be carried out continuously, subject to regular observation and every encouragement from the doctor.

2.2. GENERAL PRINCIPLES OF ARTERIAL HYPERTENSION TREATMENT

The goal of treatment is to reduce the risk of cardiovascular diseases and complications; therefore, the aggressiveness of hypertension treatment and target blood pressure levels are determined by the severity of associated risk factors, the severity of subclinical organ damage and manifest diseases of the cardiovascular system.

The object for pharmacotherapy in patients with hypertension is not only blood pressure, but also other reversible risk factors, as well as conditions that determine the patient's prognosis within the framework of the cardiovascular continuum.

Along with antihypertensive pharmacotherapy, the most important place in the treatment of hypertensive patients is taken by lifestyle changes, which are used to initiate treatment in low-risk patients.

The task of antihypertensive therapy is to achieve a steady decrease in blood pressure to a level<140/90 мм рт. ст. и максимально близкого к оптимальному АД (см. классификацию АД) в зависимости от переноси- мости лечения.

The decrease in blood pressure should be gradual; in order to avoid undesirable side reactions associated with hypotension and deterioration of regional blood circulation, one should strive to achieve and maintain the target blood pressure level with the minimum necessary means, which implies: a) rational choice of the drug (drugs); b) adequate combination of antihypertensive drugs; c) rational dosage of drugs.

It is recommended to use long-acting or long-acting antihypertensive drugs that provide a 24-hour effect with a single dose. This allows achieving a stable hypotensive effect, round-the-clock protection of target organs and increasing patient adherence to the prescribed treatment.

The best way to treat hypertension in acute situations (cerebrovascular accident, acute left ventricular failure, arterial embolism, acute pain, hypercatecholaminemia, various

origin) - impact on the cause underlying the pathological condition.

Pharmacological drugs that are used for the treatment of hypertension should affect one or more links in the pathogenesis of hypertension:

1) reduce the total peripheral vascular resistance (OPSS);

2) decrease the minute volume of blood flow (MVV);

3) reduce the volume of circulating blood (BCC);

4) prevent vascular wall remodeling and the development of left ventricular myocardial hypertrophy.

In addition, they must have the following properties for the "ideal" antihypertensive drug (Mustone A. L., 2006, as amended):

Be highly effective when used as monotherapy;

It is good to combine with other drugs;

Quickly achieve target blood pressure values;

Prescribed once (per day) to maintain high patient adherence to treatment;

Have an effective duration of action over 24 hours;

Give a direct dose-dependent effect;

Have an optimal tolerance profile.

Although at present none of the drugs in use fully possess all these properties, the rapid progress of pharmacological science gives rise to the hope that such a drug will be found in the foreseeable future.

For a comparative assessment of the effectiveness of antihypertensive drugs, it is recommended to use the so-called T / P ratio (tough / peak ratio), which is the ratio of the blood pressure decrease at the end of the interdose interval (before the next drug intake) to the blood pressure decrease. during the period of maximum action. The use of the T / P ratio allows you to get an idea of \u200b\u200bthe duration and uniformity of the antihypertensive drug action. Antihypertensive drugs prescribed 1 time per day should have a T / P of at least 50% with a pronounced hypotensive effect and at least 67% with a slight peak effect. The T / P value, close to 100%, indicates a uniform decrease in blood pressure throughout the day and the absence of a negative effect of the drug on varia-

ability of blood pressure, confirming the validity of the dose and a single dose of the drug. Drugs with a high T / P also have a maximum aftereffect, so they can control blood pressure when a dose is skipped. A T / P value of less than 50% indicates insufficient hypotensive effect at the end of the interdose interval or excessive hypotension at the peak of the drug action, which requires correction of the frequency of administration and / or dose of the drug. In addition, low T / P may indicate high variability in blood pressure.

2.3. ANTI-HYPERTENSIVE DRUGS

Means that reduce the tone of sympathetic innervation in various links

1. Adrenoblockers.

1.1. β-blockers.

1.2. α-blockers.

1.3. Mixed adrenergic blockers.

2. Means affecting the vasomotor center.

2.1. Α 2 -adrenoreceptor agonists.

2.2. Imidazoline receptor agonists.

Ca 2+ channel blockers.

Drugs affecting the renin-angiotensin and endothelin systems.

1. Angiotensin-converting enzyme inhibitors.

2. Angiotensin II receptor blockers.

3. Inhibitors of renin synthesis.

4. Blockers of endothelin receptors.

Diuretics

1. Thiazide and thiazide-like diuretics.

2. Loop diuretics.

3. Potassium-sparing diuretics.

Currently, there are five main groups of antihypertensive drugs - the so-called drugs of the first stage. These include:

1) thiazide diuretics (TD);

2) calcium channel blockers (CCBs);

3) inhibitors of angiotensin-converting enzyme (ACE inhibitors);

4) angiotensin II receptor blockers (BAR);

5) β-blockers.

If we proceed from the severity of the antihypertensive effect, then monotherapy with drugs of the first stage gives approximately the same effect. They are effective in 55-45% of cases of mild to moderate arterial hypertension.

Angiotensin-converting enzyme inhibitors

aCE inhibitors are divided into three classes (Table 2.4). Class I includes lipophilic ACE inhibitors such as captopril; Class II ACE inhibitors are prodrugs that become active after biotransformation in the liver; the prototype of these drugs is enalapril. Class II drugs are divided into three subclasses. Subclass IIa includes drugs, the active metabolites of which are excreted mainly (more than 60%) through the kidneys. Active metabolites of drugs of subclass IIb have two main pathways of elimination (liver and kidney), while metabolites of subclass IIc are characterized predominantly by hepatic (more than 60%) elimination. Class III ACE inhibitors are hydrophilic drugs such as lisinopril, which are not metabolized in the body, do not bind to proteins, and are excreted by the kidneys.

Table 2.4.Classification of angiotensin-converting enzyme inhibitors

The angiotensin-converting enzyme is involved in the conversion of angiotensin I to angiotensin II (AT-II) and, due to additional kininase activity, inactivates bradykinin. Physiological effects of AT-II are realized mainly through two types of angiotensin receptors - AT 1 and AT 2. As a result of the activation of AT 1 -receptors, vasoconstriction occurs, which leads to an increase in OPSS and blood pressure, stimulates the synthesis and secretion of aldosterone, respectively, increases the reabsorption of Na + and water, increases the BCC and blood pressure, increases the hypertrophy and proliferation of cardiomyocytes and smooth muscle cells of the vascular wall. Through activation of AT 2 receptors, vasodilation, the release of nitric oxide (endothelial relaxing factor) and vasodilating prostaglandins (PG), in particular PGI 2, are mediated.

ACE inhibitors, suppressing the activity of ACE, simultaneously affect the renin-angiotensin-aldosterone (RAAS) and kallikrein-kinin systems (Scheme 2.1). At the same time, due to a decrease in the formation of AT-II, the cardiovascular and renal effects of the RAAS activation are weakened, and due to the accumulation of bradykinin, the vasodilating effect of ACE inhibitors is potentiated. In addition, quinapril is characterized by the restoration of the function of extra-synaptic M 1 -cholinergic receptors located in the vascular endothelium and involved in vasodilation.

Thus, ACE inhibitors give the following hemodynamic effects:

Expansion of arteries, decrease in TPR, decrease in blood pressure, decrease in afterload;

Expanded veins, decreased preload;

Secondary decrease in cardiac output by reducing pre- and afterload;

Increased natriuresis, diuresis, decreased BCC;

Reverse development of left ventricular hypertrophy;

Suppression of the development of smooth muscle hypertrophy and fibrous changes in the arterial wall, which contributes to vascular dilation.

ACE inhibitors are characterized by nonlinear pharmacokinetics, in which the effectiveness of the drug and the duration of its action can increase abruptly with increasing dose. Doses of ACE inhibitors are selected empirically, starting with the lowest recommended, under the control of blood pressure. HELL is necessary

Scheme 2.1.The mechanism of action of an ACE inhibitor at the cellular and systemic level

measure at the maximum effect of the drug and at the end of the interdose interval (usually 24 hours after taking a long-acting ACE inhibitor). The degree of decrease in blood pressure at the peak of the action of an ACE inhibitor should not exceed the degree of decrease in blood pressure at the end of the interdose interval by more than 1.5-2 times.

The main indications for the use of ACE inhibitors in hypertension

Heart failure.

Left ventricular dysfunction.

Transferred MI.

Diabetic nephropathy.

Nephropathy.

LV hypertrophy.

Atrial fibrillation.

Metabolic syndrome.

Absolute contraindications to the use of ACE inhibitors in hypertension

Pregnancy.

Angioedema.

Hyperkalemia.

Tolerance to an ACE inhibitor can be assessed on the 3-5th day, and clinical efficacy - no earlier than 10-14 days. The recommended doses of drugs are presented in table. 2.5.

Side effects of ACE inhibitors

1. Arterial hypotension, which most often develops after taking the first dose in patients with severe left ventricular dysfunction or renal artery stenosis. In addition, a decrease in blood pressure is possible in elderly patients, as well as in patients receiving nitrates, diuretics or other drugs that lower blood pressure. To reduce the risk of hypotension in these categories of patients, it is recommended:

Start treatment with small doses of drugs;

For 24-48 hours before the appointment of an ACE inhibitor, stop diuretic drugs;

After taking the first dose, the patient should be in bed for several hours.

The end of the table. 2.5

Note:* - in elderly patients, the dose is reduced by 2 times.

2. Proteinuria and increased serum creatinine. Renal impairment usually occurs in patients who have had a history of kidney disease, as well as with one or two-sided renal artery stenosis. To prevent this side effect it is necessary:

Start ACE inhibitors with low doses;

Correct the dose of the drug depending on the glomerular filtration rate;

Give preference to drugs with a dual route of excretion (groups IIb and IIc);

Monitor creatinine levels in the first 3-5 days of treatment, and then once every 3-6 months.

3. Hyperkalemia (\u003e 5.5 mmol / L). The likelihood of development increases with the simultaneous administration of potassium-sparing diuretics, potassium preparations, NSAIDs, in patients with diabetes mellitus, obstruction of the urinary tract, interstitial nephritis.

4. Neutropenia. This complication often occurs in patients with insufficient renal function, with the simultaneous administration of immunosuppressants, procainamide (novocainamide), pyrazolones.

5. Dry, painful cough - a consequence of interstitial edema of the tissues of the upper respiratory tract (due to an increase in the content of bradykinin), often restricts the use of ACE inhibitors in patients with bronchopulmonary pathology. It is more common in women, black and Mongoloid people and smokers. Cough usually occurs in the first days of treatment with an ACE inhibitor, but sometimes - several months or even years after starting the drug. It disappears in 1-2 weeks after the withdrawal of the ACE inhibitor.

6. Quincke's edema. It occurs mainly in women in the first week of treatment and disappears within a few hours after the drug is discontinued. The likelihood of occurrence does not depend on the chemical structure

aCE inhibitors.

Avoid the simultaneous appointment of patients receiving ACE inhibitors, β-blockers and diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), since the latter block the synthesis of prostaglandins and can cause fluid retention in the body with an exacerbation of the disease (Scheme 2.2). The most dangerous are indomethacin and rofecoxib, the safest is acetylsalicylic acid.

Angiotensin II receptor blockers

Losartan (Kozaar).

Valsartan (Diovan).

Olmesartan (Olmetek).

Irbesartan (April).

Candesartan (Atacand).

Telmisartan (Pritor).

Eprosartan (Teveten).

Tasosartan.

The angiotensin-converting enzyme is far from the only enzyme that ensures the formation of AT-II in the body (it accounts for no more than 20% of AT-II), while the remaining 80% are synthesized under the action of other enzymes (chymase, etc.). Therefore, one of the effective approaches to inhibiting excessive activity of the RAAS is the blockade of angiotensin receptors. Currently, there is a fairly large group of drugs that block type 1 receptors for angiotensin II. Their mechanism of hypotensive action is associated with a weakening of the effects of angiotensin II, which are realized through AT 1 -receptors (see Scheme 2.1). The blockade of AT 1 -receptors leads to the expansion of peripheral vessels, a decrease in systemic vascular resistance and blood pressure; in addition, the secretion of aldosterone decreases, as a result of which the reabsorption of Na + and water, BCC and blood pressure decreases. The proliferative effects of angiotensin II on cardiomyocytes and vascular smooth muscle cells are weakened.

AT 1 receptor blockers (BAR) disrupt the negative feedback mechanism that regulates the synthesis and release of angiotensinogen and renin into the blood. Therefore, long-term administration of drugs of this group in the blood increases the content of angiotensinogen, renin, angiotensin I and II. Under conditions of blockade by AT 1 -receptor drugs, the resulting angiotensin II cannot interact with them, which causes additional stimulation of AT2-receptors leading to an increase in the synthesis and release of endothelial relaxing factor (ERF), PGI 2, increased arterial vasodilation (see Scheme 2.1).

Scheme 2.2.Supposed mechanisms of weakening the effects of antihypertensive drugs under the influence of NSAIDs (Preobrazhensky D.V. et al., 2002)

End of the table

In terms of their antihypertensive activity, BAPs are comparable to other antihypertensive drugs of the first stage and are better tolerated. In addition, in patients with hypertension receiving bipolar disorder (in particular, valsartan), the likelihood of developing new cases of atrial fibrillation is 17% lower, and the risk of persistent atrial fibrillation is 32% lower than in patients receiving calcium channel blockers (in particular, amlodipine ).

The maximum antihypertensive effect of BAR develops by the 3-4th week of treatment, and according to some reports, even later. It is important to note that BARs do not disrupt the physiological course of the daily (day-night) pressure curve; they are not characterized by either hypotension of the first dose or a sharp increase in blood pressure after sudden drug withdrawal. The same antihypertensive efficacy and tolerability of bipolar disorder have been established in patients of various ages (including those over 65), gender and race.

Indications for the use of BAR in hypertension

Heart failure.

Diabetic nephropathy.

Proteinuria / microalbuminuria.

Atrial fibrillation.

Metabolic syndrome.

Intolerance to ACE inhibitors.

Absolute contraindications to the use of BAR in hypertension

Pregnancy.

Bilateral renal artery stenosis.

Hyperkalemia.

The number of side effects that can develop with the use of BAR is small - occasionally there may be headache, dizziness, general weakness, nausea. In terms of their organoprotective properties, BARs are probably not inferior to ACE inhibitors, and today they are the first line agents in the treatment of arterial hypertension, although the final place of these agents in the treatment of hypertension may still be clarified.

Endothelin receptor blockers

Darusentan.

One of the most potent vasoactive substances are endothelial peptides endothelin (ET). Three representatives of this

metas - ET-1, ET-2, ET-3 - are produced by various tissues, in which they are present as modulators of vascular tone, cell proliferation and hormone synthesis. The cardiovascular effects of endothelin are mediated through specific receptors of type A (vasoconstriction) and type B (vasodilation) with a predominance of the action of the former. In terms of the strength of the vasoconstrictor effect, ET exceeds AT-II by 30 times.

Among the blockers of endothelin receptors (bosentan, sitaxentan, tezosentan, ambrisentan, darusentan) for the treatment of arterial hypertension (primarily resistant), only darusentan has been proposed so far, but the final judgment about its effectiveness and safety can be made only after extensive clinical studies. Other drugs in this group have found use in the treatment of heart failure and pulmonary hypertension.

Renin synthesis blockers

Aliskiren (Rasilez).

One of the approaches to blockade of RAAS is its inhibition at the earliest stage of activation (renin formation) with the help of specific inhibitors of renin synthesis. The drugs of this group have the ability to selectively block the conversion of angiotensinogen to AG-I, which determines their specificity. Due to this, there is a decrease in the levels of angiotensin I and angiotensin II in the blood and a concomitant decrease in blood pressure. The maximum decrease in plasma renin activity is observed within 1 hour after taking the drug (300 mg) and lasts 24 hours. With the course of administration, the severity of this effect does not decrease.

The effectiveness of aliskiren in monotherapy (according to preliminary data) is comparable to the effectiveness of a combination of two traditionally prescribed antihypertensive drugs. In addition, it can be combined with diuretics, calcium channel blockers and ACE inhibitors.

In terms of the incidence of adverse events (diarrhea, headache, rhinitis), aliskiren is comparable to losartan. The final judgment on the effectiveness and safety of the drug can be made at the end of large clinical trials.

β -adrenergic blockers and mixed adrenergic blockers

Another group of drugs with a pronounced hypotensive effect is β-blockers. The classification of β-blockers is presented in the lecture “Clinical Pharmacology of Treatment ischemic disease hearts ".

The mechanism of the hypotensive action of β-blockers is primarily associated with the blockade of β 1 -adrenoreceptors of the heart, which leads to a decrease in the strength and frequency of heart contractions and, accordingly, cardiac output. By blocking β 1 -adrenergic receptors of the juxtaglomerular apparatus of the kidneys, the drugs reduce the release of renin, and hence the formation of angiotensin II and aldosterone. In addition, non-selective BAB, blocking presynaptic β 2 -adrenergic receptors, reduce the release of catecholamines into the synaptic cleft. By reducing the activity of SAS, β-blockers lead to regression of myocardial hypertrophy. β 1 -adrenergic blockers with additional vasodilating properties are able to reduce the systemic vascular resistance by expanding the peripheral vessels (see the lecture "Clinical pharmacology of drugs for the treatment of coronary heart disease"). Basic information on the use of β-blockers in hypertension are presented in table. 2.7.

The side effects of β-blockers are presented in more detail in the lecture "Clinical pharmacology of drugs for the treatment of coronary heart disease."

The drugs in this group are the means of choice:

For the treatment of hypertension with pronounced activation of SAS and RAAS;

Combination of hypertension with ischemic heart disease, tachyarrhythmias, heart failure;

In pregnant women (selective BAB);

In case of intolerance or in the presence of contraindications to the appointment of an ACE inhibitor and bipolar disorder.

Indications for use β -adrenergic blockers for hypertension

Angina pectoris.

Postponed myocardial infarction.

Heart failure (bisoprolol, metoprolol succinate, carvedilol, nebivolol - for patients over 70 years old).

Tachyarrhythmias.

Pregnancy (in trimesters, the use of atenolol, propranolol, metoprolol tartrate, labetalol is acceptable).

Glaucoma.

End of Table 2.7

Absolute contraindications for use β -adrenergic blockers for hypertension

Bronchial asthma.

AV block II-III degrees (in the absence of a permanent pacemaker).

β -adrenergic blockers for hypertension

Peripheral vascular disease, Raynaud's syndrome.

Metabolic syndrome.

Impaired glucose tolerance.

Athletes and physically active patients.

Chronic obstructive pulmonary disease.

It should be noted that β-blockers (primarily atenolol) have the lowest efficacy in preventing the development of strokes compared to other classes of antihypertensive drugs (ACE inhibitors, BAR, diuretics, calcium channel blockers). In addition, there is evidence that β-blockers, especially in combination with thiazide diuretics, should not be used in patients with metabolic syndrome or at high risk of developing diabetes mellitus. Meanwhile, in patients with diabetes mellitus β-blockers are as effective in reducing the risk of cardiovascular complications as in patients without diabetes mellitus.

Of the group of mixed adrenergic blockers, carvedilol is the most commonly used for the treatment of hypertension. The drug blocks β 1 - and α 1 -adrenergic receptors, additionally has antioxidant and antiproliferative activity (in relation to smooth muscle cells). Start treatment with a dose of 12.5 mg, average therapeutic dose 25-50 mg / day once. Another mixed adrenergic blocker - labetalol - can be used for hypertension in pregnant women.

Calcium channel blockers

The classification of calcium channel blockers is presented in the lecture “Clinical pharmacology of agents for the treatment of ischemic heart disease”.

Depending on the chemical class, calcium channel blockers can affect the leading pathophysiological

logical mechanisms of hypertension - an increase in OPSS (for example, dihydropyridines) or an increase in IOC (mainly phenylalkylamines). In addition, these drugs dilate the renal vessels, improve renal blood flow, and have an antiplatelet effect. CCBs do not adversely affect the metabolism of carbohydrates and lipids, do not cause bronchospasm and orthostatic hypotension.

CCBs are one of the drugs of choice for the treatment of hypertension in combination with paroxysmal tachycardia (phenylalkylamine derivatives), bronchial asthma.

Mechanisms of the antihypertensive action of calcium channel blockers

The blockade of the slow calcium channels of the myocardium and the conducting system leads to a decrease in the strength and heart rate, which is accompanied by a decrease in cardiac output (decrease in stroke volume and IOC). This mechanism of action is more typical for phenylalkylamine derivatives.

Blockade of calcium channels of vascular smooth muscle cells causes dilatation of arterioles, a decrease in OPSS and blood pressure. This mechanism of action underlies the hypotensive effect of dihydropyridine derivatives.

Along with the actual antihypertensive effect, CCBs slow down the development of left ventricular hypertrophy, and, which is very important, the progression of atherosclerosis of the carotid and coronary arteries.

Indications for the use of CCB in hypertension

Dihydropyridine CCBs (long-acting and long-acting dihydropyridines: nifedipine, amlodipine, lacidipine, etc.)

Angina pectoris.

Left ventricular hypertrophy.

Atherosclerosis of the carotid, coronary arteries.

Pregnancy.

AH in persons of the Negroid race.

Non-dihydropyridine CCBs (verapamil, diltiazem)

Angina pectoris.

Atherosclerosis of the carotid arteries.

Supraventricular tachyarrhythmias.

Absolute contraindications to the use of CCBs in hypertension

AV block II-III degrees (non-dihydropyridine calcium channel blockers).

Heart failure (nondihydropyridine calcium channel blockers).

Relative contraindications to the use of CCBs in hypertension

Tachyarrhythmias (long-acting and long-acting dihydropyridines).

Heart failure (long-acting and long-acting dihydropyridines).

CCBs have some peculiarities of influence on various “end points”. So, against the background of therapy with drugs of this group, the risk of developing heart failure and myocardial infarction is slightly higher than against the background of therapy with other antihypertensive drugs. At the same time, CCBs reduce the risk of cerebral stroke to a slightly greater extent than other antihypertensive drugs.

Additional indications for the appointment of dihydropyridine CCBs are: elderly patient age, isolated systolic hypertension, concomitant exertional angina, peripheral arterial disease, signs of atherosclerotic changes in the carotid arteries, pregnancy. For nondihydropyridine calcium channel blockers, additional indications for the appointment are concomitant exertional angina, signs of atherosclerotic changes in the carotid arteries, supraventricular rhythm disturbances.

Some information on the use of calcium channel blockers in hypertension are given in table. 2.8.

Short-acting nifedipine (as opposed to its long-acting forms) with long-term use worsens the prognosis of patients with hypertension, ischemic heart disease, therefore it is not used for systematic treatment of hypertension.

Side effects of CCB

Blockade of calcium channels in the heart can lead to bradycardia, atrioventricular block, cardiodepression. These side effects are common with phenylalkylamines.

The result of blockade of calcium channels of peripheral vessels is orthostatic hypotension, reflex tachycardia. In addition, patients may experience: redness of the face, swelling of the ankles of non-cardiac origin caused by vasodilation, gingivitis, and constipation.

Diuretics

The widespread use of diuretic drugs for antihypertensive therapy is due to the fact that their treatment is economically beneficial and does not cause an excessive decrease in blood pressure, and therefore there is no need for frequent medical supervision; in addition, drugs do not induce a rebound phenomenon. Diuretics are the drugs of choice in the treatment of hypertension in the elderly, including those with heart failure.

Diuretic classification

1. Acting on the thick ascending part of the loop of Henle (loop diuretics):

Furosemide (Lasix).

Bumetanide (Bufenox).

Pyrethanides (Arelix).

Ethacrynic acid (Uregit).

Torasemid (Diuver).

2. Acting on the initial part of the distal tubule:

2.1. Thiazide diuretics (benzothiadiazine derivatives):

Dichlothiazide (Hypothiazide).

Metolazone (Zaroxolin).

Cyclomethiazide (Cyclopentiazide).

Polythiazide (Renese).

2.2. Non-thiazide (thiazide-like) diuretics:

Clopamide (Brinaldix).

Chlorthalidone (Oxodolin).

Indapamide (Arifon).

Xypamide (Aquaphor).

3. Acting on the end part of the distal tubule and collecting ducts (potassium-sparing diuretics):

3.1. Competitive aldosterone antagonists:

Spironolactone (Veroshpiron).

Eplerenone (Inspra).

End of Table 2.8

Note:* - for forms of prolonged action.

3.2. Sodium channel blockers:

Triamteren (Daitek).

Amiloride (Modamid).

4. Acting on the proximal tubule (carbonic anhydrase inhibitors):

Acetazolamide (Diacarb).

5. Combined drugs:

Triampur (triamterene + dichlothiazide).

Moduretic (amiloride + dichlothiazide).

Furesis (furosemide + triamterene).

Spiro-D (furosemide + spironolactone).

Thiazide and thiazide-like diuretics are most commonly used to treat hypertension. In the mechanism of their hypotensive action, two components can be conventionally distinguished. The first is associated with the diuretic effect itself and is realized at the cellular level due to the suppression of electrically neutral Na + and Cl - transport through the luminal membrane of the distal convoluted tubules, which leads to an increase in sodium excretion and, consequently, water. This is accompanied by a decrease in the BCC and, accordingly, a decrease in blood return to the heart and cardiac output. This mechanism underlies the positive effect of thiazide diuretics in the first weeks of hypertension treatment and is dose-dependent (manifested in diuretic doses).

The second component manifests itself even when administered in non-diuretic doses and is due to a decrease in the systemic vascular resistance due to:

Strengthening the excretion of Na + and water from the vascular wall, leading to a decrease in its thickness and response to pressor effects;

Reducing the sensitivity of adrenergic receptors to catecholamines;

Stimulation of the synthesis of vasodilating prostaglandins;

Disorders of Ca 2+ and Na + metabolism in vascular smooth muscle cells.

Comparative studies have shown that there is no significant difference in the antihypertensive activity of low (less than 25 mg hydrochlorothiazide per day or equivalent doses of other drugs) and high doses (more than 25 mg) thiazide diuretics. At the same time, low doses of diuretics are much better tolerated by patients and are not accompanied by significant electrolyte and metabolic disturbances.

Unlike β-blockers, diuretics are equally effective in preventing cardiovascular complications in patients with hypertension, both middle and elderly and old age and are able to improve the long-term prognosis in these patients with arterial hypertension. Diuretics are more effective than β-blockers in preventing the development of coronary artery disease and death, which makes them one of the first-line drugs in the initial therapy of hypertension.

Indications for the use of diuretics for hypertension

Thiazide and thiazide-like diuretics (low doses):

Isolated systolic hypertension in the elderly.

Heart failure.

AH in persons of the Negroid race. Aldosterone antagonists:

Heart failure.

Postponed myocardial infarction. Loop diuretics:

Heart failure.

End stages of kidney disease.

Absolute contraindications to the use of diuretics in hypertension

Gout (thiazide diuretics).

Renal failure (aldosterone antagonists).

Hyperkalemia (aldosterone antagonists).

Relative contraindications to the use of diuretics in hypertension

Pregnancy.

Metabolic syndrome (high doses and combination with β-blockers).

Side effects of thiazide diuretics

1. Renal (hypokalemia, hyponatremia, hypomagnesemia, hypercalcemia, metabolic alkalosis).

2. Extrarenal (hyperglycemia associated with inhibition of insulin secretion by β-cells of the islets of Langerhans; hyperuricemia with the onset of gouty syndrome; increased blood cholesterol and triglyceride levels; secondary hyperaldosteronism with prolonged use).

Unlike thiazide diuretics, the natriuretic effect of loop diuretics is more pronounced, but the antihypertensive effect is less pronounced.

Note:* - possible long-term treatment with non-diuretic doses of thiazides as part of combined antihypertensive therapy.

The mechanism of action of loop diuretics is associated with blockade in the thick section of the ascending knee of the nephron loop (Henle loop) of the Na +, K + cotransport and two C1 - ions. The result is an increase in urine output, a decrease in BCC, blood return to the heart, and cardiac output. In addition, due to an increase in the synthesis of vasodilating prostaglandins in the vascular wall, arterioles and veins expand, which leads at the systemic level to a decrease in systemic vascular resistance, a decrease in post- and preload, cardiac output, and in the kidneys - to an increase in renal blood flow and, consequently, filtration and natriuresis.

The side effects of loop diuretics are similar to those of thiazide diuretics (except for the effect on calcium levels (hypocalcemia). In addition, gastrointestinal dysfunction may occur, manifested by nausea, decreased appetite, abdominal pain, dyspeptic symptoms.

In addition, with prolonged therapy with diuretics, their diuretic effect may decrease due to the development of secondary hyperaldosteronism.

The mechanism of action of aldosterone antagonists is based on the blockade of aldosterone receptors with the subsequent violation of the implementation of the main effects of mineralocorticoids. In the nuclear apparatus of the cells of the renal epithelium, this leads to a violation of the expression of certain genes, the result of which is a decrease in the synthesis of permeases, and, as a consequence, an increase in natriuresis and diuresis, a decrease in the secretion of potassium in the urine. At the systemic level, this is manifested by a decrease in the activity of the RAAS, a slight increase in urine output (up to 200 ml / day) and a decrease in the BCC. The antihypertensive effect of spironolactone is especially pronounced in conditions of primary and secondary hyperaldosteronism.

Most often, aldosterone antagonists are used in combination with thiazide or loop diuretics (if necessary, their long-term use) for the prevention of secondary hyperaldosteronism and hypokalemia. The effect of the use of drugs develops in about 3 days, and it may take up to 3 - 4 weeks to achieve a detailed clinical effect. Side effects include hyperkalemia, hormonal disturbances (gynecomastia, decreased libido, impotence in men, menstrual cycle, coarsening of the voice in women).

The newer drug eplerenone (Inspra) is a more selective blocker of aldosterone receptors compared to spironolactone. Its high selectivity avoids most of the side effects from the endocrine system. The actual diuretic effect of the drug is insignificant.

The mechanism of action of another potassium-sparing diuretic, triamterene, is associated with the blockade of sodium channels in the luminal membrane of the collecting duct epithelium. As a result, the release of Na + from the lumen of the tubules into the cells decreases. This leads to a decrease in the supply of K + through the basement membrane and a decrease in its secretion into the urine. The antihypertensive effect of triamterene is associated with a decrease in circulating blood volume and cardiac output. Side effects: crystalluria, cylinduria, urolithiasis.

Agonistsα 2 -adrenergic receptors

Clonidine (Clonidine).

Guanfatsin (Estulik).

Methyldopa (Dopegit).

IN last years the frequency of use of α 2 -adrenoreceptor agonists, clonidine and guanfacine, for the treatment of hypertension, significantly decreased, the mechanism of hypotensive action of which is associated with the activation of inhibitory α 2 -adreno- and imidazoline I 1 -receptors in the central nervous system. Clonidine is currently not recommended for the systematic treatment of hypertension and is used mainly for the relief of hypertensive crises. Side effects of the drug are a consequence of the activation of α 2 -adrenergic receptors and include dry mouth, lethargy, depression, bradycardia, recoil syndrome, and the development of tolerance.

Methyldopa (Dopegit) is metabolized into methylnorepinephrine, which activates the inhibitory α 2 -adrenoreceptors of the vasomotor center, which leads to a decrease in sympathetic impulses and blood pressure. In addition, it is a "false" mediator that disrupts synaptic transmission by competing with norepinephrine in the synaptic cleft. Treatment is started with 250 mg 2-3 times a day, in the subsequent daily dose can be increased to 1 g in 2-3 doses. Methyldopa is a traditional drug for the treatment of hypertension in pregnant women.

Side effects include lethargy, drowsiness, night fears, depression, and the development of parkinsonism. With prolonged use, autoimmune myocarditis may occur, hemolytic anemia, hepatitis.

Imidazoline receptor agonists

Moxonidine (Physiotens).

Rilmenidine (Albarel).

Imidazoline receptor agonists are a new class of antihypertensive drugs, the place of which in the therapy of hypertension is currently being specified. The mechanism of action of the drugs is associated primarily with the activation of central imidazoline I 1 receptors, which leads to suppression of the activity of the sympathetic nervous system and a decrease in blood pressure. In addition, they interact with imidazoline receptors in the epithelium of the renal tubules, enhancing natriuresis. They can also activate inhibitory a 2 - adrenergic receptors, but the affinity of drugs for them is much less than for imidazoline receptors. Compared to clonidine, the drugs have fewer side effects, tolerance develops a little less often and they practically do not cause recoil syndrome.

Indications for the use of imidazoline receptor agonists in hypertension

Metabolic syndrome

Absolute contraindications to the use of imidazoline receptor agonists in hypertension

AV block.

Severe heart failure.

Severe depression.

Moxonidine is prescribed 0.1 mg orally 1 time per day. After 5-7 days, the dose can be increased to 0.2 mg / day once (under the control of blood pressure), after 2-3 weeks, the dose is increased to 0.4 mg / day once (or 0.2 mg 2 times a day) ... The maximum daily dose is 0.6-0.8 mg.

Rilmenidine is prescribed 1 mg once a day. If the effect is insufficient after one month of treatment, the dose can be increased to 2 mg / day in two divided doses.

Sympatholytics

Central sympatholytics (rauwolfia alkaloids) are currently not recommended for the systematic treatment of hypertension, due to their low efficacy and a large number of side effects. Reserpine in synaptic terminals selectively and persistently disrupts the active transport of catecholamines from the cytosol to granules, as a result of which neurotransmitters are destroyed by monoamine oxidase. This leads to depletion of catecholamine reserves, impaired synaptic transmission and a decrease in blood pressure. Reserpine is characterized by a slowly developing moderate hypotensive effect and a pronounced psychosedative effect.

Side effects: depression, increased suicidal behavior, fear, drowsiness, nightmares. In addition, due to the activation of the parasympathetic division of the autonomic nervous system, bradycardia, atrioventricular blockade, an increase in the acid-forming function of the stomach, bronchospasm, and nasal congestion are possible.

and -adrenergic blockers

Prazosin (Adversuten).

Terazosin (Haitrin).

Doxazosin (Tonokardin).

For the treatment of hypertension, α 1 -adrenergic blockers are sometimes used - prazosin, doxazosin, terazosin. These drugs block the α 1 -adrenoreceptors of peripheral vessels, which leads to the expansion of arterioles, a decrease in systemic vascular resistance and blood pressure. In addition, afterload decreases and cardiac output decreases secondarily.

Indications for use and -adrenergic blockers for hypertension

Benign prostatic hyperplasia.

Impaired glucose tolerance.

Dyslipidemia.

Relative contraindications for use α -adrenergic blockers for hypertension

Orthostatic hypotension.

Heart failure.

Treatment with α 1 -adrenergic blockers begins with the minimum dose that the patient should take before bedtime,

changing diuretic drugs (to avoid the phenomenon of "first dose", manifested by orthostatic hypotension). The main advantage of drugs in this group is their beneficial effect on metabolic parameters (in contrast to β-blockers and diuretics). However, this is leveled by their side effects: orthostatic hypotension, edema of non-cardiac origin, tachycardia, rapidly developing tolerance. In addition, in low doses, which are relatively well tolerated by patients, the hypotensive effect of α 1 -adrenergic blockers is usually insufficient, and in high doses, the number of side effects increases sharply. The recommended doses of drugs are presented in table. 2.10.

Table 2.10.Recommended doses and individual pharmacokinetic parameters of α 1 -adrenergic blockers used for the treatment of arterial hypertension

2.4. PHARMACOTHERAPY OF ARTERIAL HYPERTENSION

Blood pressure targets

It is necessary to strive to reduce blood pressure to a level< 140/90 мм рт. ст. и ниже (при хорошей переносимости) у всех больных АГ. У больных сахарным диабетом и у пациентов с высоким и очень

high cardiovascular risk (concomitant diseases of the cardiovascular system and kidneys - stroke, myocardial infarction, renal dysfunction, proteinuria), the target blood pressure should be<130/80 мм рт. ст. К сожалению, достичь этого уровня АД непросто, даже при комбинированной антигипертензивной терапии, особенно у пожилых пациентов, у больных сахарным диабетом и в целом у пациентов с сопутствующими повреждениями сердечнососудистой системы. Таким образом, для скорейшего и простейшего достижения целевого АД следует начинать антигипертензивную терапию еще до появления значимых кардиоваскулярных повреждений.

Antihypertensive therapy

Previously, a staged treatment regimen for hypertension was widely used, involving the initial appointment of one antihypertensive drug in small or medium doses with subsequent dose escalation and (or) a combination with other drugs (s) with insufficient effectiveness at the previous stage of treatment. At present, the need for initial combination therapy has been postulated in a significant number of hypertensive patients.

Choosing an antihypertensive drug

The main advantages of antihypertensive treatment are due to the reduction in blood pressure as such. According to the European guidelines for hypertension (2007), representatives of the five main classes of antihypertensive drugs (thiazide diuretics, calcium channel blockers, ACE inhibitors, angiotensin receptor antagonists and β-blockers) are suitable for both initial and maintenance antihypertensive treatment in monotherapy or in combination with each other. In this case, β-blockers, especially in combination with thiazide diuretics, should not be used in patients with metabolic syndrome or with a high risk of developing diabetes mellitus. Since many patients require a combination of antihypertensive drugs, too much attention to the choice of the first drug is often not warranted. Nevertheless, there are many pathological conditions in which the priorities of some medicines in front of others.

Drugs of choice when prescribing antihypertensive treatment depending on concomitant diseases or conditions (Recommendations EOAG-EOK, 2007)

Note:aCE inhibitors - angiotensin-converting enzyme inhibitors; BKK - calcium channel blockers; BAR - angiotensin II receptor blockers; BAB - β -adrenergic blockers; AA are aldosterone antagonists.

* - non-dihydropyridine CCBs.

Ultimately, the choice of a specific drug or combination of drugs depends on the following factors:

Previous experience with the drug (class of drugs) in a particular patient;

The predominant efficacy and safety of the drug for a given cardiovascular risk profile;

The presence and nature of concomitant (noncardiac) pathology, which can limit the use of certain classes of antihypertensive drugs (Table 2.11);

Possibilities of interaction with other antihypertensive drugs and with drugs prescribed for other conditions;

The age and race of the patient;

Features of hemodynamics;

The cost of treatment.

Table 2.11.The main contraindications to the appointment of antihypertensive drugs, depending on the associated diseases and conditions

Note:PEX - implanted pacemaker; AAB -α- adrenergic blockers; BKK dgp - dihydropyridine calcium channel blockers; CCB n / dgp - nondihydropyridine calcium channel blockers; AIR are agonists of imidazoline receptors.

Criteria for choosing a monotherapy or combination of antihypertensive drugs

Clinical experience suggests that monotherapy of hypertension allows reaching the target blood pressure level in only a small proportion of patients, while the overwhelming majority of patients require a combination of two or more antihypertensive drugs.

Treatment of hypertension can be started with monotherapy or with a combination of two low-dose antihypertensive drugs. In the future, if necessary, you can increase the dose or the amount of drugs used.

It is advisable to begin treatment with monotherapy in patients with grade I hypertension with low or medium cardiovascular risk (Scheme 2.3). Initially, one drug is prescribed at a low dose; if it is not effective enough, the dose is increased to full; if ineffective or poorly tolerated, a drug of a different class is prescribed in a low, and then in a full dose. The criterion of "positive response" to treatment: lowering blood pressure ≥20 mm Hg. Art. for systolic and ≥10 mm Hg. Art. for diastolic blood pressure. This is called sequential monotherapy. Its disadvantages are that the target values \u200b\u200bof blood pressure against the background of monotherapy can be achieved only in 20-30% of patients, and the frequent change of drugs and doses increases the complexity of treatment, reduces the degree of trust in the doctor and patient adherence to treatment, and also unnecessarily prolongs the time. necessary to normalize blood pressure. If monotherapy is ineffective, they switch to combined treatment.

A combination of antihypertensive drugs is initially required for patients with grade II-III hypertension or high and very high cardiovascular risk (see Scheme 2.3). Treatment can be started with a "low dose" combination, which causes fewer side effects and complications than full dose monotherapy. If the low-dose combination is partially effective, the dose of one or both of the components may be increased, or a third drug at a low dose may be prescribed. Some patients may need three or more full-dose drugs to achieve target BP. Most often, combination therapy is needed by patients with diabetes mellitus, kidney disease and severe concomitant diseases of the cardiovascular system. The disadvantages of the tactics of initial (initial) combined antihypertensive therapy should be considered: the risk of unreasonable prescription of an "extra" drug, difficulties in determining

Scheme 2.3.Tactics for the treatment of arterial hypertension: the choice between monotherapy and combination therapy (Recommendations EOAG-EOK, 2007)

dividing the drug that is the culprit for the allergy or poor treatment tolerance. The benefits of combination treatment:

Faster than with effective monotherapy, the achievement of target blood pressure;

More effective control of hypertension in general;

Better tolerance with less pronounced side effects;

Reducing the time and number of attempts required to select an effective therapy, which helps to increase the doctor's confidence and patient confidence in him;

The ability to prescribe fixed drug combinations in one tablet, simplifying treatment and increasing patient adherence to therapy.

However, not all antihypertensive drugs can be effectively and safely combined. A rational combination of drugs should have the following properties:

The summation or potentiation of the hypotensive effects of the drug combination;

Compensation for counter-regulatory mechanisms triggered by the use of each of the drugs that make up the combination;

No side effects due to the interaction of combined drugs;

The ability to effectively prevent subclinical target organ damage and reduce the risk of cardiovascular complications in controlled trials.

The effectiveness of various combinations from most classes of antihypertensive drugs is presented in table. 2.12.

Table 2.12.Various combinations of antihypertensive drugs (Chazova I.E., Ratova L.G., 2006, as amended)

In 2007, European experts recommended only six rational combinations of five main classes of antihypertensive drugs for the treatment of hypertension:

1) thiazide diuretic + ACE inhibitor (TD + ACE inhibitor);

2) thiazide diuretic + angiotensin II receptor blocker (TD +

BAR);

3) calcium channel blocker + ACE inhibitor (CCB + ACE inhibitor);

4) calcium channel blocker + angiotensin II receptor blocker (CCB + BAR);

5) calcium channel blocker + thiazide diuretic (CCB + TD);

6) β-blocker + calcium channel blocker (dihydrop-

readin) (BAB + BKK).

The combination of thiazide diuretics and potassium-sparing agents (triamterene, amiloride, spironolactone) was also recognized as expedient, the rationality of the combination of ACE inhibitors and BAR, renin blockers and thiazide diuretics is being studied. The undoubtedly effective combination of thiazide diuretics with β-blockers, recommended and successfully used earlier, is now recognized as undesirable due to the increased negative metabolic effects. It should not be used in patients at risk of diabetes mellitus and metabolic syndrome.

The most effective drug combinations

1. Currently, the combination of an ACE inhibitor and a diuretic is one of the most widely prescribed. Its use allows reaching the target blood pressure level in more than 80% of patients. In this case:

There is a potentiation of the antihypertensive effects of drugs;

ACE inhibitors reduce the activity of the RAAS, which increases with prolonged administration of diuretics;

A diuretic increases the effectiveness of an ACE inhibitor in patients with normo- and hyporenin forms of hypertension;

ACE inhibitors prevent the development of hypokalemia in the presence of diuretics;

ACE inhibitors do not affect lipid metabolism and reduce hyperuricemia and hyperglycemia that occurs while taking diuretics.

This combination is recommended primarily for patients with heart failure, left ventricular hypertrophy, diabetic nephropathy. It is also effective in patients with severe hypertension, in elderly patients with ineffective monotherapy

aCE inhibitors.

2. In terms of antihypertensive effects, BARs are close to ACE inhibitors, therefore their combination with diuretics has almost the same advantages as the combination of ACE inhibitors with diuretics.

The combined use of BAP and a diuretic leads to a noticeable decrease in blood pressure in patients with both high and low renin activity.

3. The combination of ACE inhibitors + CCB (as well as BAR + CCB) is effective in both high and low-rooted forms of hypertension. The use of these drugs allows:

To potentiate the hypotensive effect;

Strengthen the natriuretic effect;

To increase the effectiveness of an ACE inhibitor in patients with normo- and hyporenin forms of hypertension;

Increase the effectiveness of dihydropyridine CCBs by suppressing ACE inhibitors activity of SAS;

To reduce the severity of edema of the legs while taking CCBs (most typical for dihydropyridine CCBs);

Reduce dry cough while taking an ACE inhibitor;

Achieve organoprotective action (including nephroprotective effect due to the expansion of afferent arterioles in the kidneys under the influence of ACE inhibitors and afferent and efferent arterioles under the influence of non-dihydropyridine CCBs);

Eliminate the possibility of a negative effect on lipid, carbohydrate and purine metabolism.

4. The combination of β-blockers and CCBs (dihydropyridine derivatives) allows:

Achieve additivity in the hypotensive effect;

Decrease the activation of SAS, which develops at the initial stage of the use of dihydropyridine

BPC;

Reduce the severity of edema of the legs while taking

BKK.

The combination is indicated for hypertensive patients with coronary artery disease, as well as for patients with severe hypertension refractory to monotherapy.

5. The combination of CCBs and diuretics does not seem obvious, since it allows an increase in adverse orthostatic reactions and a compensatory increase in the activity of the renin-angiotensin system. In the same time:

The antihypertensive effect of both drugs is noticeably potentiated;

The effectiveness of treatment of isolated systolic hypertension in elderly patients increases;

The severity of organoprotective effects is increasing.

6. The combination of β-blockers and diuretics is still very often used. In this case:

The hypotensive effects of drugs are potentiated;

- β-blockers prevent the development of hypokalemia on the background of diuretics;

- β-blockers prevent the activation of SAS and RAAS against the background of the appointment of diuretics.

This combination is not only highly efficient but also cost effective. At the same time, with the simultaneous administration of β-blockers and diuretics, their negative effect on carbohydrate and lipid metabolism is potentiated, and potency decreases. This combination is not used in patients with metabolic syndrome and a high risk of diabetes, and small doses of diuretics are used to reduce the adverse effect on lipid and glucose metabolism (equivalent to no more than 6.25-12.5 mg of hydrochlorothiazide).

7. When a β-blocker is used together with an α 1 -adrenoceptor blocker, the following occurs:

Potentiation of the hypotensive effect;

Decrease of β-blockers activation of SAS, which develops at the initial stage of the use of α 1 -adrenergic blockers;

Decrease in a 1 -adrenergic blockers of vasospasm caused by non-selective β-blockers;

Reduction of α 1 -adrenergic blockers of the adverse effect of β-blockers on lipid and carbohydrate metabolism.

However, the long-term effects of such a combination of antihypertensive drugs are poorly understood.

8. Modern drugs of central action (agonists of imidazoline receptors) are well combined with all other classes of antihypertensive drugs. However, when they are combined with β-blockers, caution must be exercised due to the risk of developing bradycardia. The effect of this combination on long-term prognosis has not been studied.

There are both low-dose and full-dose combination drugs with a fixed composition of the main antihypertensive drugs (Table 2.13). The advantages of fixed rational combinations include:

Ease of administration and dose titration process, increasing patient adherence to treatment;

Mutual increase in the antihypertensive effect of the drugs included in the combined dosage form;

An increase in the number of patients with a stable decrease in blood pressure due to the multidirectional antihypertensive effect of its components;

Reducing the incidence of side effects, both due to lower doses of combined antihypertensive drugs, and due to mutual neutralization of these effects;

Reducing the cost of treatment;

Elimination of the possibility of using irrational combinations;

The most effective organ protection and reduction of the risk and number of cardiovascular complications.

Fixed combinations have two main disadvantages:

Dose fixation limits the ability to vary drug doses. However, this is overcome by issuing combinations containing different doses of the same components;

Certain difficulties in identifying and correlating adverse events with the influence of one or another component of the drug.

Less effective drug combinations

Currently, there is no convincing evidence in favor of the use of combinations of β-blocker + ACE inhibitors and β-adrenergic blockers + BAR. It is believed that both drugs act unidirectionally - they reduce the activity of the RAAS, therefore, potentiation of the antihypertensive action does not occur when they are administered together. Nevertheless, there are some peculiarities of the drugs action that can determine the synergism of their antihypertensive effect. Thus, it is assumed that the hyperreninemia resulting from ACE inhibition can be significantly reduced by β-blockers, which suppress renin secretion by the juxtaglomerular apparatus of the kidneys. In turn, the vasoconstriction that occurs with the appointment of BAB can be markedly reduced when using ACE inhibitors with vasodilating properties. Sometimes such a combination can be recommended when severe tachycardia persists with low RAAS activity. In patients with chronic heart failure, the need to use an ACE inhibitor in combination with a β-blocker is beyond doubt, but in patients with hypertension, this combination cannot be considered optimal.

Table 2.13. The composition of some combined antihypertensive drugs

Continuation of table 2.13

The end of the table. 2.13

End of table 2.13

Note:* - in the form of succinate.

The combination of ACE inhibitors and BAR is rarely used in clinical practice, since it is believed that both drugs act on different levels of the same system - RAAS - and potentiation of the antihypertensive action does not occur when administered together, since BAR causes a complete decrease in RAAS activity. At the same time, ACE inhibitors suppress the reactive increase in the synthesis of AT-II caused by BAR, and therefore weaken the indirect stimulation of type II angiotensin receptors, which is considered one of the important mechanisms of the antihypertensive action of BAR. nephroprotection in patients with arterial hypertension.

Irrational drug combinations

Irrational combinations include those combinations of drugs, the use of which either does not potentiate the antihypertensive effect, or side effects increase. These include combinations: β-blocker + CCB of the phenylalkylamine series, β-blocker + centrally acting drug, CCB of the dihydropyridine series + α 1 -adrenergic blocker.

To maximize the effectiveness of treatment for hypertension, the doctor should follow several rules:

It is advisable to prescribe a fixed combination of drugs (in one tablet), which simplifies the regimen and improves patient compliance;

It is necessary to give preference to drugs with prolonged action to provide a 24-hour effect with a single dose. This allows to achieve a stable hypotensive effect and permanent protection of target organs, in addition, to increase the patient's adherence to treatment;

The effectiveness of round-the-clock monitoring of blood pressure can be assessed by measuring blood pressure before taking the next dose of the drug or during outpatient monitoring;

Special attention should be paid to the side effects of drugs, as they are the most important reason for refusing treatment (lack of adherence to treatment);

In uncomplicated hypertension and in elderly patients, the volume of therapy is increased gradually until the target blood pressure is reached;

At high cardiovascular risk, target BP should

to be achieved as soon as possible, by the method of combination therapy with a relatively rapid increase in the dose, along with the antihypertensive treatment itself, eliminateable risk factors (hyperglycemia, hypercholesterolemia, etc.) are corrected according to generally accepted standards; - taking care of maintaining a high patient's adherence to treatment is a fundamentally important component of hypertension therapy, it includes: planning regular patient visits, medical education of the patient (including hypertension schools); clarification of the essence of the drugs and discussion of possible side effects; regular encouragement in relation to the patient's achieved lifestyle changes; encouraging blood pressure self-control; involvement of relatives in the process of implementing medical recommendations, a simple and understandable regimen of taking medications, tied to the daily routine.

Criteria for the effectiveness of antihypertensive therapy

The results of the therapy can be divided into short-term (immediate), medium-term (intermediate) and long-term (long-term). Immediate results are determined after a few weeks or months of treatment and include a decrease in blood pressure to an acceptable level, no side effects, improved laboratory parameters, adequate patient compliance with doctor's prescriptions, a beneficial effect on the quality of life. Interim results, sometimes called surrogate endpoints of treatment, are an indicator of the effectiveness of antihypertensive and organoprotective therapy. They include the effect on the state of the function of the heart and kidneys, left ventricular hypertrophy, the progression of atherosclerosis, angina pectoris, the effect on the state of carbohydrate and lipid metabolism. Long-term outcomes represent treatment endpoints and include indicators such as cardiac, cerebrovascular, and renal complications, aortic and peripheral arterial lesions, and mortality (from cardiac and noncardiac causes).

Short-term criteria for the effectiveness of antihypertensive therapy (1-6 months from the start of treatment)

Reduction of blood pressure and / or blood pressure by 10% or more, or reaching the target blood pressure level.

Lack of hypertensive crises.

Maintaining or improving the quality of life.

Influence on modifiable risk factors.

Medium-term criteria for the effectiveness of antihypertensive therapy (more than 6 months from the start of treatment)

Achievement of target blood pressure values.

Absence of damage to target organs or reversible dynamics of existing complications.

Elimination of modifiable risk factors.

Long-term criteria for the effectiveness of antihypertensive therapy

Stable maintenance of blood pressure at the target level.

No progression of target organ damage.

Compensation for existing cardiovascular complications.

2.5. TREATMENT OF HYPERTONIC CRISES

Hypertensive crises (HCR) usually mean conditions with a sudden increase in blood pressure, which are heterogeneous in clinical manifestations and prognosis and can pose a threat to life or health. HCR can complicate all stages of hypertension, but most often they occur at II-III st. A sudden increase in blood pressure can be provoked by neuropsychic trauma, alcohol consumption, sharp fluctuations in atmospheric pressure, cancellation of antihypertensive therapy, etc. In the pathogenesis of HCR, there are:

The vascular mechanism is an increase in the total peripheral resistance as a result of an increase in vasomotor (neurohumoral effects) and basal (with sodium retention) tonus of arterioles;

The cardiac mechanism is an increase in cardiac output, myocardial contractility and ejection fraction in response to an increase in heart rate, circulating blood volume.

MS Kushakovsky (2004) distinguishes three types of hypertensive crises.

Neurovegetative. This type of hypertensive crisis occurs most often. Blood pressure rises at night or during awakening, accompanied by agitation, severe headaches, tachycardia. BP rises rapidly: systolic up to 230-250 mm Hg. Art., diastolic up to 120-125 mm Hg. Art.

When edematous formthe patient is inhibited, obese, lethargic, the face is puffy, urine output is sharply reduced.

Convulsive form is rare, observed in the most severe course of hypertension and is manifested by loss of consciousness, tonic and clonic seizures.

Among hypertensive crises, emergency and urgent conditions are distinguished. Emergency hypertensive crises (HCR type I) mean hypertensive conditions characterized by a pronounced increase in blood pressure (\u003e 180/120 mm Hg), complicated by signs of onset or progressive dysfunction of target organs (unstable angina pectoris, acute left ventricular failure, aortic aneurysm dissection, eclampsia, stroke, edema of the papilla of the optic nerve, etc.). However, even if the increase in blood pressure does not exceed 180/120 mm Hg. Art., but leads to the appearance or aggravation of symptoms of damage to target organs, such a condition should be considered as type I HCR.

To prevent or limit damage to target organs in this case, an immediate decrease in blood pressure is required during the first minutes and hours (not necessarily to normal) with the help of parenteral drugs.

Emergency conditions in hypertensive crises

Hypertensive encephalopathy.

AH with signs of left ventricular failure.

AH in myocardial infarction.

AH with unstable angina.

AH with aortic dissection.

Severe hypertension associated with subarachnoid hemorrhage or cerebrovascular accident.

Crisis with pheochromocytoma.

Hypertension in case of poisoning with amphetamines, LSD, cocaine or ecstasy.

Hypertension during surgery.

Severe preeclampsia or eclampsia.

The initial goal of the treatment of urgent hypertensive conditions is to reduce the mean blood pressure by no more than 25% in the interval from several minutes to one hour with the help of parenterally administered antihypertensive drugs. Subsequently, if blood pressure is stable, it

reduce over the next 2-6 hours to 160 mm Hg. (systolic) and 100-110 mm Hg. Art. (diastolic) (switching to oral dosage forms). However, an excessive decrease in blood pressure should be avoided, which can cause renal, cerebral or coronary ischemia. If this blood pressure level is well tolerated and the patient's condition is clinically stable, then over the next 24-48 hours, a further gradual decrease in blood pressure to normal levels can be carried out.

Patients with ischemic stroke for whom clinical trials have not shown the benefit of urgent antihypertensive treatment;

Patients with aortic dissection in whom systolic blood pressure should be reduced to< 100 мм рт. ст., если они это переносят.

Under urgent hypertensive conditions (HA type II) are understood situations associated with a sharp increase in blood pressure without progressive dysfunction of target organs. This also includes cases of asymptomatic increase in blood pressure ≥220 mm Hg. Art. and / or BPd ≥120 mm Hg. Art.

In these situations, a gradual decrease in blood pressure by 15-25% of the initial or ≤160/110 mm Hg is necessary. Art. within 12-24 hours (using oral antihypertensive drugs). Evaluation of the effectiveness and correction of emergency therapy is carried out after the time required for the onset of the onset of the hypotensive effect of the drug (15-30 minutes).

To relieve the convulsive form of hypertensive crisis, diazepam (Seduxen, Relium, Sibazon) is additionally prescribed at a dose of 10-20 mg (2-4 ml of a 0.5% solution). The drug is administered intravenously slowly until seizures are eliminated. You can also prescribe magnesium sulfate 2.5 g intravenously slowly (10 ml of 25% solution in 10 ml of 0.9% sodium chloride solution). In this case, the main danger is respiratory arrest. Intravenous drip of magnesium sulfate (10 ml of 25% solution in 250 ml of 0.9% sodium chloride solution) is less dangerous. With respiratory depression, intravenous administration of calcium chloride is necessary.

For the treatment of hypertensive crises, the doctor should have a relatively small, but complete, and most importantly, a well-known set of antihypertensive drugs (Table 2.14).

Table 2.14. The main drugs used to relieve hypertensive crisis

Continuation of table. 2.14

Continuation of table 2.14

Continuation of table. 2.14

Continuation of table 2.14

The end of the table. 2.14

End of table 2.14

Note:* - at intravenous administration clonidine, a short-term increase in blood pressure is possible due to the activation of peripheral α 1 - and α 2 -adrenoreceptors of blood vessels; ** - introduction through a special system; *** - you can repeat the bolus injection after 5 minutes or increase the infusion up to 300 μg / min.

Requirements for a parenteral drug for the treatment of hypertensive crises

A short time of the onset of the hypotensive effect and its preservation 3-4 hours after the termination of the administration.

Dose-dependent predictable effect.

Minimal effect on cerebral and renal blood flow, myocardial contractility.

Effective in most patients.

No contraindications for use in most patients.

The minimum range of side effects.

Requirements for an oral drug for the treatment of hypertensive crises

Rapid (20-30 min) onset of hypotensive action in oral administrationlasting 4-6 hours.

Dose-dependent predictable hypotensive effect.

Suitable for most patients (no side effects).

Availability.

After the start of antihypertensive therapy, it is advisable to observe a doctor for at least 6 hours for timely detection possible complications HCR (primarily disorders of cerebral circulation and infarction) and side effects of drug therapy (eg, orthostatic hypotension). With development orthostatic hypotension recommend bed rest with blood pressure monitoring. With an excessive decrease in blood pressure, intravenous drip infusion of fluids (for example, isotonic sodium chloride solution) is possible, with persistent hypotension, it is possible to add vasopressors (for example, dopamine) to therapy.

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For citation:Leonova M.V. New and promising medicationsblocking the renin-angiotensin-aldosterone system // RMZh. Medical Review. 2013. No. 17. P. 886

The role of the renin-angiotensin-aldosterone system (RAAS) in the development of arterial hypertension (AH) and other cardiovascular diseases is currently considered dominant. In the cardiovascular continuum, hypertension is among the risk factors, and the main pathophysiological mechanism of damage to the cardiovascular system is angiotensin II (ATII). ATII is a key component of the RAAS - an effector that implements vasoconstriction, sodium retention, activation of the sympathetic nervous system, cell proliferation and hypertrophy, the development of oxidative stress and inflammation of the vascular wall.

At present, two classes of drugs that block the RAAS have already been developed and widely used in clinical practice - ACE inhibitors and ATII receptor blockers. The pharmacological and clinical effects of these classes are different. ACE is a peptidase from the group of zinc metalloproteinases that metabolizes ATI, AT1-7, bradykinin, substance P, and many other peptides. The mechanism of action of ACE inhibitors is mainly associated with the prevention of the formation of ATII, which promotes vasodilation, natriuresis and eliminates the pro-inflammatory, proliferative and other effects of ATII. In addition, ACE inhibitors prevent the degradation of bradykinin and increase its level. Bradykinin is a powerful vasodilator, it potentiates natriuresis, and most importantly, it has a cardioprotective effect (prevents hypertrophy, reduces ischemic myocardial damage, improves coronary blood supply) and has a vasoprotective effect, improving endothelial function. However, high level bradykinin is the cause of the development of angioedema, which is one of the serious disadvantages of ACE inhibitors, which significantly increase the level of kinins.
ACE inhibitors are not always able to completely block the formation of ATII in tissues. It has now been established that other enzymes not associated with ACE, primarily endopeptidases, to which the action of ACE inhibitors does not apply, can also participate in its transformation in tissues. As a result, ACE inhibitors cannot completely eliminate the effects of ATII, which may be the reason for their insufficient effectiveness.
The solution to this problem was facilitated by the discovery of ATII receptors and the first class of drugs that selectively block AT1 receptors. The adverse effects of ATII are realized through AT1 receptors: vasoconstriction, secretion of aldosterone, vasopressin, norepinephrine, fluid retention, proliferation of smooth muscle cells and cardiomyocytes, activation of SAS, as well as the mechanism of negative feedback - the formation of renin. AT2 receptors perform "useful" functions such as vasodilation, repair and regeneration processes, antiproliferative action, differentiation and development of embryonic tissues. The clinical effects of ATII receptor blockers are mediated through the elimination of the “harmful” effects of ATII at the level of AT1 receptors, which provides a more complete blocking of the adverse effects of ATII and an increase in the effect of ATII on AT2 receptors, which complements the vasodilating and antiproliferative effects. ATII receptor blockers have a specific effect on the RAAS without interfering with the kinin system. The lack of influence on the activity of the kinin system, on the one hand, reduces the severity unwanted effects (cough, angioedema), but, on the other hand, deprives ATII receptor blockers of an important anti-ischemic and vasoprotective effect, which distinguishes them from ACE inhibitors. For this reason, the indications for the use of ATII receptor blockers in the majority repeat the indications for the appointment of ACE inhibitors, making them alternative drugs.
Despite the introduction of RAAS blockers into the widespread practice of treating hypertension, the problems of improving outcomes and prognosis remain. These include: the possibility of improving blood pressure control in the population, the effectiveness of treatment of resistant hypertension, the possibility of further reducing the risk of cardiovascular diseases.
The search for new ways of influencing the RAAS is actively continuing; other closely interacting systems are being studied and drugs with multiple mechanisms of action are being developed, such as ACE and neutral endopeptidase (NEP) inhibitors, endothelin-converting enzyme (EPE) and NEP inhibitors, ACE / NEP / EPF inhibitors.
Vasopeptidase inhibitors
In addition to the known ACE, vasopeptidases also include 2 other zinc metalloproteinases - neprilysin (neutral endopeptidase, NEP) and endothelin-converting enzyme, which can also be targets for pharmacological effects.
Neprilisin is an enzyme produced by the vascular endothelium and is involved in the degradation of natriuretic peptide and bradykinin.
The natriuretic peptide system is represented by three different isoforms: atrial natriuretic peptide (A-type), brain natriuretic peptide (B-type), which are synthesized in the atrium and myocardium, and endothelial C-peptide, which by their biological functions are endogenous inhibitors of RAAS and endothelin-1 (Table 1). The cardiovascular and renal effects of natriuretic peptide consist in a decrease in blood pressure through the effect on vascular tone and water-electrolyte balance, as well as in antiproliferative and antifibrotic effects on target organs. According to the most recent data, the natriuretic peptide system is involved in metabolic regulation: lipid oxidation, adipocyte formation and differentiation, adiponectin activation, insulin secretion and carbohydrate tolerance, which may provide protection against the development of metabolic syndrome.
To date, it has become known that the development of cardiovascular diseases is associated with dysregulation of the natriuretic peptide system. So, in hypertension, there is a deficiency of natriuretic peptide, leading to salt sensitivity and impaired natriuresis; in chronic heart failure (CHF) against the background of deficiency, there is an abnormality in the functioning of the hormones of the natriuretic peptide system.
Therefore, to potentiate the natriuretic peptide system in order to achieve additional hypotensive and protective cardiorenal effects, it is possible to use NEP inhibitors. Inhibition of neprilysin leads to potentiation of the natriuretic, diuretic and vasodilating effects of the endogenous natriuretic peptide and, as a result, to a decrease in blood pressure. However, NEP is involved in the degradation of other vasoactive peptides, in particular ATI, ATII, and endothelin-1. Therefore, the balance of the effects of influence on vascular tone of NEP inhibitors is variable and depends on the prevalence of constrictor and dilating influences. With long-term use, the antihypertensive effect of neprilisin inhibitors is weakly expressed due to the compensatory activation of the formation of ATII and endothelin-1.
In this regard, the combination of the effects of ACE inhibitors and NEP inhibitors can significantly potentiate hemodynamic and antiproliferative effects as a result of the complementary mechanism of action, which has led to the creation of drugs with a dual mechanism of action, united by the name vasopeptidase inhibitors (Table 2, Fig. 1).
Known inhibitors of vasopeptidases are characterized by varying degrees of selectivity to NEP / ACE: omapatrilate - 8.9: 0.5; fazidoprilat - 5.1: 9.8; sampatrilate - 8.0: 1.2. As a result, vasopeptidase inhibitors received much greater opportunities to achieve a hypotensive effect, regardless of the RAAS activity and the level of sodium retention, and in organoprotection (regression of hypertrophy, albuminuria, vascular stiffness). The most studied in clinical trials was omapatrilate, which showed a higher hypotensive efficacy in comparison with ACE inhibitors, and in patients with CHF led to an increase in the ejection fraction and improved clinical outcomes (IMPRESS, OVERTURE studies), but without advantages over ACE inhibitors.
However, in large clinical trials using omapatrilate, a higher incidence of angioedema was found in comparison with ACE inhibitors. It is known that the incidence of angioedema when using ACE inhibitors is from 0.1 to 0.5% in the population, of which 20% of cases are life-threatening, which is associated with a multiple increase in the concentrations of bradykinin and its metabolites. The results of a large multicenter study OCTAVE (n \u003d 25 302), which was specially designed to study the incidence of angioedema, showed that the incidence of this side effect during treatment with omapatrilate exceeds that in the enalapril group - 2.17% versus 0.68% (relative risk 3.4). This was explained by an increase in the effect on kinin levels during synergistic inhibition of ACE and NEP associated with inhibition of aminopeptidase P, which is involved in the degradation of bradykinin.
A new dual vasopeptidase inhibitor that blocks ACE / NEP is ilepatril, which has a higher affinity for ACE compared to NEP. When studying the pharmacodynamic effects of ilepatril on the effect on the activity of RAAS and natriuretic peptide in healthy volunteers, it was found that the drug dose-dependently (in doses of 5 and 25 mg) and significantly (more than 88%) suppresses ACE in blood plasma for a duration of more than 48 hours, regardless of salt sensitivity ... At the same time, the drug significantly increased the plasma renin activity for 48 h and decreased the aldosterone level. These results showed a pronounced and more prolonged suppression of the RAAS, in contrast to the ACE inhibitor ramipril at a dose of 10 mg, which was explained by the more significant tissue effect of ilepatril on ACE and a higher affinity for ACE, and a comparable degree of RAAS blockade in comparison with the combination of 150 mg irbesartan + 10 mg ramipril. In contrast to the effect on RAAS, the effect of ilepatril on natriuretic peptide was manifested by a short-term increase in the level of its excretion in the period 4-8 hours after taking a dose of 25 mg, which indicates a smaller and weak affinity for NEP and distinguishes it from omapatrilat. Moreover, in terms of the level of excretion of electrolytes, there is no additional natriuretic action in comparison with ramipril or irbesartan, the drug does not, as well as other inhibitors of vasopeptidases. The maximum hypotensive effect develops 6-12 hours after taking the drug, and the decrease in mean blood pressure is 5 ± 5 and 10 ± 4 mm Hg. at low and high salt sensitivity, respectively. According to its pharmacokinetic characteristics, ilepatril is a prodrug with an active metabolite, which is rapidly formed with a maximum concentration reached after 1-1.5 hours and slowly eliminates. Phase III clinical trials are currently underway.
An alternative pathway to double suppression of RAAS and NEP is represented by a combination of blockade of ATII and NEP receptors (Fig. 2). In contrast to ACE inhibitors, ATII receptor blockers do not affect kinin metabolism, so they potentially have a lower risk of developing angioedema complications. The first drug, an ATII receptor blocker with an effect of inhibition of NEP in a 1: 1 ratio, is currently undergoing phase III clinical trials - LCZ696. The combined drug molecule contains valsartan and an NEP inhibitor (AHU377) in the form of a prodrug. In a large study in patients with hypertension (n \u003d 1328), LCZ696 at doses of 200-400 mg showed an advantage in the hypotensive effect over valsartan at doses of 160-320 mg in the form of an additional decrease in blood pressure by 5/3 and 6/3 mm Hg. ... ... The antihypertensive effect of LCZ696 was accompanied by a more pronounced decrease in pulse blood pressure: by 2.25 and 3.32 mm Hg. respectively, in doses of 200 and 400 mg, which is currently considered as a positive prognostic factor for the effect on the stiffness of the vascular wall and cardiovascular outcomes. At the same time, the study of neurohumoral biomarkers against the background of treatment with LCZ696 showed an increase in the level of natriuretic peptide with a comparable degree of increase in the level of renin and aldosterone in comparison with valsartan. Patients with hypertension were well tolerated and no cases of angioedema were observed. Currently, the PARAMOUMT study has been completed in 685 patients with CHF and intact ejection fraction. The results of the study showed that LCZ696 faster and more pronouncedly reduces the level of NT-proBNP (the primary endpoint is a marker of increased activity of sodium uretic peptide and a poor prognosis in CHF) in comparison with valsartan, and also reduces the size of the left atrium, which indicates regression of its remodeling ... The study in patients with CHF and reduced EF is ongoing (the PARADIGM-HF study).
Endothelin system inhibitors
The endothelin system plays an important role in the regulation of vascular tone and regional blood flow. Among the three known isoforms, endothelin-1 is the most active. In addition to the well-known vasoconstrictor effects, endothelin stimulates the proliferation and synthesis of the extracellular matrix, and also, due to a direct effect on the tone of the renal vessels, participates in the regulation of water-electrolyte homeostasis. The effects of endothelin are realized through interaction with specific A-type and B-type receptors, the functions of which are mutually opposite: vasoconstriction occurs through the A-type receptors, and vasodilation occurs through the B-type. In recent years, it has been established that B-type receptors play an important role in the clearance of endothelin-1, i.e. when these receptors are blocked, the receptor-dependent clearance of endothelin-1 is disrupted and its concentration increases. In addition, B-type receptors are involved in the regulation of the renal effects of endothelin-1 and the maintenance of water-electrolyte homeostasis, which is important.
Currently, the role of endothelin has been proven in the development of a number of diseases, incl. AH, CHF, pulmonary hypertension, chronic diseases kidney; shows a close relationship between endothelin levels and metabolic syndrome, endothelial dysfunction and atherogenesis. Since the 1990s. a search for endothelin receptor antagonists suitable for clinical use is in progress; already known 10 drugs ("centana") with varying degrees of selectivity to the A / B-type receptors. The first non-selective antagonist of endothelin receptors, bosentan, in a clinical study in patients with hypertension showed hypotensive efficacy comparable to that of the ACE inhibitor enalapril. Further studies of the efficacy of endothelin antagonists in hypertension have shown their clinical significance in the treatment of resistant hypertension and at high cardiovascular risk. These data were obtained in two large clinical trials, DORADO (n \u003d 379) and DORADO-AS (n \u003d 849), in which darusentan was added to triple combination therapy in patients with resistant hypertension. In the DORADO study, resistant hypertension was combined with chronic kidney disease and proteinuria in patients; as a result of the addition of darusentan, not only a significant decrease in blood pressure was observed, but also a decrease in protein excretion. The antiproteinuric effect of endothelin receptor antagonists was subsequently confirmed in a study in patients with diabetic nephropathy when using avosentan. However, in the DORADO-AS study, no advantages in additional blood pressure reduction over comparison drugs and placebo were found, which was the reason for the termination of further studies. In addition, in 4 large studies of endothelin antagonists (bosentan, darusentan, enrasentan) in patients with CHF, conflicting results were obtained, which was explained by an increase in the concentration of endothelin-1. Further research on endothelin receptor antagonists has been suspended due to adverse effects associated with fluid retention (peripheral edema, volume overload). The development of these effects is associated with the effect of endothelin antagonists on B-type receptors, which changed the search for drugs that affect the endothelin system through other pathways; and endothelin receptor antagonists currently have only one indication - the treatment of pulmonary hypertension.
Taking into account the high importance of the endothelin system in the regulation of vascular tone, a search is under way for another mechanism of action through vasopeptidase - the EE, which participates in the formation of active endothelin-1 (Fig. 3). The blocking of the EE and the combination with the inhibition of NEP can effectively suppress the formation of endothelin-1 and potentiate the effects of the sodium uretic peptide. The advantages of the dual mechanism of action are, on the one hand, in preventing the disadvantages of NEP inhibitors associated with possible vasoconstriction mediated by the activation of endothelin, on the other hand, the natriuretic activity of NEP inhibitors makes it possible to compensate for fluid retention associated with nonselective blockade of endothelin receptors. Daglutril is a dual inhibitor of NEP and EE, which is in phase II clinical trials. Studies have shown pronounced cardioprotective effects of the drug due to a decrease in remodeling of the heart and blood vessels, regression of hypertrophy and fibrosis.
Direct renin inhibitors
It is known that ACE inhibitors and ATII receptor blockers by a feedback mechanism increase the activity of renin, which is the reason for the escaping effectiveness of RAAS blockers. Renin is the very first stage of the RAAS cascade; it is produced by the juxtaglomerular cells of the kidneys. Renin, through angiotensinogen, promotes ATII formation, vasoconstriction and aldosterone secretion, and also regulates feedback mechanisms. Therefore, inhibition of renin makes it possible to achieve a more complete blockade of the RAAS system. The search for renin inhibitors has been going on since the 1970s; for a long time it was not possible to obtain an oral form of renin inhibitors due to their low bioavailability in the gastrointestinal tract (less than 2%). The first direct renin inhibitor suitable for oral administration, aliskiren, was registered in 2007. Aliskiren has a low bioavailability (2.6%), a long half-life (24-40 hours), and an extrarenal elimination pathway. Pharmacodynamics of aliskiren is associated with an 80% decrease in ATII levels. In clinical studies in patients with hypertension, aliskiren in doses of 150-300 mg / day led to a decrease in SBP by 8.7-13 and 14.1-15.8 mm Hg. respectively, and DBP - by 7.8-10.3 and 10.3-12.3 mm Hg. ... The hypotensive effect of aliskiren was observed in different subgroups of patients, including patients with metabolic syndrome, obesity; in severity, it was comparable to the effect of ACE inhibitors, ATII receptor blockers, and an additive effect was noted in combination with valsartan, hydrochlorothiazide and amlodipine. A number of clinical studies have shown the organoprotective effects of the drug: antiproteinuric effect in patients with diabetic nephropathy (AVOID study, n \u003d 599), regression of left ventricular hypertrophy in patients with hypertension (ALLAY study, n \u003d 465). So, in the AVOID study, after 3 months of treatment with losartan at a dose of 100 mg / day and reaching the target blood pressure level (<130/80 мм рт.ст.) при компенсированном уровне гликемии (гликированный гемоглобин 8%) больных рандомизировали к приему алискирена в дозах 150-300 мг/сут или плацебо. Отмечено достоверное снижение индекса альбумин/креатинин в моче (первичная конечная точка) на 11% через 3 мес. и на 20% - через 6 мес. в сравнении с группой плацебо. В ночное время экскреция альбумина на фоне приема алискирена снизилась на 18%, а доля пациентов со снижением экскреции альбумина на 50% и более была вдвое большей (24,7% пациентов в группе алискирена против 12,5% в группе плацебо) . Причем нефропротективный эффект алискирена не был связан со снижением АД. Одним из объяснений выявленного нефропротективного эффекта у алискирена авторы считают полученные ранее в экспериментальных исследованиях на моделях диабета данные о способности препарата снижать количество рениновых и прорениновых рецепторов в почках, а также уменьшать профибротические процессы и апоптоз подоцитов, что обеспечивает более выраженный эффект в сравнении с эффектом ингибиторов АПФ . В исследовании ALLAY у пациентов с АГ и увеличением толщины миокарда ЛЖ (более 1,3 см по данным ЭхоКГ) применение алискирена ассоциировалось с одинаковой степенью регресса ИММЛЖ в сравнении с лозартаном и комбинацией алискирена с лозартаном: −5,7±10,6 , −5,4±10,8, −7,9±9,6 г/м2 соответственно. У части пациентов (n=136) проводилось изучение динамики нейрогормонов РААС, и было выявлено достоверное и значительное снижение уровня альдостерона и активности ренина плазмы на фоне применения алискирена или комбинации алискирена с лозартаном, тогда как на фоне применения монотерапии лозартаном эффект влияния на альдостерон отсутствовал, а на активность ренина - был противоположным, что объясняет значимость подавления альдостерона в достижении регресса ГЛЖ.
In addition, a series of clinical studies of aliskiren are being conducted in the treatment of other cardiovascular diseases with an assessment of the effect on the prognosis of patients: studies ALOFT (n \u003d 320), ASTRONAUT (n \u003d 1639), ATMOSPHERE (n \u003d 7000) in patients with CHF, the ALTITUDE study in patients with diabetes mellitus and high cardiovascular risk, the ASPIRE study in patients with postinfarction remodeling.
Conclusion
To solve the problems of preventing cardiovascular diseases, the development of new drugs with a complex multiple mechanism of action continues, allowing for a more complete blockade of the RAAS through a cascade of mechanisms of hemodynamic and neurohumoral regulation. The potential effects of such drugs make it possible not only to provide an additional antihypertensive effect, but also to achieve blood pressure control in high-risk patients, including resistant hypertension. Medicines with multiple mechanisms of action show advantages in a more pronounced organoprotective effect, which will prevent further damage to the cardiovascular system. The study of the advantages of new drugs that block RAAS requires further research and assessment of their effect on the prognosis of patients with hypertension and other cardiovascular diseases.

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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. Later, in experimental and clinical studies, it was possible 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 undesirable phenomena.

Another circumstance that makes it possible to count on the additional capabilities of direct renin inhibitors in protecting the target organs of hypertension compared to other RAAS blockers is that when drugs blocking RAAS at other levels are used, according to the law of negative feedback, an increase in prorenin concentration occurs, 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 from the point of view of their capabilities in reducing elevated blood pressure. Back in the early 1990s, when many of the organoprotective effects of ACE inhibitors were not established as reliably as they are today, it was shown that as their dose increases, 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 effectiveness of which was confirmed in controlled clinical trials of phase III, with a sufficient duration of action and lowering elevated blood pressure even in a monotherapy regimen, and its appointment today can be considered as an innovative approach to the treatment of hypertension. Comparisons were made of its effect on plasma concentration and the 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 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 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)

Pharmacokinetics

When alisikren is taken orally, the bioavailability of the drug is 2.6%, the connection with proteins is 47-51%, and the unchanged half-life of the drug in the blood plasma is 40 hours, which makes it possible to calculate that the duration of its antihypertensive action may exceed 24 hours. At the same time, there is no accumulation of the drug in the body and the equilibrium concentration of aliskiren in the blood plasma is achieved between 5 and 7 days when taken 1 time per day. It is excreted by the intestines (91%) unchanged. It is used at a dose of 150 mg / day, if necessary, increase the dose after 2 weeks to 300 mg 1 time / day.

The indication for the appointment of aliskiren is AG.

Contraindications:

Hypersensitivity;

Severe chronic renal failure;

· Nephrotic syndrome;

· Renovascular hypertension;

· Programmed hemodialysis;

· Severe liver failure;

· Age up to 18 years;

· Pregnant women.

Side effects:

Diarrhea;

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