The mechanism of action of APF inhibitors. ACE inhibitors: new generation drugs

The most common among the world's population are cardiovascular diseases, so a fairly large percentage of people take "heart" drugs, and this, as a rule, is not one drug, but several. In this case, the question arises about their safe combination. In this article we will talk about dangerous combinations of "heart" drugs.

The term "heart drugs" is rather generalized and non-specific. Medicines for the treatment of arterial hypertension, angina pectoris, myocardial infarction, cardiomyopathies, cardiac arrhythmias and conduction disorders, and many others are suitable for this description. To make some clarity, it is necessary to make a reservation that in the article we will talk about the most widely used drugs that affect the work of the heart, and about their possible combinations with each other.

The following groups of drugs will be considered:

Note: all drugs are written in international non-proprietary name (INN).

I. Beta-blockers:

1.non-selective: propranolol, carvedilol, oxprenolol, pindolol, nadolol.
2. selective: atenolol, metoprolol, bisoprolol, nebivolol, talinolol.

II... Calcium channel blockers (calcium antagonists):

1. nondihydropyridine: verapamil, diltiazem;
2.dihydropyridine: nifedipine, amlodipine, S-amlodipine, lercanidipine.

III. ACE inhibitors:captopril, perindopril, enalapril, ramipril, zofenapril, fosinopril, lisinopril.

IV. Angiotensin II receptor blockers: losartan, valsartan, candesartan, ibresartan, telmisartan.

V. Diuretics:

1.thiazide: hydrochlorothiazide, chlorthalidone.
2.thiazide-like: indapamide.
3. loop diuretics: furosemide, torasemide.
4. potassium-sparing diuretics: spironolactone, eplerenone.

Note: the classification shows the most famous representatives drugs... If you have not found your drug here, then you can find out to which group it belongs by looking in the instructions for it (find the line "pharmacotherapeutic group"), or in the reference books on medicinal products (Vidal, RLS, reference book by M.D. Mashkovsky) ...

Recommendations for the treatment of arterial hypertension from 2013, developed by the European Society of Hypertension and the European Society of Cardiology, established the following irrational (i.e. dangerous) combinations "Heart" drugs:

1.beta-blockers + nondihydropyridine calcium channel blockers (verapamil, diltiazem).This combination is a GREAT ERROR on the part of the doctor, since drugs of both groups cause a decrease in heart rate. With a joint appointment, their total effect on the heart rate is so pronounced that life-threatening conditions can occur (up to heart rhythm disturbances). If, by coincidence, the patient can only be prescribed a combination of beta-blockers with calcium channel blockers, then from the latter group, dihydropyridine drugs (nifedipine, amlodipine, lercanidipine) are preferred.

Note: A combination of beta-blockers and nondihydropyridine calcium antagonists is sometimes used to control ventricular rhythm in persistent atrial fibrillation. BUT! Only in this case!

2. ACE inhibitor + potassium-sparing diuretic. Potassium-sparing diuretics include spironolactone and eplerenone. Like all diuretics, the group of potassium-sparing drugs removes excess fluid from the body while maintaining potassium in the blood. ACE inhibitors also contribute to the accumulation of potassium in the body. With a combination of drugs of both groups, a condition dangerous to the heart - hyperkalemia - can occur, which can cause cardiac arrest in diastole. If your doctor has prescribed you a drug of any of these groups, you need to periodically check your potassium level (during dose selection, once a week, when the optimal dose of the drug is selected - once a month). The norm of potassium in blood plasma for adults is 3.5-5.1 mmol / l.

3. Beta-blocker and centrally acting drugs.TO last group include methyldopa, clonidine, moxonidine, rilmenidine. These groups share similar mechanisms of action, clinical effects, and - most importantly - side effects... Due to the mutual amplification of undesirable effects, these two groups are not used together.

4. ACE inhibitor and angiotensin II receptor blocker.Previously, this combination of drugs was possible, but since 2013 it has been established that the combination of these two groups negatively affects the kidneys, causing renal failure in a relatively short time.

The same Recommendations say about possible, but less studied drug combinations ... It is possible that someday these combinations will pass into the group of rational or dangerous. These combinations include the following:

1. ACE inhibitor + beta-blocker;
2. Angiotensin II receptor blocker + beta-blocker;
3. Dihydropyridine calcium antagonists + beta-blockers.

Rational and as safe as possible are the following combinations of drugs:

1. Diuretic (thiazide) + angiotensin II receptor blocker;
2. Diuretic (thiazide) + calcium antagonist;
3. Diuretic (thiazide) + ACE inhibitor;
4. Angiotensin II receptor blocker + calcium antagonist;
5. ACE inhibitor + calcium antagonist.

These are, perhaps, all the features of the most frequent combinations of "heart" drugs. Of course, in each individual case, in relation to a particular drug, there are characteristics characteristic only of it. But the basic rules for prescribing several "heart" drugs are the above.

• The mechanism of action of drugs
• Types of drugs
• Indications for appointment
• Side effects

ACE inhibitors (angiotensin-converting enzyme inhibitors) are a group of drugs that are actively used to combat hypertension of various origins.

But the peculiarities of the mechanism of action of these funds allow them to be used not only if necessary arterial pressure, but also with functional insufficiency of the heart and kidneys.

The mechanism of action of drugs

As the name of the drugs in this group suggests, they have a direct effect on the chemical conversion of angiotensin. It is a hormone that has the ability to constrict the lumen of blood vessels, thereby increasing blood pressure, and to release another hormone, aldosterone, from the adrenal cortex.

The cycle of formation of angiotensin begins in the human kidney. Under the influence of adrenaline, they synthesize a specific enzyme renin, which, after entering the bloodstream, turns into angiotensinogen, or angiotensin 1. Subsequently, as a result of a series of chemical transformations, angiotensin, or angiotensin 2, is formed from this substance.

ACE inhibitors prevent the conversion of angiotensin 1 into angiotensin 2, blocking the action of the enzyme necessary for this reaction, thereby preventing an increase in blood pressure. The decrease in blood pressure when using these drugs is smooth, not accompanied by an increase in heart rate, which occurs when using drugs that have a direct effect on the blood vessels and expand them.

With prolonged use of ACE inhibitors, the severity of compensatory (working) hypertrophy of the left ventricle and the walls of arterial vessels decreases. The progression of renal failure is slowed down. The blood supply to the heart muscle is improved with concomitant coronary heart disease.

By preventing blood vessels from narrowing, these drugs stop a complex chain reaction in which bradykinin, a substance that breaks down when necessary to expand the lumen of arteries and veins, plays a key role. By preventing the creation of the conditions necessary for the destruction of this chemical compound, angiotensin inhibitors thereby increase its concentration in blood plasma. At the same time, many pathological processes in the kidneys, heart muscle and walls of blood vessels are stopped, since bradykinin is a kind of blocker of pathological reactions that develop in chronic heart failure.

In 1/5 of all cases, the formation of angiotensin occurs outside the specified cycle (in the process of integration by tissue chemases). Then treatment with angiotensin inhibitors is ineffective.

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Types of drugs

The modern pharmaceutical industry offers a rich assortment of ACE inhibitors, which for convenience are classified into several groups. So, there are:

1. Preparations of natural origin. They are found in small amounts in hibiscus, garlic, and whey.
2. Phosphonate based preparations. They have a high ability to penetrate into tissues with a high concentration of angiotensin-converting enzyme, therefore they stabilize pressure for a long period and protect the organs of the circulatory system.
3. Dicarboxylate-based preparations. Effective in the fight against arterial hypertension, accompanied by renal pathologies, including impaired renal function due to diabetes mellitus. Help with treatment hypertensive crises, since they relatively quickly reduce the level of blood pressure. Some drugs from this group are included in the list of vital pharmacological drugs.
4. Preparations based on sulfhydryl groups. They also have the ability to affect tissue chemases, due to which their effectiveness does not depend on the level of renin in the blood plasma.

In clinical pharmacology, this classification is often simplified: all types of ACE inhibitors are divided into two main groups, that is, into a group where the main active ingredient is perindopril, and a group of drugs, the main active ingredient of which is enalapril maleate. Preparations based on enalapril represent the first generation of angiotensin inhibitors, since it was this active substance that was discovered by pharmacologists in the first place.

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Indications for appointment

Angiotensin inhibitors are actively used in the treatment of patients with problems such as:

1. Arterial hypertension (including symptomatic).
2. Chronic heart failure.
3. Prevention of recurrent stroke after hemorrhagic stroke or transient ischemic attack.
4. Ischemic heart disease, prevention of coronary ischemia.

The use of drugs from this group is especially useful in the presence of concomitant chronic kidney pathologies.

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Additional effects on the body

Like many other drugs, with prolonged systematic use, angiotensin inhibitors have a general healing effect on the patient's body.

Inhibitor action:

1. Protect blood vessels in the heart, brain, kidneys and retina from dystrophic changes... An important role in this is played by a sufficient amount of bradykinin in the blood. Reduces the risk of developing chronic renal failure.
2. Promote increased coronary and renal blood flow, improving myocardial blood supply.
3. Slow down the development of compensatory expansion of the left ventricular cavity and hypertrophy of its muscles.
4. Normalizes heart function by increasing serum potassium levels and helping to maintain a regular heart rate.
5. Reduces the severity of proteinuria (excretion of protein in the urine).
6. They increase the physical endurance of the patient by increasing the blood supply to the muscles.

Practice shows that the regular use of angiotensin inhibitors (especially the latest generation) significantly improves the patient's quality of life.

ACE inhibitors or angiotensin-converting enzyme inhibitors are a group medicinesthat help with hypertension. ACE is a substance that transforms angiotensin of the first group into the second group. In turn, angiotensin II is able to increase the patient's blood pressure. The mechanism of action is carried out in two ways, namely through the narrowing of the blood vessels or with the production of aldosterones by the adrenal glands. This substance is capable of retaining salt and water in the human body, which worsens health and leads to an increase in blood pressure.

Thanks to ACE inhibitors, it is possible to block the production and further negative effects of the enzyme. The drug manages to avoid the production of group II angiotensin. They are often used not only to solve the problem of hypertension, but also to increase the effectiveness of diuretics. Together with diuretics, ACE inhibitors can significantly reduce the amount of harmful salts and fluids in the human body.

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Medicines of this group for hypertension

Preparations of this type have been successfully used for more than a dozen years. In our time, the list of drugs has expanded significantly, and doctors increasingly began to prescribe new generation drugs, which are even more effective and have a minimum set of side effects.

Angiotensin-converting enzyme inhibitors began to be used 30 years ago. At one time, experts conducted a study in which the drug Captopril participated. Its effects have been compared to some diuretics and beta-blockers. All drugs showed nice results when getting rid of the symptoms of hypertension. Moreover, in patients who suffered in addition to diabetes mellitus, there was a significant improvement and no complications when using ACE inhibitors. Later, many more different tests and studies were carried out, which showed the effectiveness of these drugs in the fight against hypertension.

The mechanism of action of the inhibitors is such that these drugs can significantly reduce the risks of mortality in patients with high blood pressure. In addition, they prevent the development of strokes and heart attacks, as well as absolutely all complications that may be caused by malfunctions. of cardio-vascular system... All this is confirmed by numerous studies of scientists. At first, doctors did not pin great hopes on such drugs. However, their effectiveness exceeded all the expectations of specialists. In our time, ACE inhibitors are being improved, and a significant number of new generation drugs are being produced. Most of them are free from many side effects and are becoming more and more safe. ACE inhibitors are now the most effective means of combating hypertension in patients with diabetes mellitus.

Inhibitors differ in their chemical composition. Some of them work in a complex manner and are able to solve problems with both long-term hypertension and short-term manifestations of it, which can be caused by stress or strong emotional stress.

In hypertension, which is associated with increased activity of renin in the blood, ACE inhibitors can cause sudden pressure surges. But this is not considered critical, therefore, doctors often prescribe the use of such drugs without a preliminary analysis of the activity of renin.

ACE inhibitors can be useful for problems such as heart failure, asymptomatic left ventricular dysfunction, diabetes mellitus, left ventricular hypertrophy, myocardial infarction, nondiabetic nephropathy, atrial fibrillation, and metabolic syndrome.



Experts speak very well about drugs of this type. A big plus of ACE inhibitors is not only their effectiveness in lowering blood pressure, but also the protection of the patient's internal organs. These remedies can be beneficial for the heart, kidneys, and brain.



Heart protection products

With constantly elevated pressure, hypertrophy of the myocardium and arterial walls occurs. It is this consequence that is the most dangerous of all that hypertension can lead to. In turn, hypertrophy results in left ventricular dysfunction of both diastolic and systolic types. In addition, this pathology causes dangerous arrhythmias, progression of coronary atherosclerosis and heart failure.



All of this can be avoided by taking drugs from the ACE inhibitor series. They are able to contract the muscle of the left ventricle twice as better than other drugs for hypertension. All this improves the functioning of the heart and protects it.

Cell growth is enhanced under the influence of the second type of angiotensin hormone. ACE inhibitors suppress this process, thereby preventing myocardial and vascular hypertrophy.



Tablets to improve kidney function

Many patients, after being prescribed these types of drugs, are concerned about how much ACE inhibitors affect kidney function. Doctors say that among all the currently existing drugs for the treatment of hypertension, ACE inhibitors are best able to protect this organ.

Statistics show that nearly 20% of all people with hypertension die due to kidney problems. Insufficiency of this organ develops against the background of constantly high blood pressure... If you look at the problem from the other side, it turns out that many patients with chronic pathological ailments of the kidneys subsequently show signs of hypertension.



It is believed that ACE inhibitors are able to maximally protect the kidneys of patients who have increased content protein in the urine. Moreover, in patients who have been treated with such drugs for a long time, there are signs of improvement in chronic renal failure. As a rule, this is observed in cases where a person does not have a sharp decrease in blood pressure.

ACE inhibitors are very effective for such a problem as renovascular hypertension.

With such a disease, damage to the renal vessels occurs. In combination with diuretics, inhibitors can effectively control blood pressure levels in most patients. Nevertheless, in medicine, there have already been cases when such a combination of drugs also gave the opposite effect. This happened only in those situations when the patient has only one kidney.





The drug Cavinton - instructions for use

Combination therapy

Drugs of this type can, if necessary, be combined with some other drugs. This will be relevant for those cases when the doctor deems it appropriate to enhance the effectiveness of one medication at the expense of another. For example, ACE inhibitors, together with diuretics, often show excellent results and quickly reduce high blood pressure. But here you need to be very careful, since the mechanism of action of diuretics is designed in such a way that the described drugs can reduce systemic blood pressure and renal blood supply too much. If a similar effect has already been noted once, then they try not to prescribe this combination to the patient, so as not to aggravate the situation.



If a person has contraindications to the use of diuretics, calcium antagonists may be prescribed. The latter are capable of stretching large arteries. This is very important for patients with hypertension. This is especially true for elderly patients.

Angiotensin converting enzyme inhibitors are often used in complex therapy... However, it should be noted that this drug also has a lot of positive reviews in the treatment of high blood pressure only with it. About 50% of patients report significant improvement from ACE inhibitors alone. The rest have to combine these drugs with diuretics and calcium antagonists. It should be noted that the least sensitivity to inhibitors is observed in the elderly and patients with the hyporenin form of the disease. They must be prescribed ACE inhibitors in conjunction with diuretics, calcium antagonists or beta-blockers.

For example, if you combine the previously mentioned Captopril with a diuretic, you can quickly lower blood pressure and achieve its normalization for a fairly long period. Doctors note that such a combination of drugs makes it possible to effectively control pressure even in seriously ill patients. Approximately 80% of patients with hypertension in severe stages have a complete normalization of blood pressure when using Captopril with a diuretic or calcium antagonist.



Classification of medicines

First of all, the classification of drugs of this type is carried out according to the duration of their effect on the patient's body. TO short ACE inhibitors include Captopril. It is he who is considered the brightest representative of his type. To treat hypertension and maintain blood pressure in a normal state for a long time, it is necessary to take such a drug often enough, which can be problematic. Conversely, when a patient needs to drastically reduce high blood pressure to normal levels, Captopril with a diuretic will be the best option.

As a rule, the effect of short-term drugs is limited to a time frame of 5-6 hours. That is, blood pressure can fluctuate significantly throughout the day. If a patient has been diagnosed with hypertension, short-acting inhibitors can be very uncomfortable.

Among the drugs of the average type of duration, it is worth noting, first of all, Enalapril. It is able to reduce blood pressure for 12 hours. For this reason, hypertensive patients are prescribed drugs of this type twice a day.



List of popular medicines long acting much wider. This is due to the fact that they are more effective and convenient, therefore they are more appreciated by both doctors and patients. These include Ramipril, Lisinopril, Perindopril, Fosinopril and Moexipril. Taking medicines from this list allows you to qualitatively control the level of blood pressure.

ACE inhibitors also differ in such a feature as the need for transformation in the liver. Some drugs do not need their active substance to be converted in this organ. However, drugs such as Enalapril and Lisinopril are not active in their original form. They are activated only after they enter the liver.

The classification of ACE inhibitors is carried out according to the routes of elimination. Here the kidneys can be involved, which happens in 80% of cases, or bile. Some drugs are removed from the patient's body in two ways at the same time. The latter include Trandolapril and Moeskipril.



Classification plays a huge role in the doctor's choice of the most appropriate drug for a particular case. For example, if a person has liver problems, it is better for him to use drugs for hypertension, which will not affect this organ. These can be those drugs that are excreted without the participation of bile.

List of effective drugs

Nowadays, doctors most often prescribe new generation drugs. If the patient needs to quickly lower blood pressure, he can use Enalapril, which is the leader in its category. It is excreted by the kidneys and lasts up to 6 hours.



Captopril is another popular short-acting ACE inhibitor. It is able to stabilize pressure well, but it has to be taken 3-4 times a day in the dosage set by the doctor.

Unlike the two previous drugs, Lisinopril has a longer duration of action. This medication works on its own and does not need to be metabolized by the liver. Lisinopril is excreted through the kidneys. This drug is suitable for almost all patients, including those who are obese and those with kidney failure.

Moeskipril and Trandolapril are popular treatments for hypertension. They are contraindicated for liver failure, since they are excreted from the body with bile.



Possible side effects

Drugs in this category are very effective and almost impossible to replace. However, some of them not only normalize blood pressure, but also give unwanted effects... These include cough, hyperkalemia, and hypotension.

As with many other medicines, using inhibitors can cause allergic reactions. If the patient has already experienced such a side effect, further administration of the inhibitor will not be possible.

Published in: Rational Pharmacotherapy in Cardiology 2005; # 1; P.49-68 Working Group on ACE Inhibitors of the European Society of Cardiology

Working group members: Jose Lopez-Sendon, Chair * (Spain), Karl Swedberg (Sweden), John McMurray (UK), Juan Tamargo (Spain), Aldo P. Maggioni (Italy), Henry Dargie (UK), Michal Tendera ( Poland), Finn Waagstein (Sweden), Jan Kjekshus (Norway), Philippe Lechat (France), Christian Torp-Pedersen (Denmark)

European Society of Cardiology Practice Guidelines Committee: Silvia G. Priori (Chair) (Italy), Maria Angeles Alonso Garcia (Spain), Jean-Jacques Blanc (France), Andrzej Budaj (Poland), Martin Cowie (UK), Veronica Dean ( France), Jaap Deckers (Netherlands), Enrique Fernandez Burgos (Spain), John Lekakis (Greece), Bertil Lindahl (Sweden), Gianfranco Mazzotta (Italy), Keith McGregor (France), Joao Morais (Portugal), Ali Oto (Turkey ), Otto A. Smiseth (Norway)

Reviewers: Maria Angeles Alonso Garcia (coordinator) (Spain), Diego Ardissino (Italy), Cristina Aven-dano (Spain), Carina Blomstrem-Lundqvist (Sweden), Denis Clement (Belgium), Helmut Drexler (Germany), Roberto Ferrari ( Italy), Keith A. Fox (UK), Desmond Julian (UK), Peter Kearney (Ireland), Werner Klein (Austria), Lars Kober (Denmark), Giuseppe Mancia (Italy), Markku Nieminen (Finland), Witold Ruzyllo ( Poland), Maarten Simoons (Netherlands), Kristian Thygesen (Denmark), Gianni Tognoni (Italy), Isabella Tritto (Italy), Lars Wallentin (Sweden)

* Contact person: Jose Lopez-Sendon, Cardiology, Area 1 200, Hospital Universitario Gregorio Maranon, Doctor Esquerdo 46, 28007 Madrid, Spain. Tel .: + 34-91-586-8295; Fax: + 34-91-586-6672. E-mail address: [email protected] (J. Lopez-Sendon).

The original text of the Opinion, prepared by the experts of the European Society of Cardiology on the use of ACE inhibitors in cardiovascular diseases, was published in the European Heart Jornal,

2004;25:1454-1470.

© 2004 European Society of Cardiology. Adapted translation from of English language and replication made with the consent of the European Society of Cardiology.

Preamble

The recommendations and opinions of experts consider all the available data on a specific issue, which helps the doctor to weigh the benefits and risks of a particular diagnostic or therapeutic intervention. Accordingly, such documents can be useful for a doctor in his daily practice.

In recent years, a large number of recommendations and expert opinions have been issued by the European Society of Cardiology and other organizations. This could affect the quality of the published documents, which can only be guaranteed if the process of their development cannot be questioned. For this reason, these organizations have created guidelines for the preparation of recommendations and expert opinions. Although there are clear standards for the preparation of high-quality recommendation documents, nevertheless, the results of the analysis of recommendations published in peer-reviewed journals from 1985 to 1988 showed that methodological standards in the vast majority of cases were not met. It is very important that the format of the recommendations ensures that they are easy to interpret. After the release of the recommendations, it is necessary to monitor their implementation. The Committee for Practice Guidelines of the European Society of Cardiology oversees and coordinates the preparation of new recommendations and expert opinions by working and expert groups and advisory boards. Experts involved in this process are encouraged to provide information on possible conflicts of interest. Special forms are kept at the headquarters of the European Society of Cardiology. The committee is also responsible for approving recommendations and expert opinions. The working group proposed a classification of the recommendations and highlighted the levels of evidence.

Evidence levels

Introduction

The reninangiotensin system plays an important role in the development of cardiovascular diseases. Over the past decade, numerous studies have been carried out in which the clinical efficacy of angiotensin-converting enzyme (ACE) inhibitors has been studied in various clinical conditions... Based on the data obtained, it was recommended to use the drugs of this group in patients with heart failure, arterial hypertension, acute and postponed myocardial infarction. This document discusses the feasibility of prescribing ACE inhibitors in patients with cardiovascular disease and provides clinical data supporting their benefits.

Members of the Working Group on ACE Inhibitors for Cardiovascular Diseases were appointed by the European Society of Cardiology's Practice Guidelines Committee. Original articles were searched for peer-reviewed journals included in the Medline database. In addition, recommendations from the European Society of Cardiology and the American Heart Association / American College of Cardiology were reviewed.

Highlighting the gradation of recommendations simplifies their perception. The class of recommendation is determined based on the results of clinical trials. They are performed in matched patients who may not be representative of the general sample. For example, patients who have contraindications to treatment are excluded from studies. However, the “strength” of evidence may reflect a different clinical effect (reduced morbidity and mortality, reduced symptoms and frequency of combined endpoints, small but statistically significant effect, rapidly achieved effect, or effect manifested only several years after the start of treatment). Finally, in specific cases, the recommended drug may be just one of the treatment options, while others may be the same or even more acceptable.

The document prepared by the working group was distributed to the members of the editorial board appointed by the European Society of Cardiology and approved by the Society's Practice Guidelines Committee. The final document was sent to the European Heart Journal for peer review.

This opinion reflects the opinion of the European Society of Cardiology and has been prepared on the basis of a thorough analysis of the available data. Physicians should consider this data when making decisions. However, this document does not replace the responsibility of the doctor, who must make a decision in a specific situation after discussing all issues with the patient, and, if necessary, with his relatives or guardians.

Pharmacology

Definition

ACE inhibitors competitively inhibit angiotensin-converting enzyme. ACE is a nonspecific enzyme that is involved in the metabolism of many small peptides, in particular, it converts the inactive octapeptide angiotensin I to angiotensin II. In addition, ACE inhibitors competitively inhibit kininase, an enzyme that catalyzes the degradation of bradykinin and other peptides with potent vasodilating properties. The main effects of angiotensin II are shown in table. one.

Classification of ACE inhibitors

ACE inhibitors are divided into three categories depending on the nature of the group that binds to the zinc atom in the ACE molecule - sulfhydryl, carboxyl or phosphonyl (Table 2).

Pharmacokinetics

The absorption of various ACE inhibitors is variable (25-75%). Food intake does not affect or reduce the rate of absorption, but does not change the rate of absorption. Some ACE inhibitors are prodrugs and are converted to active metabolites by hydrolysis in the liver or gastrointestinal tract. Plasma drug concentrations peak 1-4 hours after administration. Prodrugs are more lipophilic and better penetrate target tissues after conversion to active metabolites.

Most ACE inhibitors and their metabolites are excreted mainly by the kidneys, while fosinopril, zofenopril, trandolapril and spirapril have two routes of excretion (liver and kidney). Captopril is rapidly excreted from the body, which determines the short duration of its action (less than 6 hours). At the same time, ramiprilat (the active metabolite of ramipril) and especially trandolaprilat are excreted more slowly than other ACE inhibitors (Table 2).

In patients with congestive heart failure, decreased absorption and biotransformation may delay the onset of action of ACE inhibitors. Due to impaired renal perfusion, renal clearance may decrease, which leads to an increase in maximum concentrations medicinal substances in plasma and the duration of their action. In this regard, in case of impaired renal function (creatinine clearance less than ≤30 ml / min), a dose reduction is indicated. Fosinopril, spirapril, trandolapril and zofenopril are excreted in both urine and bile, so their clearance does not change significantly with deteriorating renal function (Table 2).

Mechanism of action

ACE inhibitors competitively block the conversion of angiotensin I to angiotensin II and reduce its levels in blood and tissues. In addition, they reduce the secretion of aldosterone and vasopressin and the activity of sympathetic nervous systemand also suppress the trophic effects of angiotensin II. However, drugs in this group do not inhibit the action of angiotensin II, which is mediated by AT1 and AT2 receptors, and do not directly interact with other components of the reninangiotensin system. ACE inhibitors also inhibit kininase II and increase levels of bradykinin, which stimulates B2 receptors and induces the release of nitric oxide (NO) and vasoactive prostaglandins (prostacyclin and prostaglandin E2).

With long-term treatment, the decrease in plasma ACE levels appears to be of lesser importance. In this situation, the pharmacological effects of ACE inhibitors are more associated with the suppression of ACE in various tissues (vessels, kidneys, heart).

Table 1. Effects of angiotensin II

Vessels	Vasoconstriction Stimulates the release of norepinephrine, aldosterone, vasopressin and endothelin-1
Heart	Inotropic and chronotropic action Narrowing of the coronary arteries
Adrenal glands	Secretion of aldosterone and adrenaline
Brain	Secretion of vasopressin Secretion of substance P, LHRH and ACTH Stimulation of the thirst center Activation of the sympathetic nervous system
Kidney	Vasoconstriction (predominantly of the efferent arteriole) Contraction of mesangial cells Increased renal tubular sodium reabsorption Increased excretion of calcium in the distal nephrons Decreased secretion of renin
Platelets	Stimulation of platelet adhesion and aggregation
Endothelial cells	NO inactivation (suppression of endothelial NO synthase) Expression of oxidized LDL endothelial receptors (LOX-1)
Sympathetic activity	Enhancement of impulse transmission in peripheral noradrenergic endings Release of catecholamines by the adrenal medulla
Fibrinolysis	Increased expression of PAI-1 and 2
Inflammation	Activation and migration of macrophages Increased expression of adhesion molecules (VCAM-1, ICAM-1, P-selectin), chemotactic proteins (MCP-1) and cytokines (IL-6)
Trophic effects	Hypertrophy of cardiac myocytes Stimulation of migration, proliferation and hypertrophy of vascular smooth muscle cells Stimulation of protooncogenes (fos, myc, jun) and MAPKs (ERKs, JNK) Increased production of growth factors (PDGF, bFGF, IGF-1, TGFb1) Increased synthesis of extracellular matrix proteins (fibronectin, collagen types I and III, laminin-b1 and b2) and metalloproteinases
Atherosclerosis	Stimulation of NAD / NADP oxidase activity and production of superoxide anions, lipid peroxidation

ACTH: adrenocorticotropic hormone; bFGF: major fibroblast growth factor; ERKs: protein kinases regulated by extracellular signals; JNK: Jun N-terminal kinases, LHRH: luteinizing hormone releasing hormone, ICAM: intracellular adhesion molecule; IGF-1: insulin-like growth factor, IL-6: interleukin 6, LOX-1: lipoxygenase-1; MCP-1: monocytic chemoattractant protein -1; MAPKs: mitogen-activated protein kinases; PDGF: platelet growth factor, NAD / NADP - nicotinamide adenine dinucleotide / nicotinamide adenine dinucleotide phosphate; NO: nitric oxide, PAI: plasminogen activator inhibitor; TGF: transforming growth factor; VCAM: vascular cell adhesion molecule.

ACE inhibitors have the same mechanism of action, so their effects are common to the entire class of these drugs. Nevertheless, ACE inhibitors differ significantly in their affinity for tissue ACE and pharmacokinetic properties, which can determine significant differences in their tissue concentrations and clinical effects. However, the clinical significance of these differences has not been established. In fact, we can assume that all modern ACE inhibitors have the same antihypertensive effect. Therefore, the choice of drug and dose should be based on the results of clinical trials that have demonstrated the benefits of a particular ACE inhibitor.

Table 2. Pharmacological properties of various ACE inhibitors

A drug	Period half-life (h)	Excretion by the kidneys (%)	Standard daily dose (mg)	Dose (mg) at renal failure (creatinine clearance 10-30 ml / min)
Containing a sulfhydryl group
Benazepril *	11	85	2.5-10 two times	2.5-10 two times
Captopril	2	95	25-100 three times	6.25-1 2.5 three times
Zofenopril *	4,5	60**	7.5-30 twice	7.5-30 twice
Containing a carboxyl group
Cilazapril	10	80	1.5-2.5 once	0.5-2.5 once
Enalapril *	11	88	2.5-20 two times	2.5-20 two times
Lisinopril *	12	70	2.5-10 once	2.5-5 once
Perindopril *	>24	75	4-8 once	2 one time
Quinapril *	2-4	75	10-40 once	2.5-5 once
Ramipril * Spirapril	8-14 1,6	85 50**	2.5-10 once 3-6 once	1.25-5 once 3-6 once
Trandolapril	16-24	15**	1 -1 once	0.5-1 once
Containing a phosphinyl group
Fozinopril *	12	50**	10-40 once	10-40 once

* Prodrug
** Largely excreted by the liver

Effects of ACE Inhibitors

Hemodynamic effects / p\u003e

ACE inhibitors reduce total peripheral vascular resistance, increase natriuresis, but cause small changes in heart rate. These effects are partially associated with inhibition of tissue ACE and blockade of angiotensin II production in certain target tissues.

In patients with normal and high blood pressure who do not suffer from congestive heart failure, ACE inhibitors have little effect on cardiac output or wedge pressure in the pulmonary capillaries. When using them, unlike other vasodilators, reflex tachycardia does not develop, which may be a consequence of a change in the sensitivity of baroreceptors, stimulation vagus nerve and / or decreased activity of the sympathetic nervous system. After physical exertion or changes in body position, the heart rate is not disturbed. ACE inhibitors cause regression of cardiac hypertrophy in patients with arterial hypertension and reduce endothelial dysfunction in patients with coronary heart disease and normal blood pressure, arterial hypertension, type 2 diabetes mellitus and heart failure. Improvement in endothelial function is associated with a weakening of vasoconstriction and an increase in NO production with an increase in bradykinin levels.

In patients with congestive heart failure, ACE inhibitors dilate the veins and arteries. With venodilation, the capacity of the peripheral vascular bed increases, the pressure in the right atrium and pulmonary artery decreases, the wedging pressure in the pulmonary capillaries, the volume and pressure of filling the left ventricle, which leads to a rapid decrease in blood congestion in the lungs. As a result of the expansion of the arteries, peripheral vascular resistance decreases and cardiac output increases. ACE inhibitors improve relaxation and distensibility of the heart, and their long-term use leads to a decrease in left ventricular hypertrophy and blood pressure in patients with arterial hypertension.

Neurohumoral effects

Short-term therapy with an ACE inhibitor is accompanied by a decrease in angiotensin II and aldosterone levels and an increase in renin production and angiotensin I concentration. Angiotensin II increases sympathetic tone in the central nervous system and in the periphery and stimulates the secretion of catecholamines in the adrenal medulla, therefore ACE inhibitors reduce the levels of adrenaline, norepinephrine and vasopressin in plasma.

In addition, an increase in the level of angiotensin I can lead to an increase in the production of bradykinin, which has vasodilating properties, and to an increase in the synthesis of angiotensin II under the action of alternative enzymes, for example, chymase. With long-term treatment, levels of angiotensin II and aldosterone may return to baseline values \u200b\u200bdue to the activation of alternative pathways (aldosterone escape phenomenon). Aldosterone secretion is maintained by steroidogenic factors such as hyperkalemia, hypermagnesemia, and adrenocorticotropic hormone. On the other hand, ACE inhibitors increase the levels of kinins, prostacyclin and NO, which may partly explain their vasodilating, antithrombotic, and antiproliferative effects.

Antiproliferative Effects

ACE inhibitors also have an antiproliferative effect (reduce hypertrophy of the vascular and myocardial walls and proliferation of the extracellular matrix) and suppress left ventricular remodeling after myocardial infarction. The latter effect is associated with a decrease in preload / postload of the ventricle, blockade of the proliferative effects of angiotensin II, a decrease in the activity of the sympathetic nervous system, and inhibition of the action of aldosterone, which causes cardiac hypertrophy and interstitial and perivascular fibrosis. With myocardial hypertrophy, ACE inhibitors cause a decrease in heart mass and improve its diastolic function. The drugs of this group prevent the apoptosis of cardiac myocytes when the heart is overloaded with pressure.

Effects on the kidneys

ACE inhibitors reduce renal vascular resistance, increase renal blood flow, and increase the excretion of sodium and water ions. In this case, the glomerular filtration rate (GFR) does not change or decreases slightly, so the filtration fraction decreases. This effect is associated with the predominant expansion of postglomerular efferent arterioles, which leads to a decrease in hydrostatic pressure in the capillaries of the glomeruli and GFR. The increase in natriuresis is due to improved renal hemodynamics, decreased secretion of aldosterone and bradykinin, which have a direct effect on the tubules, and suppression of the direct renal effects of angiotensin II. ACE inhibitors prevent the growth of microalbuminuria and the appearance of overt proteinuria, slow down the progression of renal failure in patients with various nondiabetic nephropathies and prevent or slow down the progression of nephropathy in patients with type 1 diabetes mellitus.

Other effects

The reninangiotensin system plays an important role in the development and progression of atherosclerosis. In animal experiments, ACE inhibitors slowed down atherogenesis. The antiatherogenic properties of drugs in this group may be associated with blockade of angiotensin II formation, increased levels of bradykinin and NO, which lead to suppression of migration and proliferation of vascular smooth muscle cells, taxis and activation of inflammatory cells, reduction of oxidative stress and improvement of endothelial function. In studies SAVE (The Survival And Ventricular Enlargement) and SOLVD (Studies Of Left Ventricular Dysfunction), as well as in a meta-analysis of clinical trials, ACE inhibitors have been shown to reduce the risk of developing unstable angina and repeated myocardial infarction in patients with left ventricular dysfunction and congestive heart failure. In the Heart Outcomes Prevention Evaluation (HOPE) study, ramipril therapy led to a decrease in morbidity and mortality in patients at risk of atherothrombotic cardiovascular complications. The HOPE SECURE study examined the effects of ramipril and vitamin Ε on the condition of the carotid arteries using ultrasound. It has been shown that long-term therapy with an ACE inhibitor delays the progression of carotid atherosclerosis in patients with vascular diseases or diabetes mellitus who do not suffer from heart failure or left ventricular dysfunction.

Effect on the fibrinolytic system

ACE inhibitors have a modulating effect on the balance of the fibrinolytic system by reducing the formation of angiotensin II, which stimulates the synthesis of a type 1 plasminogen activator (PAM) inhibitor, and increasing bradykinin levels, which stimulates tissue plasminogen activator. Thus, ACE inhibitors reduce the concentration of PAI-1 and the molar ratio of its level to the content of tissue plasminogen activator.

In addition, ACE inhibitors block platelet aggregation induced by angiotensin II, as they increase the production of NO and prostacyclin.

Side effects

AcE inhibitors are well tolerated in most patients, although they can cause various adverse reactions.

Arterial hypotension. Clinically obvious arterial hypotension may develop, associated with the elimination of the vasoconstrictor effect of angiotensin II, especially after taking the first dose of an ACE inhibitor, in particular in patients with high plasma renin activity (for example, against the background of high-dose diuretic therapy or congestive heart failure).

Dry cough develops in 5-10% of patients. It is not always easy to differentiate it from a cough associated with blood congestion in the lungs or concomitant diseases such as the respiratory system. The cause of cough during treatment with ACE inhibitors has not been established, but it may be due to increased levels of bradykinin and / or substance Ρ in lung tissue... The cough does not depend on the dose, is more common in women and representatives of the Mongoloid race, develops within 1 week to several months after the start of treatment and sometimes forces therapy to be stopped. Some patients tolerate treatment with ACE inhibitors, resumed after a certain break. After stopping therapy, the cough usually goes away within 3-5 days. ACE inhibitors do not differ in their ability to induce cough.

Hyperkalemia associated with decreased secretion of aldosterone is rare in patients with normal renal function, but often develops in patients with congestive heart failure and the elderly. The incidence of hyperkalemia is increased in patients with renal failure and diabetes mellitus, patients receiving potassium or potassium-sparing diuretics, heparin, or non-steroidal anti-inflammatory drugs (NSAIDs).

Sharp renal failure... ACE inhibitors can increase blood urea nitrogen and creatinine levels. In most patients, the concentration of creatinine remains stable or decreases to baseline values \u200b\u200bwith continued therapy. Acute renal failure is more likely to develop during treatment with high-dose diuretics, in the presence of hyponatremia, bilateral renal artery stenosis, stenosis of the predominant renal artery, one kidney, and after kidney transplantation. In these conditions, the secretion of renin and the level of angiotensin II increase, which causes selective narrowing of the efferent arteriole of the glomeruli and maintains GFR. ACE inhibitors reduce angiotensin II levels, dilate efferent arterioles and decrease glomerular filtration, which leads to an increase in creatinine levels. The risk of acute renal failure with treatment with ACE inhibitors is especially high in elderly patients with congestive heart failure. After the abolition of ACE inhibitors, renal function is restored in virtually all patients.

Proteinuria. ACE inhibitors can cause proteinuria. However, its presence is not a contraindication to the prescription of drugs of this group, since they had a nephroprotective effect in kidney diseases accompanied by proteinuria (for example, in diabetic nephropathy).

Angioedema is a rare side effect, but it can be life-threatening. Symptoms range from mild gastrointestinal disturbances (nausea, vomiting, diarrhea, colic) to severe shortness of breath associated with laryngeal edema and death. Angioedema is more likely to occur during the first month of therapy, and also in African Americans. The manifestations disappear within a few hours after the withdrawal of the ACE inhibitor. The cause of angioedema is the accumulation of bradykinin and its metabolite, desargininebradykinin, and inhibition of the complement esterase-1 inactivator.

Teratogenic action. The use of ACE inhibitors in the second and third trimesters of pregnancy can cause the development of fetal malformations (oligohydroamnion, pulmonary hypoplasia, intrauterine growth retardation, kidney defects, anuria and neonatal death).

Others side effectsnot associated with ACE blockade include lack and other disturbances in taste (especially in the elderly), neutropenia, and maculopapular rash. Neutropenia is rare. It is more common in patients with kidney disease and vasculitis.

Contraindications

A history of angioedema, allergy and bilateral renal artery stenosis are absolute contraindications to the appointment of ACE inhibitors. Although drugs in this group can be used in women of reproductive age, they should be discontinued immediately in case of pregnancy, including anticipated pregnancy. Low blood pressure (systolic less than 90 mm Hg) with ACE inhibitors is acceptable if there are no symptoms of hypotension. ACE inhibitor therapy should be discontinued if the potassium level is more than 6.0 mmol / L or the creatinine level is more than 50%, or more than 3 mg / dL (256 mmol / L). Moderate renal impairment (serum creatinine not more than 3 mg / dL, or 265 mmol / L), mild hyperkalemia (<6.0 ммоль/л) и пониженное АД (снижение систолического АДдо 90 мм рт. ст.) не являются противопоказаниями к лечению ингибиторами АПФ, однако в таких случаях проводить его следует под контролем функции почек. Риск развития гипотонии и дисфункции почек повышается при увеличении дозы у пожилых больных и пациентов с тяжелой застойной сердечной недостаточностью, при лечении диуретиками в высоких дозах, дисфункции почек или гипонатриемии. Ингибиторы АПФ, как и другие вазодилататоры, не следует назначать больным с динамической обструкцией выносящего тракта левого желудочка .

Interaction with other drugs

Antacids reduce the bioavailability of ACE inhibitors. NSAIDs can reduce the vasodilating effects of drugs in this group. Potassium-sparing diuretics, potassium supplements, and high-potassium salt substitutes may contribute to the development of hyperkalemia with ACE inhibitor therapy, so such combinations should be avoided. At the same time, the combination of an ACE inhibitor with spironolactone can be beneficial, although it should be used under close supervision. If urea or creatinine levels rise significantly, it is advisable to discontinue nephrotoxic drugs (eg, NSAIDs, cyclosporine). ACE inhibitors can cause an increase in plasma digoxin and lithium levels. Patients receiving diuretics are especially sensitive to the vasodilating effect of ACE inhibitors. In some studies, concomitant therapy with salicylates reduced the effectiveness of ACE inhibitors in patients with congestive heart failure. However, a meta-analysis of treatment outcomes in more than 20,000 patients showed no signs of weakening the beneficial effect of ACE inhibitors with concomitant use of aspirin.

Dosage

The dose of the ACE inhibitor is selected taking into account the clinical situation and the individual response to treatment. Table 2 shows the average daily doses of various drugs, and in table. 4 shows the starting and target doses in patients with chronic heart failure.

Indications for the appointment of ACE inhibitors

• All patients with heart failure and asymptomatic left ventricular dysfunction.
• No contraindications (history of angioedema, pregnancy, bilateral renal artery stenosis)
FROM
• exercise caution
• Severe renal impairment (creatinine\u003e 2.5 mg / dL or\u003e 221 μmol / L)
• Hyperkalemia (K\u003e 5.0 mmol / L)
• Arterial hypotension (decrease in systolic blood pressure less than 90 mm Hg), accompanied by symptoms
• Interaction with other drugs: potassium preparations, potassium-sparing diuretics (including spironolactone), salt substitutes with a high potassium content, NSAIDs, angiotensin II receptor blockers

What to promise the sick?

• The primary goal of therapy is to prevent death and hospitalization. Functional class and tolerance to physical activity may not improve

When to start treatment?

• Immediately after establishing the diagnosis and excluding contraindications

Doses of ACE inhibitors

• Start treatment with a low dose
• The dose should be doubled every 2 weeks (accelerated dose titration is possible in patients with asymptomatic left ventricular dysfunction, mild heart failure, arterial hypertension and hospitalized patients)
• The dose should be increased to the target or maximum tolerated

Monitoring

• Clinical condition, BP regularly during titration
• Kidney function: creatinine and serum potassium
• Inform the patient about the benefits of treatment
• Encourage him to report adverse events (dizziness, symptoms of hypotension, cough)

Solution of problems

Arterial hypotension

• Evaluate the feasibility of continuing the use of other drugs that lower blood pressure (nitrates, calcium antagonists, other vasodilators)
• In the absence of fluid retention, discuss dose reduction or discontinuation of diuretics
• Reduce dose

Cough

• Eliminate other causes of cough (lung and bronchial diseases, pulmonary edema)
• If the cough is very troubling and reappears after temporary discontinuation and resumption of an ACE inhibitor, discuss the possibility of prescribing an angiotensin II receptor blocker

Deterioration of kidney function

• At the beginning of treatment, there may be a slight increase in creatinine levels (within<3 мг/дл, или 266 мкмоль/л) и калия (<6 ммоль/л). Если эти изменения небольшие и не сопровождаются симптомами, то какиелибо действия не требуются. Продолжить наблюдение
• Discuss the possibility of canceling nephrotoxic drugs (NSAIDs), potassium drugs, potassium-sparing diuretics. If there are no signs of blood stagnation, reduce the dose of diuretics
• If creatinine / potassium levels remain high, halve the dose of the ACE inhibitor. Re-measure creatinine and potassium levels. Refer the patient for a consultation with a specialist

NSAIDs are non-steroidal anti-inflammatory drugs. Only doses of ACE inhibitors, which have been studied in large placebo-controlled studies in patients with heart failure, are indicated. In some European countries, other ACE inhibitors are also registered for the treatment of heart failure.

Clinical efficacy and practical application

ACE inhibitors are effective in many cardiovascular diseases, including chronic heart failure, asymptomatic left ventricular dysfunction, acute myocardial infarction, arterial hypertension, as well as in patients at high cardiovascular risk. The therapy is of particular benefit to these patients in the presence of diabetes mellitus. Therapy with ACE inhibitors should be carried out under the control of blood pressure, renal function and serum potassium levels and start with a low dose, followed by a gradual increase, especially in patients with arterial hypotension or heart failure.

Heart failure

In the absence of contraindications, ACE inhibitors are used as first-line agents in patients with low systolic function of the left ventricle (ejection fraction less than 40-45%), combined or not combined with clinical signs of heart failure (class I, level of evidence A) (Table 3 ). Beneficial effects of ACE inhibitors include reductions in mortality, readmission rates, and progression of heart failure seen in men and women, black and white, and non-diabetic and non-diabetic patients, although the benefit of treatment was less in women. Doses of ACE inhibitors should not be titrated for symptomatic effect, but should be increased to target doses that have been shown to be effective in large controlled trials in patients with heart failure and left ventricular dysfunction (class I, level of evidence A) (Table 4). Although the effectiveness in heart failure is characteristic of the entire class of ACE inhibitors, nevertheless, not all of them have been studied in this condition, and adequate doses are not known in all cases.

In the CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study) and SOLVD studies, ACE inhibitors have been shown to increase survival in patients with chronic heart failure of any severity (NYHA functional classes I-IV). In patients with clinical signs of heart failure, both the incidence of sudden death and mortality from progressive heart failure are reduced. In the CONSENSUS study, patients with functional class IV were followed for an average of 188 days. When treated with an ACE inhibitor (enalapril), mortality at 6 months was significantly reduced (26% versus 44%). In the SOLVD study, patients with functional classes II-III were followed up for an average of 3.45 years. The overall mortality rate was 39.7% in the placebo group and 35.2% in the main group. The reduction in mortality was 45 cases per 1000 patients treated, and the number of patients who should have been treated for 1 year to prevent one death in 3.5 years (NNT) was 22. In large studies, ACE inhibitors reduced the rate of hospitalization (for any reasons and especially about the progression of heart failure). For example, in the SOLVD study, the number of patients who should have been treated to prevent one hospitalization for heart failure and for any reason in 3.5 years was 4.5 and 3.0, respectively.

The V-HeFT II (Vasodilator Heart Failure Trial) study compared the efficacy of enalapril and the combination of hydralazine with isosorbide dinitrate in men with heart failure. After 2 years, mortality in the enalapril group was significantly lower than in the hydralazine / isosorbide dinitra group (18% and 25%, respectively). A decrease in mortality in the enalapril group was associated with a decrease in the incidence of sudden death. This beneficial effect was more significant in patients with less severe symptoms (functional classes I or II). At the same time, oxygen consumption at maximum exercise increased only with hydralazine and isosorbide dinitrate treatment.

The AIRE (Acute Infarction Ramipril Efficacy) study examined the efficacy of ramipril in patients with heart failure after a recent myocardial infarction (MI). Already shortly after the start of treatment, a significant decrease in mortality was detected.

Overall, ACE inhibitors have been shown to increase survival, prevent progression of heart failure, and improve quality of life, although a decrease in functional class has not been demonstrated in all studies. In most placebo-controlled studies, therapy with ACE inhibitors was accompanied by an increase in exercise tolerance and a decrease in symptoms of heart failure, but this effect was not always observed. This suggests that the benefits of long-term therapy with ACE inhibitors in heart failure may not be related to mechanisms that control symptoms and increase exercise tolerance.

Target dose

In these studies, ACE inhibitors were used at high doses (Table 4), although they differed significantly from patient to patient. It should be emphasized that the scheme for the use of ACE inhibitors in clinical practice should be consistent with that in large clinical trials. In a large study ATLAS (Assessment of Treatment with Lisinopril And Survival), the results of treatment with an ACE inhibitor in low and high doses were compared in patients with II-IV functional classes according to NYHA. Overall mortality did not differ between groups, but the incidence of the combined endpoint (death from any cause and hospitalization from any cause) was significantly lower in patients who received the high dose of the drug, as was the total number of hospitalizations (decrease by 24%). For this reason, the high target doses of ACE inhibitors used in mainstream clinical trials are also recommended for routine clinical practice, although increasing the dose from medium to high is likely to be of little benefit.

In the randomized study NETWORK, patients with functional class II-IV heart failure received enalapril at doses of 2.5 mg twice daily, 5 mg twice daily, or 10 mg twice daily. After 24 weeks, there was no relationship between the dose of the drug and the clinical results of treatment. Mortality in 3 groups was 4.2, 3.3 and 2.9%, respectively (the difference is not significant). The incidence of the combined endpoint (death, hospitalization due to heart failure, or its progression) was also similar (1 2.3, 1 2.9 and 14.7%, respectively).

In the ATLAS and NETWORK studies, there was no difference in the frequency of endpoints for treatment with ACE inhibitors at medium and high doses. Thus, physicians should try to increase the dose of ACE inhibitors to the target values, the effectiveness of which has been demonstrated in relevant clinical studies (provided that it is well tolerated). Practical recommendations for the use of ACE inhibitors in heart failure are given in table. four .

Comparison of ACE inhibitors with angiotensin II receptor blockers

Several studies have compared the clinical efficacy of ACE inhibitors and angiotensin II receptor blockers. In most of them, receptor blockers did not have an advantage over ACE inhibitors. The ELITE-2 study included 3152 patients with chronic heart failure. During an average of 555 days, mortality was comparable in the losartan and captopril groups (11.7% and 10.4%, respectively). In the OPTIMAAL (Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan) study, 5447 patients with heart failure after myocardial infarction were randomized to receive either losartan or captopril. Mortality after 2.7 years of follow-up was similar in the two groups (18% and 16%, respectively). In the VALIANT study (Valsartan in Acute Myocardial Infarction), 15 703 patients with myocardial infarction complicated by left ventricular systolic dysfunction and / or heart failure were randomized to receive captopril, valsartan, or a combination of the two drugs. At 24.7 months, there was no difference in mortality or other outcomes between the three groups. In contrast, in the CHARM-added study (Candesartan in Heart Failure: Assessment of Reduction in Mortality and morbidity), the addition of candesartan to an ACE inhibitor resulted in a clinically significant reduction in cardiovascular outcomes, although mortality did not change.

Given that there is no difference between ACE inhibitors and angiotensin II receptor blockers in studies completed to date, ACE inhibitors should remain first-line drugs in patients with heart failure. Ongoing clinical trials in various subgroups of patients, as well as in patients with heart failure and intact systolic function, will clarify the comparative role of the drugs of the two groups in the treatment of heart failure.

In a large study, OVERTURE (Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events) compared the efficacy of an ACE inhibitor and omapatrilate (an ACE inhibitor and neutral endopeptidase) in 5570 patients with chronic heart failure. At 14.5 months, there was no difference in the incidence of the combined primary endpoint (death or hospitalization for heart failure) between the two groups.

Asymptomatic left ventricular systolic dysfunction

Table 3. The use of ACE inhibitors in heart failure

Patients with asymptomatic left ventricular systolic dysfunction (ejection fraction less than 40-45%) should receive ACE inhibitors unless contraindicated (class I, level of evidence A) (Table 3). One large study (the prophylactic part of SOLVD) randomized patients with low left ventricular ejection fraction (≤0.35) who did not show clinical signs of heart failure. They were given a placebo or enalapril. Most of the patients suffered from coronary heart disease and had MI. On average, after 3.12 years, ACE inhibitor therapy led to a decrease in the risk of death or hospitalization for onset or progressive heart failure from 24.5% to 20.6%. The decrease in the number of hospitalizations for progression of heart failure was approximately 70 cases per 1000 treated patients (NNT for 3 years was 14). The risk of developing heart failure decreased from 38.6% to 29.8%, and the median time to symptoms of heart failure increased from 8.3 months in the placebo group to 22.3 months in the main group. No reduction in overall mortality or hospitalization for any reason has been reported with ACE inhibitor treatment. However, recently Jong et al. , who continued the SOLVD-P study, reported a significant decrease in mortality (50.9% versus 56.4%) during 11.3 years in patients of the main group. Of interest is the fact that enalapril significantly reduced the incidence of diabetes mellitus in patients with left ventricular dysfunction, especially in the presence of impaired fasting glycemia.

The efficacy of ACE inhibitors in patients with left ventricular dysfunction after myocardial infarction has been studied in two large studies - SAVE (Survival And Ventricular Enlargement) and TRACE (Trandolapril Cardiac Evaluation). Treatment with captopril and trandolapril resulted in a decrease in mortality and readmission rates.

Diastolic heart failure

The problem of treating diastolic heart failure remains controversial, mainly due to a lack of research. ACE inhibitors can improve relaxation and distensibility of the heart, as well as suppress neurohumoral activation and regress left ventricular hypertrophy with long-term treatment. Accordingly, ACE inhibitors are recommended for the treatment of heart failure in patients with intact left ventricular systolic function (class PA, level of evidence C) (Table 3).

An alternative is likely to be angiotensin II receptor blockers, as evidenced by the efficacy of candesartan in this sample, demonstrated in the CHARM-preserved study. In any case, the role of different treatments for diastolic heart failure needs further study.

Acute myocardial infarction

Oral ACE inhibitors within 36 hours of acute MI are beneficial (class H, level of evidence A), especially in the presence of left ventricular anterior wall infarction, decreased ejection fraction, and mild to moderate heart failure (class I, level of evidence A) (Table 5). After acute myocardial infarction, patients with clinical signs of heart failure or asymptomatic left ventricular dysfunction should receive long-term therapy with ACE inhibitors (class I, level of evidence A). Therapy is also indicated for high-risk patients and patients with diabetes mellitus (class I, level of evidence A) (Table 5). The benefit of ACE inhibitors after acute MI appears to be most significant in diabetic patients.

Table 5. The use of ACE inhibitors in myocardial infarction

Large trials can be divided into 2 groups (early and late intervention), depending on the timing of ACE inhibitors after acute MI. Several short-term studies suggesting early prescription of ACE inhibitors included any patients with acute myocardial infarction: CONSENSUS-2 (2nd Cooperative New Scandinavian Enalapril Survival Study), ISIS 4 (4th International Study of Infarct Survival), GISSI-3 (the 3rd Study of the Gruppo Italiano per lo Studio della Sopravivenza), CCS-1 (The 1st Chinese Cardiac Study). Conversely, other randomized trials included high-risk patients and started treatment later and continued for a longer period: SAVE (Survival and Ventricular Enlargement), AIRE (Acute Infarction Ramipril Efficacy), and TRACE (Trandolapril Cardiac Evaluation). These studies involved patients with clinical signs of heart failure (AIRE) or left ventricular systolic dysfunction (SAVE, TRACE). Both types of studies have shown that ACE inhibitors reduce mortality after acute MI.

The appointment of ACE inhibitors in the early stages after myocardial infarction (<24-36 ч) оказывало небольшое влияние на смертность, что, вероятно, отражало более низкий сердечно-сосудистый риску пациентов, включенных в эти исследования, и короткую продолжительность лечения. Клиническая значимость достигнутого эффекта была спорной, что позволяет подвергнуть сомнению целесообразность применения ингибиторов АПФ у пациентов группы низкого риска.

In the ISIS 4 study, 58,050 patients were prescribed captopril or placebo, on average, 8 hours after the onset of symptoms of acute MI. During 5 weeks, mortality was slightly, but significantly lower in the captopril group (7.2 and 7.7%, respectively). The absolute difference was 4.9 deaths per 1000 patients per month. The beneficial effect of the drug persisted for at least 1 year (a difference of 5.4 deaths per 1000 patients). After 1 month, the difference was small and statistically insignificant. The absolute benefit of treatment was more pronounced in certain high-risk subgroups, for example, in patients with a history of myocardial infarction (difference 18 deaths per 1000 patients), patients with clinical signs of heart failure (difference 14 deaths per 1000 patients) and anterior wall infarction left ventricle. On the contrary, in patients with other localization of infarction, the benefits of therapy with captopril were not found. The incidence of recurrent myocardial infarction, postinfarction angina pectoris, cardiogenic shock, and stroke was similar in the two groups. Therapy with captopril was accompanied by an increase in the incidence of arterial hypotension, which required discontinuation of treatment (10.3 and 4.8%, respectively).

The GISSI-3 study included 19,394 patients who received lisinopril or placebo. After 6 weeks, mortality was lower in the lisinopril group (6.3 and 7.1%, respectively). This difference persisted after 6 months. The incidence of recurrent myocardial infarction, postinfarction angina pectoris, cardiogenic shock, and stroke did not differ between the lisinopril and placebo groups.

In the CCS-1 study, 13,634 patients with acute MI were randomized to receive captopril or placebo. In the main group, a tendency towards a decrease in mortality after 35 days was revealed (9.1 and 9.6%, respectively; the difference is not significant).

In the CONSENSUS-2 study, 6090 randomized patients received enalapril or placebo within 24 hours of acute MI. The therapy was started with an intravenous infusion of enalapril, after which the patients continued to take the drug by mouth. After 1 and 6 months, mortality in the two groups did not differ significantly (respectively 6.3 and 10.2% in the placebo group and 7.2 and 11.0% in the enalapril group). Arterial hypotension in the early stages was observed in 12% of patients in the enalapril group and 3% of patients in the placebo group. It was concluded that therapy with enalapril, started within 24 hours after the onset of acute myocardial infarction, does not improve patient survival over the next 180 days.

Finally, the Survival of Myocardial Infarction Long Term Evaluation (SMILE) study included 1,556 patients within 24 hours of the onset of symptoms of acute MI (they did not undergo thrombolysis). Patients were prescribed zofenopril or placebo. The incidence of death or severe heart failure at 6 weeks was significantly lower in the zofenopril group (7.1% and 10.6%, respectively). An insignificant decrease in mortality was also noted, but after 1 year it was significantly lower in the zofenopril group (10.0 and 14.1%).

A meta-analysis of the results of treatment with ACE inhibitors in more than 100,000 patients with myocardial infarction showed a decrease in mortality within 30 days from 7.6% in the placebo group to 7.1%. The difference between the groups was 5 cases per 1000 patients who received an ACE inhibitor for 4-6 weeks (NNT \u003d 200). The beneficial effect was more pronounced (up to 10 per 1000) in high-risk groups, for example, in patients with heart failure or myocardial infarction of the anterior wall of the left ventricle. In contrast, there was no effect in low-risk patients, including those with inferior wall MI who did not have heart failure. In patients with diabetes mellitus, only a tendency towards a decrease in mortality was revealed. ACE inhibitors also reduced the incidence of nonfatal heart failure (14.6% and 15.2%, respectively), but did not affect the risk of recurrent MI or stroke. Therapy with drugs in this group was accompanied by an increase in the frequency of persistent hypotension (17.6 and 9.3%) and renal dysfunction (1.3 and 0.6%).

The results of the analysis showed that the beneficial effect was manifested mainly during the first week: early administration of ACE inhibitors saved the lives of 239 patients, including 200 patients during the first week after MI. These data indicate that ACE inhibitors can be used in the acute phase of myocardial infarction, but only in high-risk patients. When using them, intravenous administration of enalapril should be avoided and treatment should be started with a low dose, which is gradually increased over 48 hours under the control of blood pressure and renal function.

Later intervention. These studies demonstrated a more significant benefit of ACE inhibitor therapy, which was prescribed to selected high-risk patients at a later time (more than 48 hours) after MI and continued for a long time.

The SAVE study included 2230 patients with left ventricular ejection fraction less than 40%. They were randomized 3-16 days after MI and given captopril or placebo. At 42 months, mortality was lower in the captopril group (20% and 25%, respectively). In addition, treatment with captopril resulted in a decrease in the incidence of fatal and non-fatal cardiovascular complications, including heart failure, hospitalization, and recurrent MI. The beneficial effect was independent of thrombolytic therapy and treatment with aspirin or β-blockers.

The TRACE study enrolled 1,749 patients with left ventricular systolic dysfunction (ejection fraction less than 35%), with and without overt heart failure, who were prescribed trandolapril or placebo 3-7 days after myocardial infarction. Within 24-50 months, mortality was lower in the trandolapril group (34.7 and 42.3%, respectively; p<0,001). Терапия трандолаприлом привела также к снижению риска развития внезапной смерти и тяжелой сердечной недостаточности, но не влияла на риск повторного ИМ. Проанализированы отдаленные результаты лечения спустя 6 лет после его начала . Ожидаемая продолжительность жизни составила 4,6 года в группе плацебо и 6,2 года в группе трандолаприла. Таким образом, медиана продолжительности жизни у больных, получавших трандолаприл во время исследования, увеличилась на 15,3 мес (27%) Следовательно, лечение ингибитором АПФ в критический период ассоциируется с улучшением отдаленного прогноза.

In the 1986 AIRE study, patients with clinical signs of heart failure following acute myocardial infarction were randomized into 2 groups to receive ramipril or placebo, which was prescribed 3-10 days after myocardial infarction. Patients were followed up for at least 6 months (mean 15). Mortality decreased significantly in the ramipril group (17% and 23%, respectively). The reduction in the frequency of the combined endpoint (death, severe / refractory heart failure, MI, or stroke) was also statistically significant. The beneficial effect was manifested already in the first 30 days and was comparable in different patient samples.

In a meta-analysis of studies suggesting the later appointment of ACE inhibitors, there was a decrease in mortality from 29.1% to 23.4% over an average of 2.6 years. The difference between the groups was 57 deaths per 1000 patients treated (NNT 18). Research has also shown that ACE inhibitors reduce the risk of heart failure and the hospitalization rate for heart failure. With treatment with ACE inhibitors, the risk of recurrent MI decreased from 13.2% to 10.8%, and the risk of hospitalization for heart failure - from 5.5% to 11.9%.

Research findings have sparked controversy over how ACE inhibitors should be used in patients with MI. Some authors suggested prescribing treatment to all patients and continuing it only in the presence of clinical signs of heart failure or left ventricular systolic dysfunction. According to other experts, the small benefit of early therapy was actually only seen in high-risk patients; accordingly, they should be prescribed ACE inhibitors. In this case, therapy should be continued indefinitely. The HOPE (Heart Outcomes Protection Evaluation) and EUROPA (EURo-pean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease) studies, which demonstrated the benefits of the use of ACE inhibitors in patients with coronary atherosclerosis (or high-risk patients ) (see secondary prevention).

Arterial hypertension

ACE inhibitors are indicated for the treatment of hypertension (class I, level of evidence A) (Table 6). Current guidelines recommend lowering BP to different values \u200b\u200bdepending on the risk profile (the higher the risk, the lower the target BP). In hypertensive patients, the primary goal of treatment is blood pressure control, which can be achieved with a variety of drugs that reduce the risk of cardiovascular complications with long-term therapy, including diuretics, β-blockers, ACE inhibitors, calcium antagonists, and angiotensin II receptor blockers. ... Adequate blood pressure reduction can only be achieved with a combination of antihypertensive drugs. A number of large, long-term comparative studies have not found the benefits of any particular treatment regimen. The results of these studies should be interpreted with caution, as some of them did not have sufficient statistical power. In addition, small differences in blood pressure at the time of randomization could have a significant impact on long-term results, and the antihypertensive therapy regimen changes over the long term. Taking into account the results of these studies, as well as information obtained from other sources (for example, in patients with heart failure, MI, etc.), a specific drug should be selected individually. Thus, ACE inhibitors can be considered as first-line agents in patients with heart failure, left ventricular systolic dysfunction or diabetes mellitus, MI or stroke, as well as in patients at high risk of coronary heart disease, since the effectiveness of drugs in this group in these samples was confirmed in special studies (Table 6).

Table 6. The use of ACE inhibitors in arterial hypertension

In the STOP-2 (Swedish Trial in Old Patients with hypertension) study, 6614 patients aged 70-84 years with arterial hypertension were randomized into two groups and received therapy with standard antihypertensive drugs (atenolol, metoprolol, pindolol or hydrochlorothiazide) or new drugs (enalapril , lisinopril, felodipine, or isradipine). The decrease in blood pressure was similar in all groups. The incidence of the primary combined endpoint (fatal stroke and MI and other cardiovascular complications) was comparable in the comparison groups. There were no differences in the incidence of the other combined endpoint (fatal and nonfatal stroke, fatal and nonfatal MI, death from other cardiovascular complications).

One of the secondary goals of the ABCD (Appropriate Blood Pressure Control Diabetes) study was to compare the effectiveness of nisoldipine and enalapril in preventing the development and progression of diabetic complications within 5 years in 470 patients. Using multiple regression analysis, it was shown that nisoldipine therapy is associated with a higher incidence of fatal and non-fatal MI than enalapril treatment, but the number of such outcomes was too small to draw any conclusions. Mortality rates were similar in the two groups.

The CAPPP study (The Captopril Prevention Project) compared the effects of ACE inhibitors and standard therapy (diuretics, β-blockers) on cardiovascular morbidity and mortality in 10,985 hypertensive patients. The two regimens did not differ in their effect on the risk of cardiovascular complications (combination of MI, stroke, and cardiovascular death), but the incidence of stroke was higher in the captopril group. At the same time, the incidence of diabetes decreased with captopril treatment. In a subgroup of patients with diabetes mellitus, an ACE inhibitor had advantages in terms of effectiveness in the prevention of cardiovascular complications.

The UKPDS (The UK Prospective Diabetes Study) randomized controlled trial compared the efficacy of an ACE inhibitor (captopril) and a β-blocker (atenolol) in patients with type 2 diabetes. Captopril and atenolol were equally effective in reducing blood pressure and the risk of macrovascular complications, including mortality, but the study was probably not statistically strong. Progression of retinopathy during

9 years old and the development of albuminuria was noted in the same percentage of patients in the two groups. The incidence of hypoglycemic reactions did not differ between groups. It was concluded that antihypertensive therapy with captopril and atenolol is equally effective in preventing diabetic complications. This study did not confirm any advantages or disadvantages of either of the two drugs. It can be assumed that the decrease in blood pressure in itself is more important than the choice of a specific antihypertensive drug.

In the PROGRESS study (Perindopril Protection against Recurrent Stroke Study), 6105 patients with and without arterial hypertension and having suffered a stroke or transient ischemic attack were randomized into two groups and received active therapy (perindopril, to which indapamide was added if necessary) or placebo. Any stroke was the primary endpoint. Within 4 years, active therapy led to a decrease in the incidence of stroke (10% and 14%, respectively) and the risk of any vascular complications. The reduction in the risk of stroke was comparable in patients with high and normal blood pressure. Combination therapy with perindopril and indapamide caused a more pronounced decrease in blood pressure and cardiovascular risk (43%) than monotherapy with perindopril. However, the latter was also accompanied by a clinically significant reduction in the risk of stroke.

A meta-analysis of 4 placebo-controlled trials of ACE inhibitors (12,124 patients, mostly with coronary heart disease) showed a 30% reduction in the risk of stroke, 20% of coronary heart disease, and 21% of major cardiovascular outcomes. The results of antihypertensive therapy of different intensities and the use of antihypertensive drugs of different classes are less convincing. When comparing therapy regimens with ACE inhibitors or diuretics / β-blockers, there was no difference in the frequency of endpoints. Only 2 studies directly compared ACE inhibitor versus calcium antagonist therapy (STOP-2 versus ABCD). When the results of the studies were pooled, there was a decrease in the risk of coronary heart disease in patients treated with ACE inhibitors, but the incidence of stroke, cardiovascular and overall mortality did not differ significantly between the comparison groups. When analyzing the frequency of heart failure, a tendency towards a decrease in the risk of its development was found when using ACE inhibitors.

Another meta-analysis included 9 randomized trials comparing "old" drugs (diuretics and β-blockers), calcium antagonists and ACE inhibitors in 62,605 patients with arterial hypertension. Outcome rates did not differ between groups.

The Australian national blood pressure study (ANBP-2) examined the results of treatment in 6083 hypertensive patients who received an ACE inhibitor (enalapril) or a diuretic (hydrochlorothiazide). Β-blockers, calcium antagonists and α-blockers were added to treatment as needed in both groups. The decrease in blood pressure was comparable in the two groups, but after 4.1 years the cumulative incidence of death and cardiovascular complications was lower in the group of patients who were prescribed ACE inhibitors (56.1 and 59.8 per 1000 person-years), mainly for by reducing the incidence of myocardial infarction, while the incidence of stroke was comparable in the two groups.

Different results were obtained in the ALLHAT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial) study, which included 33,357 patients with arterial hypertension who had at least one other cardiovascular risk factor. The patients were divided into 3 groups and prescribed chlorthalidone, amlodipine or lisinopril. The primary endpoint was death from cardiovascular causes and non-fatal MI. Secondary endpoints included all-cause death, stroke, and various combinations of cardiovascular outcomes, including coronary revascularization, hospitalization for angina pectoris, heart failure, and peripheral arterial disease. The follow-up period was 4.9 years. There was no difference in the frequency of the primary endpoint between the groups. Overall mortality was also similar in the lisinopril and chlorthalidone groups. In the lisinopril group, the incidence of cardiovascular outcomes (33.3 and 30.9%, respectively), stroke (6.3 and 5.6%) and heart failure (8.7 and 7.7%) was higher, which makes them subject to doubt the advisability of using ACE inhibitors as first-line agents in patients with arterial hypertension, not belonging to the high-risk group and not suffering from heart failure.

In general, it seems that the target BP or the degree of its reduction is more important than the choice of a particular drug, although the results of studies in patients with other cardiovascular diseases have demonstrated the benefits of ACE inhibitors in patients with heart failure, diabetes mellitus and patients at high cardiovascular risk. ...

Secondary prevention in the high cardiovascular risk group

Long-term therapy with ACE inhibitors in patients without heart failure is effective in the presence of cardiovascular disease or diabetes mellitus and several other risk factors (class I, level of evidence A) (Table 7). Several studies have examined the efficacy of ACE inhibitors in patients with coronary heart disease who do not have congestive heart failure. In the PART-2 study, in 600 patients with coronary, cerebral, or peripheral artery disease, ramipril slightly reduced blood pressure (6 mm Hg) and left ventricular mass over 2 years compared with placebo, but did not affect the wall thickness of the common carotid artery. and the incidence of major cardiovascular outcomes. These data suggest that the hypotensive effect of ACE inhibitors is more important than their other effects. In the QUIET (Quinapril Ischemic Event Trial) study, heart rate endpoints were assessed for 3 years with quinapril or placebo in patients with normal left ventricular function who underwent coronary angiography. Angiography revealed no differences in the progression of coronary atherosclerosis. The study, which included 1,750 patients without heart failure, did not have sufficient statistical power to detect differences in clinical outcomes. The Simvastatin / enalapril Coronary Atherosclerosis Trial (SCAT) studied the effects of a cholesterol-lowering drug (simvastatin) and an ACE inhibitor (enalapril) on coronary atherosclerosis in 460 patients with normal cholesterol levels. Enalapril did not differ from placebo in the effect on the severity of coronary lesions.

Table 7. The use of ACE inhibitors for the purpose of secondary prevention

Several large multicenter studies tested the hypothesis that ACE inhibitors can reduce the risk of major cardiovascular outcomes in patients with coronary heart disease and other vascular disease: HOPE (Heart Outcomes Prevention Evaluation Study), EUROPA (EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease), PEACE (Prevention of Events with Angiotensin- Converting Enzyme Inhibition) and ONTARGET (telmisartan alone and in combination with ramipril global endpoint trial).

The HOPE study included 9297 men and women with confirmed atherosclerosis (coronary heart disease, peripheral arterial disease, stroke) or diabetes mellitus and at least one other risk factor (hypertension, cigarette smoking, microalbuminuria, or dyslipidemia). 80% of patients had coronary heart disease, 55% had angina pectoris, 52% had a history of myocardial infarction, 43% had peripheral arterial atherosclerosis, 25% had a history of unstable angina, 26% had a history of coronary artery bypass grafting, in 18% - percutaneous revascularization of the coronary arteries, in 11% - stroke or transient ischemic attack. Almost half of the patients suffered from arterial hypertension and about 40% from diabetes mellitus. Patients were assigned a placebo or an ACE inhibitor (ramipril) and continued observation for an average of 5 years. The primary endpoint (cardiovascular death, myocardial infarction, or stroke) was recorded in 17.8% of patients in the placebo group and 14.0% of patients in the ramipril group (the difference was 38 primary outcomes per 1000 patients treated; NNT for 5 years \u003d 26.3). Ramipril therapy led to a decrease in the frequency of all components of this endpoint, as well as various secondary endpoints, including overall mortality (from 1 2.2 to 10.4% within 5 years), the need for revascularization, diabetic complications, the development of diabetes mellitus, cardiac arrest, progression of angina pectoris, or heart failure. Of interest is the fact that the decrease in blood pressure in the ramipril group was relatively small (systolic blood pressure - 3.3 mm Hg. Art.), So the results of treatment cannot be explained only by the antihypertensive effect of the drug.

Additional confirmation of the effectiveness of long-term therapy with ACE inhibitors in secondary prevention are the results of the EUROPA study. It included 13 655 low-risk patients without heart failure who suffered from stable coronary heart disease. They were treated with perindopril or placebo for an average of 4.2 years. Patients in the perindopril group showed a decrease in the incidence of cardiovascular outcomes (cardiovascular death, myocardial infarction and sudden death) from 10 to 8% (this meant that in order to prevent one cardiovascular outcome, treatment was required for 4.2 years in 50 sick). The benefit of an ACE inhibitor was comparable in all patient subgroups.

In combination with the results of studies in patients with heart failure and MI, the HOPE and EUROPA studies have convincingly proved the general protective effect of ACE inhibitors on blood vessels in patients with coronary heart disease and other forms of atherosclerosis. The PEACE study investigates the efficacy of an ACE inhibitor (trandolapril) in the prevention of cardiovascular outcomes in patients with confirmed coronary heart disease and normal left ventricular systolic function. The ONTARGET study compares inhibitor monotherapy

ACE (ramipril) and angiotensin II receptor blocker (telmisartan) and their combination. The results of these large ongoing studies will expand our understanding of approaches to the treatment of patients at high risk of atherosclerotic complications.

Prevention of sudden cardiac death

The use of ACE inhibitors for the prevention of sudden cardiac death in patients with left ventricular dysfunction or heart failure after MI is considered a Class I indication (level of evidence A) (Table 8). In patients with asymptomatic left ventricular dysfunction and moderate to severe heart failure, treatment with ACE inhibitors led to a 20-54% reduction in the incidence of sudden death. In some studies in patients with heart failure, this effect reached statistical significance, although sudden cardiac death was not the primary endpoint.

Table 8. The use of ACE inhibitors for the prevention of sudden death

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Diabetes mellitus is another pathology in which antiotensin-converting enzyme inhibitors are mandatory. Even if the patient has normal blood pressure without a tendency to fluctuate, it will still be necessary to drink these pills, but the drug will be taken systematically, regardless of the patient's condition and any other factors.

Renal pathologies - chronic pyelonephritis and glomerulonephritis, as well as various systemic pathologies.

In this case, the appointment is possible only after the patient is examined by a nephrologist and undergoes a number of additional medical examinations.

A number of additional studies include ultrasound of the kidneys, general urine analysis, biochemical blood test with the determination of the renal and hepatic complex.

Modern inhibitors - list of drugs

It will be necessary to divide the drugs of the given pharmacological group into two categories - drugs and prodrugs.

The fundamental difference between them is that in the first case, when the drug itself is already a medicinal compound, it enters the body and immediately begins to act.

In other words, its clinical effect manifests itself rather quickly, which makes it possible to use such pills as an emergency aid. And can be used as emergency medications.

Captopril and Lisinopril are used for (in the overwhelming majority of cases, it is prescribed - a combination of captopril with hydrochlorothiazide, a diuretic).

Captopril tablets

For routine administration, it is recommended to use prodrugs - these are compounds that by themselves do not have biochemical activity in the human body, but when ingested, they are converted into substrates that can have a pronounced clinical effect.

There are a great many examples of prodrugs from the ACE inhibitors group: Ramipril, Fosinopril and many others. There is no fundamental difference between them if we consider biochemically active molecules with substances identical in mass.

One can reasonably argue - why, then, in some cases, there is a high efficiency of antiotensin-converting enzyme inhibitors (ACE inhibitors), while in others it leaves much to be desired?

Provided that the same dosages of drugs are used, and the results of the use were established on the same people?

The answer on the surface is that everything is determined by the drug manufacturer's brand. Not all manufacturers that are represented on the pharmaceutical market today have the required certificates of conformity, but, nevertheless, they continue to function safely, supplying patients with low-quality, but cheap products.

Medicines from the ACE inhibitor group act quickly, which makes it possible to provide emergency assistance in the shortest possible time, however, their duration of exposure is short, which excludes the possibility of their use at normal blood pressure, although antihypertensive drugs are drunk systematically.

You shouldn't try to save money on medicines. Moreover, now the cost of original drugs is not much higher than the price of generic drugs, the effectiveness of which is highly questionable.

Indications and contraindications

Modern ACE inhibitors are prescribed for the treatment of pathologies such as:

1. hypertonic disease;
2. heart failure;
3. diabetes;
4. renal pathologies - chronic pyelonephritis and glomerulonephritis;
5. metabolic systemic disorders.

ACE inhibitors are drugs that are contraindicated for use in the following cases:

1. individual intolerance to the drug;
2. pregnancy at any stage of gestation and breastfeeding of the child.

Groups

What are ACE inhibitors?

There are several classifications of drugs belonging to the ACE inhibitors group.

However, the only one that is significant is their conditional division into drugs and prodrugs (this subdivision has already been given above).

Natural ACE inhibitors

In fact, there are no such natural remedies. Angiotensin-converting enzyme inhibitors are drugs that are synthetic, but this moment in no way affects their clinical efficacy.

It's worth noting that the best ACE inhibitor is the one prescribed by your doctor. You cannot engage in self-medication.

Related Videos

What are ACE inhibitors? The list of drugs and their pharmacological characteristics in the video: