Antianginal drugs (treatment of coronary heart disease and its complications (myocardial infarction))

Antianginal drugs are a group of drugs that are used to treat coronary heart disease - angina and myocardial infarction.

Coronary heart disease (CHD) is a pathological condition associated with oxygen starvation of the heart muscle (myocardium) due to insufficient blood supply to the vessels of the heart.

Chronic ischemic heart disease is manifested by angina pectoris. The causes of angina are usually narrowing of the lumen of the coronary (heart) vessels by atherosclerotic plaque (angina pectoris) or vasospasm (vasospastic angina).

Acute coronary heart disease is manifested by unstable angina and myocardial infarction. The cause of acute ischemic heart disease is partial or complete blockage of the lumen of blood vessels by a thrombus.

Unstable angina is considered a pre-infarction condition. Most often, it turns into an acute myocardial infarction, but if quickly recognized and treated, unstable angina can resolve quite safely.

The narrowing of the lumen of the coronary vessels leads to a decrease in the delivery of blood (and with blood, oxygen and nutrients) to the myocardium, which is manifested by oxygen starvation of the heart muscle, pain during physical activity or psycho-emotional stress.

Complete blockage of the lumen of the coronary vessels leads to a sharp lack of oxygen in the areas of the heart fed by these vessels and, in the absence of treatment, their death - necrosis.

Medicines used for angina are called antianginal drugs (from the old Latin name for angina: angina pectoris - angina pectoris).

Difficulties in risk stratification as a factor complicating the choice of therapy

It is well known that the intensity of preventive drug therapy for patients with coronary heart disease (CHD) should be directly determined by the level of cardiovascular risk.
Unfortunately, despite the many scales developed for this purpose, risk assessment for patients with coronary artery disease without a history of acute myocardial infarction (AMI) is today very difficult. In most cases, existing scales underestimate the risk level for patients in the high-risk group and overestimate it in the low-risk group [1]. The most significant practical difficulty here seems to be the impossibility of obtaining real information about the degree of stability of atherosclerotic plaques in the coronary vessels of a patient with coronary artery disease, which has primary prognostic value. Apparently, large atherosclerotic plaques that have a dense fibrous cap rupture less frequently, but at the same time cause pronounced clinical symptoms (in particular, anginal pain). At the same time, when they rupture and release a huge amount of procoagulant tissue factor into the vessel, the development of thrombotic occlusion of a large vessel is likely, the clinical equivalent of which is an extensive myocardial infarction with the formation of a Q wave [2].

Small plaques are less likely to lead to a significant decrease in coronary blood flow, which determines rarer and less intense attacks of anginal pain. But at the same time, small plaques can be much less stable; erosion or rupture of their thin fibrous cap can lead to the development of AMI, as a rule, without the formation of a Q wave (Fig. 1). As an illustrative example, we can cite the medical histories of patients with poorly compensated type 2 diabetes mellitus, who often have a history of several small focal infarctions and episodes of unstable angina.

According to new data, with unstable angina inside the coronary arteries, it is possible to form a kind of dynamic equilibrium, in which for a sufficiently long time small tears occur on the intimal surface or intimal erosions form, but the formation of a blood clot can be avoided due to the activation of the antithrombotic system. The use of methods for direct visualization of the structure of atheromas in vivo, such as optical coherence tomography/spectroscopy, makes it possible to identify such plaques [3].

Within the framework of this concept, it is easy to explain the results of the COURAGE study (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation), in which stenting of the coronary arteries did not lead to an improvement in prognosis, but significantly improved clinical symptoms. In all likelihood, despite the fact that anginal pain in these patients was associated with large, successfully stented plaques, the prognosis in this case was determined by small unstable plaques, the stenting of which, for obvious reasons, was not performed.

Today, assessment of the degree of stability of atherosclerotic plaques and interventions aimed at their stabilization, including through “hardening” the fibrous cap, are becoming a new paradigm in preventive cardiology. In fact, all traditional scales developed for patients with coronary artery disease solve the problem of risk assessment by analyzing factors that indirectly characterize the stability of atheromas.

Basics of treatment of coronary heart disease

Antianginal drugs are used both to relieve (eliminate) an attack of angina, and to prevent the occurrence of attacks systematically.

In addition to antianginal drugs, in the treatment of stable and vasospastic angina, drugs for the treatment of atherosclerosis (antiatherosclerotic) and the prevention of thrombus formation (antiplatelet agents) are used.

For the treatment of unstable angina and acute myocardial infarction, fibrinolytics (drugs that dissolve blood clots) and anticoagulants and antiplatelet agents (drugs that prevent recurrent thrombus formation) are used primarily not with antianginal drugs.

New non-invasive diagnostic options

One of the main directions in the development of modern cardiology is the search for minimally invasive methods for direct or indirect assessment of the stability of atherosclerotic plaques, which will make it possible to more accurately predict the risk of developing acute coronary syndrome (ACS). Their practical application seems especially important in the management of patients with average risk, for whom the choice of optimal treatment is often difficult. Today in the West, for this purpose, the most widely used integral indicator of the scale of coronary lesions is the calcium index, which is calculated when performing multislice computed tomography (MSCT) [4].

Another approach, which can also be implemented when performing MSCT, is the assessment of the distribution of contrast density in the coronary bed, which makes it possible to determine areas of the coronary arteries with low shear stress, where unstable atheromas can be expected to form [5].

Today, more and more experimental non-invasive techniques are appearing that are designed to specifically determine the state of atherosclerotic plaques.

These include the following diagnostic methods:

• MR imaging using intravascular coils and new contrast agents (eg, ultrasmall iron oxide particles that accumulate in macrophages);

• combined technologies MSCT/MRI (magnetic resonance imaging), PET/CT (positron emission tomography/computed tomography), CT/scintigraphy;

• molecular radiation diagnostics (for example, scintigraphy with 99Tc-annexin 5, 99Tc-IL-2, with labeled platelets and low-density lipoproteins).

Among the promising biochemical markers of instability of atherosclerotic plaques are lipoprotein-associated phospholipase A2, matrix metalloproteinase 9, soluble CD40 ligand, neopterin, as well as highly sensitive C-reactive protein, which is widely available for practical determination [6].

Lecture No. 19. Antianginal agents

ANTIANGINAL DRUGS

A group of pathological conditions associated with coronary insufficiency is united under the term “coronary heart disease” (CHD). According to the recommendations of WHO experts (1979), there are several classes (forms) of IHD. Among these forms, a significant place is occupied by such a common pathology as angina pectoris (or angina pectoris), as well as myocardial infarction. The Latin name for angina pectoris is angina pectoris. In this regard, drugs used for angina pectoris are called antianginal or antianginal.

Angina syndrome, classically described by Heberden in 1768, manifests itself in the form of paroxysmal, short-term pain, often localized behind the sternum, with corresponding irradiation to the arm, occurring after physical work or at rest and usually relieved within 1-10 minutes. In general, an attack that passes spontaneously lasts for 5-6 minutes, in any case no more than 20-30 minutes, since then the area of ​​the myocardium suffering from ischemia undergoes necrosis with the formation of a heart attack.

According to the WHO classification, there are two forms of angina:

I form: TYPICAL form of angina, when sclerotic changes in the coronary vessels are observed. In this case, angina pectoris is provoked by physical, mental or cold stress;

Form II: VARIANT form of angina (or vasospastic form, or Prinzmetal's angina), has recently become increasingly common in young people, without signs of vascular sclerosis. This form is most often associated with emotional overstrain, but can also occur in conditions of rest.

PATHOPHYSIOLOGICAL MECHANISMS AND CAUSES LEADING TO THE APPEARANCE AND DEVELOPMENT OF ANGINA

The main cause of myocardial ischemia is the discrepancy (imbalance) between the myocardial need for oxygen and its availability provided by the coronary blood flow. That is, one of the mechanisms causing the occurrence of an angina attack is a disruption in the delivery of oxygen to the myocardium due to spasm of the coronary vessels.

Speaking about the occurrence of this discrepancy, it seems possible to identify three “weak points” of the coronary blood flow:

1. The coronary arteries are functionally terminal and have very few collaterals.

2. At rest, the heart muscle absorbs the maximum amount of oxygen from the blood (60-70%), and therefore increasing the extraction of oxygen by the myocardium is an impossible task.

3. Coronary blood flow is mainly influenced by two factors:

- pressure in the aorta;

- resistance of coronary vessels. Blood flows to the myocardium of the left ventricle intermittently, only in diastole.

Despite all these conditions, coronary blood flow has a high reserve potential - up to 500%.

Thus, if for any reason the increase in coronary blood flow is not able to meet the increasing oxygen demands, then angina pectoris develops.

In connection with the two main causes of angina pectoris (impaired oxygen delivery and increased myocardial oxygen demand), there are two basic principles of pharmacological correction:

1. Dilation of coronary vessels and thus increasing oxygen delivery.

2. Reducing the work of the heart muscle and thus reducing the myocardial oxygen demand.

When treating a patient suffering from angina, two goals can be pursued:

1. Stop (cut off, trim, stop) an attack of angina.

2. Prevent an attack of angina pectoris, which means the possibility of chronic treatment of patients. This type of therapy allows you to prevent the development of attacks and increase tolerance (resistance) to physical and emotional stress.

CLASSIFICATION OF ANTIANGINAL DRUGS

To treat patients with angina attacks, a fairly wide arsenal of drugs with antianginal activity is used. There are many of these drugs, several dozen, however, at present there are only three groups of drugs that have won the recognition of specialists.

I. Nitrogen-containing preparations (or organic nitrates).

Previously, there were preparations of organic and inorganic nitrites (for example, amyl nitrite and sodium nitrite), that is, nitrous acid compounds, but at present they are practically not used.

II. Beta blockers.

III. Calcium antagonists (calcium channel blockers).

ORGANIC NITRATES

Nitro-containing drugs have been successfully used in the treatment of patients with angina pectoris for more than 100 years (William Mitchell, 1879). The classic drug from this group is nitroglycerin (Nitroglycerinum) - the best known and most effective drug in this group of drugs.

The mechanism of action is due to the fact that the drug has a direct myotropic effect on smooth muscles, especially blood vessels (more so veins than arteries) that are in a state of spasm. Under the influence of nitroglycerin, the vessels of the brain, neck, head, that is, the vessels of the upper body, including the heart, dilate most significantly. The predominant venodilating effect of nitroglycerin leads to changes in peripheral hemodynamics: blood deposition and a decrease in venous return, that is, blood redistribution. This is accompanied by a decrease in the load on the heart (reduction of preload) and contributes to a persistent decrease in energy use. This decrease in venous return of blood to the heart, due to the effect on capacitance vessels, is accompanied by the following effects:

- decreased pressure in both atria;

- decrease in stroke volume;

- decrease in myocardial wall tension;

- decrease in heart volume;

- decrease in blood pressure;

- reflex tachycardia.

Moderate dilation of arterioles, that is, a decrease in afterload on the heart, is accompanied by:

- decrease in blood pressure;

- increase in stroke volume.

An important fact is that nitroglycerin dilates the coronary vessels, especially the largest ones. Nitroglycerin not only dilates the coronary vessels, but also increases the number of collaterals, thereby increasing collateral blood flow. In addition, a decrease in resistance in the coronary vessels leads to such a redistribution of blood flow that the number of functioning collaterals becomes most significant in the subendocardial layer of the myocardium, and, as is known, it is in this layer that ischemia most often develops. From this point of view, it is advisable to use nitroglycerin not only for typical, but also for vasospastic forms of angina.

Thus, a decrease in resistance in the coronary vessels, especially in the epicardial parts of the myocardium, is accompanied by:

- relieving spasm of the coronary arteries;

- increased coronary blood flow.

In general, we can talk about a dual mechanism of action of nitroglycerin:

1. Direct expansion of the coronary vessels (oxygen delivery to the ischemic area of ​​the myocardium increases)

2. There is a decrease in pre- and afterload on the heart (myocardial oxygen demand decreases).

Thanks to these effects, the balance between the flow of oxygen to the myocardium and its consumption is restored, thus eliminating ischemia.

The action of nitroglycerin as a vasodilator is associated with imitation of the action of endothelial relaxing factor (ERF). Nitroglycerin has pronounced lipophilicity, easily penetrates the cell and activates the enzyme guanylate cyclase (its soluble fraction). This helps to increase the concentration of cGMP. The accumulation of the latter in smooth muscles leads to their relaxation and vasodilation. It is also known that the vascular endothelium, under the influence of certain biologically active substances (acetylcholine, bradykinin), releases a substance that dilates blood vessels - ERP, which is nitric oxide (NO). The source of this factor in the body is L-arginine.

Nitroglycerin is well absorbed by the mucous membranes of the oral cavity and gastrointestinal tract, as well as the skin. Nitroglycerin is especially well absorbed from the sublingual area. When taking the drug sublingually, its maximum concentration in the blood is reached 4 minutes after administration and begins to decrease after 15 minutes. After 45 minutes, the drug is completely eliminated from the body. Therefore, the most commonly used dosage form of nitroglycerin (reference drug) is sublingual tablets.

The effect of sublingual tablets begins after 1-2 minutes and lasts for 10-30 minutes.

Domestic tablets contain 0.5 mg of active ingredient. The tablets are very unstable and must be replaced with fresh ones every 2 months.

To relieve an attack of angina, one tablet under the tongue is usually sufficient.

Along with tablets, capsules containing a 1% oil solution of nitroglycerin are produced. Capsules may contain 0.5 and 1.0 mg of nitroglycern. After placing the capsule under the tongue, it should be crushed.

There is also a rather outdated dosage form of nitroglycerin - a 1% alcohol solution. This form requires the patient to dosage independently: 2-3 drops of the solution are applied to or under the tongue (3-4 drops correspond to one nitroglycerin tablet under the tongue). We can recommend that patients apply drops of an alcohol solution to a piece of sugar. An alcohol solution of nitroglycerin is included in Votchal drops.

In Western Europe, aerosols with nitroglycerin (Nitroglycerini spray) have been put into practical use.

Indications for use of nitroglycerin:

1) All of the listed dosage forms, being short-acting forms, are used to relieve attacks in all types of angina. In the case of typical angina, when attacks are often repeated, nitroglycerin can be used sublingually to prevent a possible attack, for example, 2-3 minutes before going outside, especially on a frosty day.

An interesting fact is that taking 25-30 doses of nitroglycerin promotes the development of such a degree of collateral circulation that it becomes possible to prevent a heart attack.

2) Tablets under the tongue can be used for thrombosis of the retinal vessels (to reduce the area of ​​the lesion).

3) In the absence of other means, nitroglycerin can be used for spasm of the biliary tract, as first aid.

From 1974-82, transdermal dosage forms (ointments, patches and discs of various designs with a fixed dose of the active substance) became widespread on the Western market.

A 2% nitroglycerin ointment is available for rubbing the skin in the heart area. In this case, nitroglycerin is slowly absorbed, its effect begins after 1 hour and lasts about 6 hours.

Patches and discs provide a therapeutic concentration of the drug in the blood for 24 hours, that is, they have a prolonged effect.

The most common transdermal systems (available in patch form):

— Nitroderm TTS;

— Deposit;

— Nitra disk, etc.

These forms of the drug are indicated for the prevention of angina attacks (before physical activity, in patients with nocturnal angina attacks).

In addition, it should be said about such a dosage form of nitroglycerin as a solution for intravenous use (perlinganite, nitroject). It is used only in an intensive care unit to relieve anginal status in patients with acute myocardial infarction.

Side effects (when taking the above dosage forms of nitroglycerin):

- severe headache associated with paralysis (sharp dilatation) of cerebral vessels and compression of pain receptors. The pain may be so intense that the patient may refuse to take the drug. After 1-2 weeks the pain goes away on its own. To relieve pain, you can prescribe ergot drugs (dihydroergotamine, dihydroergotoxin), analgin, caffeine;

- a sharp drop in blood pressure;

- weakness;

- reflex tachycardia;

- increased intracranial and intraocular pressure;

- feeling of heat, redness of the face and skin of the upper half of the body.

At the end of the 60s of our century, with the help of new technologies, namely, by using the microencapsulation method of nitroglycerin, its prolonged-release preparations for oral use were created: Sustak (Yugoslavia), Sustonit (Poland).

When entering the gastrointestinal tract, the tablets dissolve and the nitroglycerin gradually released from the microcapsules begins to act. Therefore, these tablets are indicated only for the prevention of angina attacks. The effect of sustak lasts up to 4-5 hours. These drugs are available in two forms:

- mite - contains 2.6 mg of nitroglycerin;

- forte - contains 6.4 mg of nitroglycerin.

Among such drugs: Nitrogranulong (contains 5.2 mg of nitroglycerin), Nitro-Mac Retard, Nitromint, etc. Indications for use are the prevention of angina attacks in patients with coronary artery disease. Since 1980, buccal (cheek) dosage forms of nitroglycerin have been widely used - the drugs susadrin, sustabucal, nitrobucal, nitrogard, suscard. The domestic pharmaceutical industry produces the drug TRINITROLONG (Trinitrolong; in the form of thin polymer plates 1.5-2 mm thick, containing 1.0; 2.0 or 4.0 mg of nitroglycerin). The Trinitrolong plate is placed in a strictly defined place - on the mucous membrane of the upper gum above the canines and small molars. Thanks to special adhesive properties, the plate instantly sticks to the mucous membrane in the oral cavity. Next, the process of uniform gradual resorption of the plate begins. As it dissolves, nitroglycerin enters directly through the mucosa into the systemic circulation, bypassing the liver. At the same time, a therapeutic concentration of nitroglycerin is maintained in the blood plasma for a long time. The effect of Trinitrolong begins within a few minutes and lasts for several hours.

Indications for use:

- relief of angina attacks;

- prevention of angina attacks.

There are several other preparations of organic nitrates, but with a slower and longer-lasting effect than nitroglycerin, for example, NITROSORBIDE (isosorbide dinitrate, isomack-retard, isoket, isodinite, etc.; available in the form of tablets for oral use at 5, 10, 20 mg). The onset of action is after 30-50 minutes, the effect lasts up to 4-6 hours. This drug is used only to prevent angina attacks. There are other dosage forms of this drug: solutions for intravenous administration (isoket or isodinite for infusion), aerosols for inhalation (isoket aerosol, isoMac spray), transdermal forms (isoket ointment, isoMac spray TD).

BETA BLOCKERS

This group of drugs has found widespread use in recent years for the treatment of a number of therapeutic diseases.

There are non-selective beta-blockers (timolol, propranolol, sotalol, nadolol, oxprenolol, pindolol, etc.) and selective beta-1 blockers (metoprolol, atenolol, acebutolol, etc.).

The therapeutic activity of this group of drugs for angina pectoris is due to their ability to block the influence of the sympathetic nervous system on the heart, which leads to a decrease in its work and a decrease in myocardial oxygen consumption.

ANAPRILIN (propranolol, inderal, obzidan; tablets of 0.01 and 0.04) is a non-cardioselective beta-blocker without its own sympathomimetic activity with a short-term effect. Anaprilin reduces all 4 functions of the heart, primarily myocardial contractility. The most pronounced effect is observed within 30-60 minutes, the therapeutic effect, due to the short half-life (2.5-3.2 hours), lasts 5-6 hours. This means that the drug should be taken 4-5 times a day. Anaprilin is used only for the prevention of angina attacks, exclusively in its typical form, since in the vasospastic form of angina against the background of blocked beta-adrenergic receptors, catecholamines will increase spasm of the coronary vessels.

Side effects: decreased myocardial contractility, bradycardia, AV block, bronchospasm; nausea, vomiting, diarrhea, general weakness, dizziness, and sometimes allergic reactions. Possible symptoms of depression. With the simultaneous use of hypoglycemic agents, there is a risk of hypoglycemia.

CALCIUM ANTAGONISTS (CALCIUM CHANNEL BLOCKERS)

The importance of calcium in the body's performance of vital functions is enormous. Calcium is necessary to regulate the processes of excitation and inhibition in both smooth and skeletal muscles. Coming from the external environment or from the intracellular depot under the influence of various stimuli, calcium interacts with calcium-binding proteins of the cytoplasm, which act as regulators.

For the heart and blood vessels, the importance of calcium is somewhat different, which is associated with the predominance (in the heart or blood vessels) of specific calcium-binding proteins. Myocardiocytes have a special protein - troponin (leiotonin), and vascular smooth myocytes have a special heat-stable calcium-dependent protein calmodulin. Depending on whether they act more on troponin or calmodulin, some calcium channel blockers have a greater effect on the heart and others on the blood vessels. For example, a calcium antagonist such as VERAPAMIL has a greater effect on the heart (its antiarrhythmic effect is very important).

The antianginal effect of drugs in this group is associated both with their direct effect on the myocardium and, above all, with their effect on peripheral hemodynamics. Calcium antagonists block calcium entry into the smooth muscle cell, thereby reducing its ability to contract. The effect of these drugs on the coronary vessels is characterized as antispastic; as a result, coronary blood flow increases, and due to the effect on peripheral vessels, blood pressure decreases. This reduces the afterload on the heart and improves blood flow in the ischemic zone. These drugs reduce the mechanical work of the heart and the myocardial oxygen demand, and increase the number of collaterals. When used in patients, the frequency and intensity of angina attacks decreases and tolerance to physical activity increases.

Nifedipine is most often used for this purpose (synonyms: phenigidine, corinfar, cordafen, cordipine, etc.; tab. 0, 01). The effect occurs within 15-20 minutes and lasts 4-6 hours. The drug is inferior to nitroglycerin in terms of antianginal effect.

Unlike verapamil, the drug has weak antiarrhythmic activity and greatly reduces diastolic pressure. It relaxes the coronary vessels especially well in vasospastic angina. In general, for this form of angina, calcium antagonists are preferable. In addition to nifedipine, second-generation nifedipine derivatives created in the 80s: isradipine (syn.: lomir) are used for the chronic treatment of angina.

This group of drugs produces a small number of side effects: decreased blood pressure, headaches, muscle weakness, nausea, constipation. Continuous use of drugs for 2-3 months leads to the development of tolerance.

For angina pectoris with bradycardia, use an ephedrine derivative - OXYPHEDRINE (ildamen, MYOPHEDRINE; tablets of 0.016). The drug has partial agonist activity towards beta-1 receptors of the heart, has a direct coronary dilatatory effect, and increases myocardial contractility without excessively increasing oxygen demand. Another similar drug NONACHLAZINE, domestically produced, is available in tablets of 0.03 - a phenothiazine derivative. The drug has a positive inotropic effect and reduces the tone of the coronary arteries.

In the treatment of patients with angina pectoris, a drug such as dipyridamole (chimes), a pyrimidine derivative, is also used. This drug acts on blood microcirculation in small vessels, preventing platelet aggregation, increases the number of collaterals and the intensity of collateral blood flow, however, it can cause a “steal” symptom, especially when administered intravenously in patients with severe coronary atherosclerosis, since the drug causes dilation of those vessels who are not affected by sclerosis. On the other hand, this drug is indicated for patients who have angina pectoris, and also due to various reasons, increased blood clotting.

Products such as validol have a reflex type of action. This drug contains menthol (25% solution of menthol in menthol ester of isovaleric acid). It is a weak antianginal agent, has a sedative effect and a moderate reflex vasodilator effect. Indicated for mild forms of angina.

Basic principles of pharmacotherapy

IHD is a chronic “benign” disease, and therefore the main goals of its treatment are to reduce the number, duration and severity of attacks of anginal pain and improve the prognosis, which is determined by the risk of developing cardiovascular complications such as AMI, life-threatening arrhythmias and chronic heart failure (CHF).

Currently, the effect on the prognosis of patients with coronary artery disease has been proven only for statins, angiotensin-converting enzyme inhibitors - ACE inhibitors (ramipril and perindopril), antiplatelet drugs and β-blockers (after AMI). In this review, we will focus on therapies that can primarily alleviate the condition of patients with exertional angina.

Antianginal and anti-ischemic therapy of chronic ischemic heart disease

Beta-blockers (BABs) are rightfully considered the cornerstone of the treatment of coronary artery disease. In the absence of absolute contraindications, selective β1-blockers should be prescribed without fail to all patients with a history of AMI due to their ability to increase the survival of such patients and reduce the incidence of recurrent AMI.

Cardioselective beta blockers serve as the main tool for the treatment of angina pectoris, and antianginal drugs of other groups should be used only after the potential of the beta blocker is maximally used [7].

It is extremely important to achieve target heart rate values ​​(HR, 55–60 beats per minute), without which antianginal therapy cannot be considered optimal. If, while using beta blockers, a patient with stable angina continues to experience attacks of anginal pain, an attempt should be made to reduce the heart rate to 50 beats per minute, unless atrioventricular (AV) block develops against this background [7]. In this case, heart rate should be measured in the morning before taking the next dose of the drug.

Today, one can often find patients taking large doses of nitrates due to severe anginal pain, but not receiving optimal beta blocker therapy.

In most cases this is due to the following factors:

• unjustified fears regarding the development of side effects, which are rare (primarily various blockades and broncho-obstructive syndrome);

• the desire to prescribe a low dose of beta blocker as part of combination antianginal therapy (the real effectiveness of which may be significantly inferior to full-dose beta blocker therapy);

• difficulties in comparing dosages of different beta blockers (today doctors often use bisoprolol at a dose of 10 mg, but avoid using metoprolol at doses above 150 mg/day, and therefore patients receiving metoprolol often have a higher heart rate);

• difficulties associated with titrating beta blockers (this especially applies to the lipophilic carvedilol, which has a difficult to predict relationship between dosage and effectiveness);

In case of intolerance to beta blockers, they can be replaced with calcium channel blockers (CCBs). It should be especially noted that none of the controlled studies of CCBs showed their effect on the survival of patients with angina pectoris.

In patients with bronchial asthma, extended-release verapamil, which has a pulse-sparing effect, can be considered the drug of choice. It should be remembered that, compared with beta blockers, its use in elderly patients is associated with a higher risk of developing AV block of II–III degrees. If a significant slowdown in AV conduction occurs during the use of verapamil, Holter ECG monitoring is justified, including to exclude second-degree AV block at night.

Dihydroperidine CCBs have a weaker antianginal effect than non-dihydroperidine CCBs, but can be successfully used by patients with conduction disorders. In a number of patients, these drugs can lead to the development of subendocardial ischemia [7].

If there are contraindications to the administration of beta blockers, primarily in the presence of AV conduction blockade of the 1st degree or bronchial asthma, the If-channel inhibitor ivabradine can be used as a pulse-lowering drug. The antianginal effect of ivabradine is realized only due to a decrease in heart rate, which is why it is “in strength” inferior to beta blockers, which have a multifaceted mechanism of anti-ischemic and cardioprotective actions. It should be noted that in a large clinical trial that included more than 10 thousand patients with coronary artery disease and heart failure, ivabradine did not show an effect on cardiovascular mortality and the frequency of hospitalizations caused by AMI and heart failure [8].

Classification of antianginal drugs

Depending on the mechanism of action, antianginal drugs are classified into:

• drugs that increase oxygen delivery to the heart: menthol, validol (menthol in isovaleric acid menthyl ester), dipyridamole;
• drugs that reduce the heart's need for oxygen: β-blockers (propranolol, metoprolol, atenolol, betaxolol, bisoprolol, nebivolol, carvedilol);
• bradycardic drugs (ivabradine);

Combined antianginal therapy

The presence of complaints of anginal pain in patients with coronary artery disease receiving first-line therapy dictates the need to add additional anti-ischemic drugs. The algorithm for their application is presented in Fig. 2.

Before initiating combination antianginal therapy, it is necessary to ensure that the target heart rate is achieved with the use of beta blockers. In case of intolerance to beta blockers, not associated with the presence of blockades, an attempt should be made to prescribe verapamil or diltiazem in monotherapy.

Adding ivabradine to a beta blocker is justified only if the heart rate with the maximum dose of beta blocker (20 mg bispoprolol or 400 mg metoprolol) exceeds 70 beats per minute or if titration of the beta blocker dose is impossible (for example, due to chronic obstructive pulmonary disease or clinically significant vascular atherosclerosis lower extremities). The use of ivabradine together with small doses of beta blockers to reduce heart rate in patients who tolerate beta blockers well, due to the lack of evidence, should be considered irrational.

If, against the background of the target heart rate, the patient continues to be bothered by anginal pain, it is optimal to prescribe a CCB as a “second” drug [11]. In some cases, long-acting nitrates/NO donors or nicorandil can also be used.

Complaints about the presence of anginal pain in patients with coronary artery disease receiving therapy with two antianginal drugs serve as a direct indication for coronary angiography with subsequent decision on the tactics of revascularization. Currently, daily combination therapy with three or more antianginal drugs can be considered justified only for those patients in whom revascularization is not possible for any reason.

Selection and control of antianginal therapy using Holter monitoring

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Author: Tikhonenko V. M.

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Coronary heart disease (CHD) remains the main disease in the structure of cardiovascular mortality. Although surgical methods for the treatment of coronary artery disease have recently been increasingly used, the vast majority of patients are treated conservatively. Empirically prescribed antianginal therapy is not always effective in a particular patient. To objectify the individual effectiveness of various drugs, a technique using paired bicycle ergometer tests is used, however, it does not reflect the effectiveness of the drug in the conditions of the patient’s normal daily life and does not provide sufficient information about the safety of the therapy.

The proposed method makes it possible to determine an effective antianginal drug during the patient’s normal activities, to identify the side effects of the drugs received and, thereby, makes it possible to make the prescribed therapy safe for the patient.

Description of the method

To determine the initial exercise tolerance (ETT) and the severity of its spontaneous fluctuations, the patient initially undergoes Holter monitoring for 24 hours while antianginal therapy is discontinued. To relieve attacks of angina, the patient can take nitroglycerin. If complete withdrawal is not possible, it is advisable to conduct a study against the background of monotherapy with an antianginal drug, preferably long-acting.

During the study, the patient performs 4 or more physical activities in the form of climbing stairs at certain times of the day: in the morning, after lunch, in the evening and immediately after a night's sleep. It is recommended to carry out stair tests at 10, 13, 16, 19 hours and after rising in the morning. Climbing stairs is carried out at the patient’s usual, uniform pace, until any complaints appear (harbingers of anginal pain, severe shortness of breath, fatigue, palpitations, etc.). In the diary, the patient indicates the time of the beginning and end of the ascent, the number of steps of the stairs climbed. The moments of the beginning and end of the rise are additionally marked by pressing the “action” button on the monitor.

To assess the physical function, knowing the patient’s weight and the number of steps completed, the volume of work performed (ORV, kg x m) is calculated as the product of the patient’s weight (kg) by the number of steps and the height of the step (m). Since the step height is usually 0.15 meters:

ORR = 0.15 x patient weight x number of steps.

If ischemic ECG changes occur before the patient has finished climbing the stairs, for example, due to the later appearance of anginal pain than ECG changes, the FN will characterize the threshold OVR - performed by the patient before the development of ischemic changes. Taking into account the uniform pace of ascent up the stairs, in this case the threshold ORR will be part of the total ORR, proportional to the time of ascent before the development of ischemic ECG changes.

The software of some monitor systems, for example, "Cardiotechnics-4000" (INKART, St. Petersburg), when forming a conclusion, allows you to automatically calculate not only the general and threshold ORR, but also the load power, heart rate before the development of an ischemic episode and the threshold heart rate when it occurs . With combined ECG and blood pressure monitoring, the “pulse x pressure” index is additionally calculated (Fig. 1).

Rice. 1. Daily monitoring data: a - graphs of heart rate, ST segment displacement, blood pressure and ECG fragments before and during the development of an ischemic episode (the arrow indicates the intake of 10 mg of nitrosorbide) b - the results of staircase loads performed before and after 2, 3, 5 and 8 hours after taking the drug, where por.HR is the threshold heart rate, IR is the Robinson index, ORR is the threshold volume of work performed (reduced by 10 times in the graph).

To assess fluctuations in physical fitness, the threshold ORR is compared when performing staircase loads during the 24-hour period of the study without taking antianginal therapy. The difference between the maximum and minimum indicators is determined, which will subsequently be used to determine the increase in threshold ORR as a criterion for the effectiveness of the antianginal drug.

To determine the effectiveness of antianginal drugs, test single doses of each drug are carried out at an average dose under the control of daily ECG monitoring according to the following scheme: the patient performs a staircase test before a single dose, then 2, 5 and 8 hours after taking the drug. Recommended regimen: 10:00-10:30 – initial staircase test, 11 o’clock – taking the drug, staircase tests at 13, 16, 19 o’clock.

The effectiveness of the drug is judged by the increase in threshold ORR during stair exercise after taking it compared to the initial threshold ORR when climbing stairs before taking it in the morning. The drug is considered effective when the threshold ORR increases by an amount that is twice the spontaneous fluctuations in ORR. If myocardial ischemia does not develop while taking the drug during exercise, then the drug can be considered highly effective. The duration of the effect can be judged by the dynamics of the threshold ORR during staircase loads after 2, 5 and 8 hours from a single dose of the drug.

When an effective drug is determined based on the results of a trial dose, it is prescribed in a standard regimen as monotherapy, or, if necessary, as part of combination therapy. After 3-5 days of a course of therapy, daily ECG monitoring is carried out to monitor the effectiveness of the prescribed treatment with the implementation of staircase loads and assessment of physical function similar to previously conducted studies. Depending on the results, the attending physician decides on the need to intensify therapy or replace the antianginal drug.

To reduce the time required for selecting therapy and more quickly determine an effective antianginal agent, it is rational to start testing with a drug whose effectiveness in a given patient is more likely. When determining it, it is necessary to take into account the conditions for the occurrence of episodes of myocardial ischemia. Therefore, during the collection of complaints and anamnesis, special attention is paid to the patient’s presence of morning spasmophilia, starting angina, cold dependence, the phenomenon of “passing through pain”, anginal attacks at rest, especially in the early morning hours, fluctuations in exercise tolerance, indicating the presence of angina in the genesis dynamic component of coronary obstruction. If signs of vasospasm are detected during history taking, testing of antianginal drugs should begin with calcium channel blockers. If a patient develops anginal pain with a stable level of physical activity, which indicates the predominance of the fixed component of coronary stenosis, it is most likely that beta blockers will be more effective.

During initial monitoring, data can be obtained that will also help in choosing the first drug to be tested. With pronounced fluctuations in the threshold ORR (more than 50%), threshold heart rate (more than 25 beats per minute), the development of ischemic ST shift without a previous increase in heart rate, the appearance of episodes of ST elevation outside the area of ​​the previous infarction, one can judge the predominance of the vasospastic component in the genesis of the attack and greater likelihood of the effect of coronary lytics. The predominance of fixed obstruction is characterized by stable threshold ORR and heart rate, a clear connection between attacks and exercise. In such patients, as a rule, drugs that reduce myocardial oxygen demand are more effective.

Also, when analyzing monitorograms, additional information about the patient can be obtained that influences the choice of therapy: the presence of cardiac arrhythmias, their number, connection with episodes of myocardial ischemia, initial tachycardia or bradycardia. With combined monitoring, additional data will be obtained on the daily blood pressure profile, the presence of arterial hyper- or hypotension, and blood pressure response to exercise. During trial administration of antianginal drugs, along with assessing their effectiveness, it will be possible to assess their effect on heart rate, cardiac arrhythmias, and hemodynamic status.

When conducting trial doses, it is possible to detect side effects of the drug that are not always felt by the patient and, accordingly, may not be detected in a timely manner. The most common are conduction disturbances when taking beta blockers or calcium antagonists, significant decreases in blood pressure, the appearance of a pronounced increase or decrease in heart rate, an increase in the number of episodes of myocardial ischemia against the background of tachycardia, and the proarrhythmic effect of drugs.

Thus, when using this technique, it is possible to choose not only an antianginal drug that is effective for a given patient, but also one that has a positive effect on other manifestations of the disease present in the patient, and, most importantly, is safe for use in this patient.

Results of applying the method

Selection of therapy according to the described method was carried out in 20 patients with coronary artery disease, exertional angina of functional class II-III, aged from 41 to 64 years (average age 55 years). In 7 patients, IHD was combined with stage II hypertension. On a dynamic ECG, when performing staircase loads, they recorded ST-T segment depression of more than 1 mm from the initial level, at a point located 0.08 seconds from point j, and lasting more than 30 seconds. In most cases, these episodes of ST-T shift were accompanied by anginal pain.

For trial use we used: isosorbide dinitrate (nitrosorbide at a dose of 20 mg orally), isosorbide-5-mononitrate prolonged action (monocinque-retard 50 mg), beta-blocker (metoprolol 50 mg), calcium channel blockers dihydroperidine derivatives (adalat SL 20 mg) and phenylalkylamine derivatives (finoptin-retard 100 mg).

In 5 patients (0.25), all five tested drugs were effective, the effectiveness of four drugs was observed in 9 patients (0.45), three drugs were effective in 3 patients (0.15), in 2 patients (0.10 ) two out of five drugs were effective, only one drug was effective in 1 patient (0.05). There were no patients in whom no effect of either drug was observed. The distribution of the pronounced effect by the number of drugs was as follows: a pronounced effect of five drugs was observed in 2 people (0.10), four drugs - in 5 (0.25), three - in 4 patients (0.20), two – in 5 patients (0.25) and one drug – in 4 patients (0.20).

In general, in the group of patients, according to the study results, the greatest effectiveness was observed with metoprolol. 2 hours after administration, the drug was effective in 19 people (0.95), and in 16 of them (0.80) it was highly effective. 5 hours after administration, the effect of the drug was observed in 13 patients (0.65), in 7 (0.35). After 8 hours, the drug continued to act in 9 patients (0.45), the pronounced effect persisted in 2 patients (0.10).

The next most effective drug in this group of patients was isosorbide-5-mononitrate. 2 hours after taking it, in 15 patients (0.75) the drug was effective, in 11 (0.55) it was highly effective. After 5 hours, the effect of the drug remained in 16 patients (0.80), in 10 patients (0.50) it was pronounced. After 8 hours, the effect was retained in 9 people (0.45), and pronounced in 6 (0.30).

Calcium channel blockers (derivatives of dihydroperidine and phenylalkylamine) demonstrated relatively identical effects: after 2 hours, finoptin-retard and adalat had an antianginal effect in 11 patients (0.55), a pronounced effect was observed in 9 people (0.45). After 5 hours, the effect of adalat also remained in 11 patients (0.55), a pronounced effect - in 7 (0.35), when taking finoptin-retard - slightly less - in 9 (0.45) and in 7 (0.35 ) respectively. Interestingly, after 8 hours, the antianginal effect of finoptin was noted in 4 patients (0.20), pronounced in 1 (0.05), and after taking adalat - in only 2 patients (0.10) and in none of the patients. no significant effect was observed.

The effectiveness of nitrosorbide 2 hours after administration was noted in 12 patients (0.60), in 7 of them (0.35) it was pronounced. After 5 hours, the effect continued to be observed in 8 patients (0.40), and remained pronounced in 2 (10.0). After 8 hours, the effect of the drug remained in only 2 people (0.10), and none of them had a pronounced antianginal effect.

Thus, it was possible to select an effective drug for all patients; in most of them, the drug had an antianginal effect for more than 5 hours; a highly effective drug was prescribed to 16 patients (0.80). Most patients had previously taken empirically selected therapy; in a third of them, previously taken drugs were ineffective. The drug, which has a pronounced antianginal effect, was previously taken by only 5 (0.25) patients.

During trial administration of the drugs, the following side effects were discovered, which subsequently did not allow the use of these medications for long-term antianginal therapy. In one patient, during a trial dose of 50 mg of metoprolol at the height of the drug's action, episodes of sinoatrial blockade with pauses lasting more than 2 seconds were recorded, and when monitoring during discontinuation of therapy, no evidence of conduction disturbances was detected in the patient. It is also noteworthy that the subjective tolerability of the beta blocker was good, and the dynamics of anginal pain was positive. It is obvious that in this case, despite the effectiveness of the drug, it could not be recommended for long-term use as an antianginal agent.

Several patients who did not have concomitant arterial hypertension developed a pronounced decrease in systolic blood pressure by more than 30 mm Hg during single doses of drugs. (up to the level of 90-95 mm Hg), diastolic blood pressure by more than 20 mm Hg. (up to 50-60 mm Hg). In two patients (0.10 from the study group), an excessive decrease in blood pressure was observed while taking Adalat SL, and in three (0.15) while taking metoprolol. In four people (0.20), a similar blood pressure reaction was observed after taking nitrates; in one of them, after taking nitrosorbide while climbing stairs at a height of load, accompanied by ischemic changes on the ECG, a decrease in blood pressure was recorded from 96/75 to 80/49 mm Hg .st.

In 5 patients (0.25), while taking nitrates and adalat, severe reflex tachycardia was observed, which in some cases led to a decrease in FTN and an increase in the number of episodes of ischemia. Worsening of fluctuations in FN, its decrease with the appearance of episodes of myocardial ischemia at rest was observed while taking a beta blocker in 2 people (0.10).

The vast majority of the described complications were not subjectively felt by patients, and therefore their detection without the use of Holter monitoring would have been impossible. Thus, the use of this technique makes it possible to determine not only an individually effective, but also a safe antianginal drug for the treatment of a patient with angina pectoris.

Literature

1. Aronov D.M. Lupanov V.P. Mikheeva T.G. Functional tests in cardiology // Cardiology.-1995.-Sh2.-p.55
2. Bochkareva E.V. Kokurina E.V. Kondratyev V.V. Metelitsa V.I. The effectiveness of the main antianginal drugs in patients with angina pectoris depending on the presence of painless episodes of myocardial ischemia //Cardiology -1998.-N2.-C.20-24
3. Gasilin V.S., Sidorenko B.A. Angina pectoris, - M: Medicine, 1985.-p.238
4. IlyinaG.V. Konstantinov V.O. Lipovetsky B.M. Plavinskaya SI. Tests with dosed physical activity (on a bicycle ergometer and treadmill). - Method indicated according to clinical. pathophysiol. and functional Diagnostics: ed. E.V.Maistrakh and B.M.Lipovetsky.-L, 1980.-p.25.
5. Kobalava Zh.D., Kotovskaya Yu.V., Tereshchenko S.N., Moiseev VS Clinical significance of 24-hour blood pressure monitoring for choosing treatment tactics for patients with arterial hypertension. //Cardiology.-1997.-N9.-p.98-100.
6. Kondratiev V.V., Kokurina E.V., Bochkareva E.V. Silent myocardial ischemia. Current state of the problem and clinically significant aspects of its development. I. Prevalence and prognostic significance of silent myocardial ischemia. //Cardiology, - 1997.-N1.-C.72-75.
7. Metelitsa V.I. Pharmacotherapy of stable angina (rationale for standard treatment). //Cardiology.-1997.-N10.-p.72-74.
8. Tikhonenko V.M., Gusarov G.V. Determination of the vasospastic genesis of angina attacks according to daily ECG monitoring.//Cardiology.- 1989.-N: 1.-P.52-56.

Management of patients with refractory angina when revascularization is impossible

The concept of refractory angina includes the following three factors:

1. Myocardial ischemia;

2. Anginal pain;

3. Impossibility of revascularization [12].

The following categories of patients are usually considered “inappropriate” candidates for revascularization [12]:

• patients with vasospastic angina;

• patients with suspected microvascular dysfunction (with objective signs of myocardial ischemia in the absence of significant coronary artery stenosis or with normally functioning bypass grafts);

• patients with a small volume of ischemic myocardium, when it is impossible to perform angioplasty (for example, with a hemodynamically significant symptom-related distal single-vessel lesion), stratified into the low-risk group;

• patients with diffuse, “thread-like” coronary atherosclerosis (typically damage to two or more coronary arteries, involving the distal bed with arteries < 1 mm in diameter);

• persons with a very high perioperative risk (due to severe concomitant diseases, this group often includes elderly people with multi-vessel disease).

It must be emphasized that the conclusion about the impossibility of revascularization should be made by a multidisciplinary team and this status can be revised taking into account changes in the patient’s condition and the possibility of attracting an experienced surgical team capable of operating on high-risk patients.

Next, we will consider drugs that can be used in “maximized” antianginal therapy regimens for such patients.

One of the highly effective antianginal drugs is nicorandil, an activator of ATP-dependent potassium channels in the plasma and mitochondrial membranes with nitrate-like properties. Usually, nicorandil is used in cases of intolerance to beta blockers and cCBs, but it can also be used as part of combination therapy. In a double-blind study involving patients with stable angina, nicorandil was shown to lead to a significant increase in exercise capacity, time to onset of anginal pain and ST depression ≥ 1 mm [13]. In the IONA randomized clinical trial (RCT), which included more than 5000 patients with chronic ischemic heart disease, nicorandil, prescribed at a dose of 20 mg twice daily, demonstrated superiority over placebo in terms of its effect on the incidence of hospitalization, which was regarded as a reduction in the risk of developing unstable angina. In approximately a third of cases, a headache may occur in the first days after taking nicorandil [13], and there is also a risk of developing tolerance to its action.

Another promising drug is ranolazine, which partially inhibits fatty acid oxidation and blocks late sodium channels (operating in diastole). Ranolazine is able to neutralize ischemia-induced sodium and calcium “overload” of cardiomyocytes, improving perfusion and diastolic function of the myocardium. In addition, it has an antiarrhythmic effect and is able to reduce the level of glycosylated hemoglobin in patients with a combination of coronary artery disease and diabetes.

Several randomized, double-blind studies (MARISA, ERICA, CARISA) have shown that ranolazine reduces the frequency of angina episodes, nitrate intake and increases exercise tolerance without clinically significant effects on heart rate and blood pressure [14]. However, in the MERLIN TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) study, in which patients with ACS were observed for a year, ranolazine did not show an effect on the risk of AMI and cardiovascular mortality. When treating angina in people with microvascular dysfunction, it is also possible to use drugs with analgesic properties, such as the phosphodiesterase inhibitor aminophylline, the antidepressant imipramine. Methods of psychotherapy and cardiac rehabilitation can also be used [15].

Non-drug methods that can alleviate the condition of some patients with refractory angina include enhanced external counterpulsation, shock wave therapy and electrical stimulation of the spinal cord [16]. An invasive procedure such as transmyocardial laser revascularization, according to a meta-analysis of 7 studies (n = 1137), cannot be recognized as an effective treatment for refractory angina [17].

Currently, the effectiveness of such experimental methods for treating resistant angina is being clarified, such as cell therapy and the use of growth factors that activate angiogenesis, including granulocyte-macrophage colony-stimulating factor, which can “mobilize” bone marrow stem cells to participate in coronary angiogenesis.

Features of the treatment of coronary heart disease

To relieve attacks of angina, organic nitrates are most often used: nitroglycerin, isosorbide dinitrate, as well as the calcium antagonist nifedipine and the vasodilator drug validol - sublingually (under the tongue). With this route of administration, the effect occurs very quickly - within 1-3 minutes.

To prevent angina attacks, beta-blockers, calcium antagonists, ivabradine, isosorbide mononitrate, isosorbide dinitrate, pentaerythrityl tetranitrate, molsidomine, as well as cardioprotective agents (trimetazidine, meldonium) are used orally.

β-blockers and calcium antagonists additionally reduce blood pressure (antihypertensive effect) and normalize heart rhythm (antiarrhythmic effect), and are therefore indicated for the treatment of angina pectoris in patients with hypertension and/or arrhythmia.

Amiodarone has a pronounced antiarrhythmic effect, so it is used for angina pectoris against the background of heart rhythm disturbances - arrhythmias.

Tolerance (addiction) develops to organic nitrate preparations - a decrease in their effect with prolonged use. To avoid tolerance when taking organic nitrates, you need to take breaks of several days or at least overnight. In case of addiction development, preference should be given to a drug with a nitrate-like effect - molsidomine.

Metabolic and antioxidant therapy

“Antioxidant therapy” fits harmoniously into traditional treatment regimens for coronary heart disease thanks to the use of drugs such as statins, ACE inhibitors, and carvedilol, which have a pronounced antioxidant effect. At the same time, the beneficial anti-ischemic, cardioprotective and anti-atherosclerotic effects of “pure” antioxidants (bioflavonoids, polyphenols, vitamins, glutathione, emoxypine, ethylmethylhydroxypyridine), shown in various biological models, have not currently been demonstrated in any large clinical study. Several prospective placebo-controlled RCTs have shown neutral and even negative effects of vitamins [18]. It was recently discovered that a number of experiments in which the positive effects of quercetin were shown were carried out with gross violations of biomedical ethics [19]. Thus, the use of antioxidants by patients with coronary artery disease, including as part of dietary supplements, is not justified.

Metabolic drugs also have a rather poor evidence base. In this regard, the European Agency for the Evaluation of Medicines has reduced the range of indications for the use of the drug trimetazidine, which can only be used as an additional antianginal agent in case of intolerance or insufficient effectiveness of first-line therapy [20]. Angina caused by microvascular dysfunction can be indicated as an area of ​​rational use of trimetazidine as part of complex antianginal therapy.

In Russia, the drug meldonium, an analogue of γ-butyrobetaine, is also used in the treatment of patients with coronary artery disease. Meldonium inhibits the enzyme γ-butyrobetaine hydroxylase, which leads to a slowdown in the biosynthesis of carnitine and the transport of long-chain fatty acids across the mitochondrial membrane in vitro (at the same time, β-oxidation of fatty acids slows down, and intracellular metabolism “switches” to glycolysis). The drug L-carnitine has the opposite effect, accelerating the transport of long-chain fatty acids into mitochondria, the β-oxidation of which is much more energetically beneficial, but also requires larger amounts of oxygen. The question of which of these strategies can be considered optimal in clinical practice, when long-term chronic myocardial ischemia can give way to acute with the development of ACS, remains open.

Modern approaches to antianginal therapy for coronary heart disease: focus on sydnonimines

Hippocrates pointed out that “pain in the region of the heart, which appears with a certain frequency in old people, is an omen of sudden death.” Bartoletti (1576–1630), Harvey (1527–1658), Morgagni (1684–1771) described cases of severe acute pain in the left half of the chest in elderly and old people, accompanied by anxiety, fear, suffocation, and fainting during an attack. The first description of classical angina belongs to W. Heberden (1772), who first used the term “angina pectoris” to refer to it in his report to the Royal Society of London and described in detail and accurately the clinical picture of angina pectoris (“Heberden’s angina pectoris”). Parry (1799) was the first to point out the connection between angina pectoris and changes in the structure of the heart and damage to the coronary arteries. He was the first to suggest that anginal (angina) pain occurs due to a decrease in the blood supply to the heart. In 1909, at the first congress of Russian therapists, a classic description of the clinical picture of myocardial infarction was given in the fundamental work of V.P. Obraztsova and N.D. Strazhesko “On the symptomatology and diagnosis of coronary artery thrombosis.” (Nikolai Dmitrievich Strazhesko - later a prominent Soviet therapist, organizer of science, academician of the USSR Academy of Sciences and the Ukrainian Academy of Sciences, Hero of Socialist Labor). Currently, cardiovascular diseases firmly hold 1st place among all causes of mortality in economically developed countries, being one of the most common pathologies among chronic non-communicable diseases. Despite this, starting from the second half of the 20th century. Countries in Western Europe and North America have seen a steady decline in mortality from cardiovascular diseases. This trend has been observed in recent years in Eastern European countries [1,2]. In the Russian Federation, more than 1 million people die from cardiovascular diseases, i.e. approximately 700 people per 100 thousand population. IHD often develops in able-bodied, creatively active individuals, significantly limiting their social and work activity, exacerbating socio-economic problems in society [1–4]. The basis for reducing morbidity and mortality in coronary artery disease is the fight against controllable risk factors for the disease. Thus, even in the classic Framingham study, launched in the USA in 1949, it was shown that the risk of developing coronary artery disease is associated with high blood pressure, high cholesterol levels, smoking, impaired glucose tolerance and left ventricular hypertrophy (results of the Framingham study are available on the Internet – website of the US National Heart Institute - www.nhlbi.nih.gov/about/framingham, 1998). 1. Non-modifiable (unchangeable) risk factors (RF) for IHD [5–7]: • age over 50–60 years; • gender (male); • burdened heredity. 2. Modifiable (changeable) risk factors [5–7]: • dyslipidemia (increased blood levels of cholesterol, triglycerides and atherogenic lipoproteins and/or decreased levels of anti-atherogenic HDL); • arterial hypertension (AH); • smoking; • obesity; • carbohydrate metabolism disorders (hyperglycemia, diabetes mellitus); • physical inactivity; • chronic stress; • poor nutrition; • hyperhomocysteinemia, etc. The combination of several risk factors in one person significantly increases the risk of IHD and, as a rule, aggravates its course. Pharmacotherapy for IHD involves mandatory preventive measures aimed at eliminating modifiable risk factors for IHD. An important role in this regard is given to the correction of hypertension, normalization of glucose levels in patients with diabetes mellitus, smoking cessation, comprehensive diet modification, control of excess weight, and physical training [1–3]. Treatment of angina pectoris involves the use of various groups of drugs that affect certain parts of the pathogenesis of coronary artery disease [3]. The main pathogenetic factor of IHD is impaired blood flow in the coronary arteries, leading to an imbalance between perfusion and metabolic needs of the myocardium. Myocardial oxygen demand is determined by the tension of the myocardial wall, heart rate and myocardial contractility and depends on metabolic processes, including those associated with transmembrane currents of calcium ions, on the volume of the ventricles of the heart and on the value of systolic blood pressure. Contractility depends on the nature of organic damage to the heart. The supply of oxygen to the heart muscle is directly related to the state of coronary blood flow, and the value of the latter depends on coronary resistance, and on the activity of the sympathetic nervous system, and on the level of perfusion pressure, and on the hemorheological properties of blood, in particular on the level of platelet aggregation [3,8– eleven]. The main goals of treatment for patients with coronary artery disease are: improving the patient’s quality of life by reducing the frequency of angina attacks and other symptoms relevant to the patient; prevention of acute myocardial infarction; improved survival. Drugs used for the treatment of coronary artery disease: • Antianginal agents: – nitric oxide donors – nitrates (nitroglycerin, isosorbide dinitrate, isosorbide-5-mononitrate); – sydnonimines (molsidomine (Sidnopharm)); – β-blockers (atenolol, bisoprolol, propranolol, etc.); – calcium antagonists (verapamil, diltiazem, etc.). • Antiatherosclerotic (hypolipidemic) agents. • Antiplatelet drugs (acetylsalicylic acid, clopidogrel). • Metabolic agents (trimetazidine). The goal of antianginal therapy for coronary artery disease is to reduce the number of angina attacks during the day until they are completely eliminated. This allows the patient to be quite active in everyday life and not feel discomfort in life due to many restrictions that preceded treatment. Such changes in the physical and psychological status of the patient objectively lead to a significant improvement in the quality of his life. In addition, in many cases, symptomatic therapy allows the patient to continue professional activity if it does not involve heavy physical labor. Antianginal treatment is considered successful in the case of complete or almost complete elimination of angina attacks and the patient’s return to normal activity (angina pectoris no more than functional class I - FC, when painful attacks occur only under significant loads) and with minimal side effects of therapy [13–15]. Nitrates. Nitrate preparations for “angina pectoris” have been used for about a century and a half. Nitroglycerin was discovered by Ascanio Sobrero in 1847 in Turin. Sobrero was also the first to draw attention to the severe headache caused by testing small amounts of nitroglycerin on the tongue. In 1849, K. Hering, studying the pharmacological effect of nitroglycerin on volunteers, confirmed that its use quite naturally causes headaches. In 1851, William Murrell first used nitroglycerin for angina pectoris in 1876, although at that time nitroglycerin was listed in the British Pharmacopoeia only as a drug for high blood pressure. Merrell, a medical practitioner who worked in two London hospitals at the same time, experimentally determined the optimal dosage from the balance of effectiveness and safety: a 1% alcohol solution of nitroglycerin, 3 drops with half an ounce of water, three times a day. In this form, the drug acted much longer than amyl nitrite, and more gently. Merrell's publication, summing up the results of several years of research, first on himself and then on patients with angina, entered the golden fund of medicine. A year later, pharmacist William Martindale developed a solid form of the drug: 1/100 grain of nitroglycerin in chocolate - which, in addition to being easier to use, had better digestibility. In 1882, the famous company Parke, Davis & Co. in the USA. began to produce nitroglycerin in five different dosages. The nitroglycerin industry boomed in 1900, with workers exposed to significant amounts of organic nitrate fumes. The results of exposure manifested themselves in the form of addiction to nitrates (as evidenced by the symptoms of “Monday disease”, disappearing by the end of the week) and withdrawal syndrome (Sunday heart attacks, “Sunday Heart Attacks”). The mechanism of the antianginal action of nitrates is to reduce the myocardial oxygen demand, which is caused by a decrease in ventricular wall tension, systolic blood pressure and ventricular volume. In addition, the antianginal effect is realized by improving the supply of oxygen to the myocardium: by increasing coronary blood flow, reducing coronary resistance, reducing spasm of the coronary arteries and increasing collateral blood flow. They also have platelet adhesion and aggregation inhibitory properties and, apparently, antithrombotic properties. The antiaggregation effects of nitrates can be considered as an important addition to their anti-ischemic action [1,2,12,14,15]. Nitrates easily penetrate all mucous membranes, as well as through the skin, so they are available in numerous dosage forms. These dosage forms can be divided into the following (Table 1) [2]: 1. Absorbed through the oral mucosa. These include: a) Classic nitroglycerin tablets for administration under the tongue, the so-called buccal (i.e., intended for application to the mucous membrane of the cheek or gum) dosage forms of nitroglycerin and isosorbitol dinitrate. b) Aerosols of nitroglycerin and isosorbitol dinitrate, which can have the same rapid effect as sublingual nitroglycerin tablets (the effect begins within 60–90 s), but are much more convenient to use. 2. For oral administration. These are various tablets and capsules of isosorbitol dinitrate, isosorbitol mononitrate and nitroglycerin. Tablets can be regular or special, made in such a way as to prolong the effect of the drug. 3. For cutaneous use. Nitroglycerin ointments and special nitroglycerin stickers (plasters) for application to the skin. Such patches are designed to last for 24 hours. 4. For intravenous administration. Ampoules with a solution of nitroglycerin and isosorbitol dinitrate. β-blockers. Drugs of this group have been used in the treatment of patients with coronary artery disease for more than forty years. β-blockers are the first choice drugs for the treatment of angina pectoris, especially in patients who have had a myocardial infarction, as they have a rapid antianginal effect and also lead to a reduction in mortality and the incidence of recurrent infarction with long-term use [1–3,14–15] . β-blockers cause an antianginal effect by reducing the myocardial oxygen demand (due to a decrease in heart rate - heart rate, lowering blood pressure and myocardial contractility), increasing the delivery of oxygen to the myocardium (due to increased collateral blood flow, its redistribution in favor of the ischemic layers of the myocardium - subendocardium), antiarrhythmic and antiaggregation effects, reducing calcium accumulation in ischemic cardiomyocytes. Calcium channel blockers (calcium antagonists). The main point of application of drugs of this group at the cellular level are slow calcium channels, through which calcium ions pass into the smooth muscle cells of blood vessels and the heart. In the presence of calcium ions, actin and myosin interact, ensuring contractility of the myocardium and smooth muscle cells. In addition, calcium channels are “involved” in generating pacemaker activity of sinus node cells and conducting impulses through the atrioventricular node. It has been established that the vasodilating effect caused by calcium antagonists occurs not only through a direct effect on the smooth muscles of the vascular wall, but also indirectly through potentiation of the release of NO by the vascular endothelium. This phenomenon was found in most dihydropyridines and isradipine, and to a lesser extent in nifedipine and non-hydropyridine drugs. For long-term treatment of angina from dihydropyridine derivatives, it is recommended to use only prolonged dosage forms or long-acting calcium antagonist drugs. Calcium channel blockers are powerful vasodilators; they reduce myocardial oxygen demand and dilate coronary arteries. The drugs can be used for vasospastic angina and concomitant obstructive pulmonary diseases [1–2.15]. Any practicing physician is well aware of the high effectiveness of nitrates for angina. At the same time, nitrates often cause various side effects - headache (sometimes unbearable), nausea, facial flushing, arterial hypotension, palpitations; With regular use, it is possible to develop tolerance to this group of drugs. In addition, it has been established that the use of nitrates is not indicated for all patients with coronary artery disease. According to the results of the ISIS-4 and GISSI-3 studies (58,050 and 19,394 patients, respectively), the use of nitrates in patients with myocardial infarction does not improve their prognosis. Moreover, the less representative but longer studies MSMI (1072 patients) and MDPIT (1779 patients) demonstrated that long-term use of nitrates after myocardial infarction leads to a significant deterioration in prognosis in these patients. In recent years, another circumstance has emerged that complicates the use of organic nitrates in men suffering from coronary artery disease: they are incompatible with the use of phosphodiesterase type 5 (PDE5) inhibitors, which include sildenafil, tadalafil and vardenafil, used for erectile dysfunction often combined with coronary artery disease [ 16]. Perhaps only drugs from the sydnonimine group can be considered as a serious alternative to nitrates; The first and typical representative is Sidnopharm, one of the widely used molsidomine drugs, its distinctive characteristic is the cost-effectiveness ratio. Molsidomine is an antianginal agent from the sydnonimine group. Not being a nitrate in chemical structure, Sydnopharm (molsidomine) has a similar effect to them, since it is capable of splitting off the nitric oxide molecule – NO; Sydnonimines and nitrates are now often combined into the group of antianginal drugs - nitric oxide donors. When ingested, molsidomine is metabolized in the liver, turning into its active derivative, SIN-1. The latter, entering the blood, is activated (SIN-1A), and the NO-group is split off from it, affecting the process of activation of guanylate cyclase. As a result, GTP is converted to cGMP, which leads to relaxation of the vascular muscle cells and vasodilation. Thus, the vasodilating effect of Sydnofarm is close to the effect of the endothelial relaxing factor. In the coronary system, it is mainly the epicardial arteries that dilate. In the venous system, molsidomine dilates mainly small and medium-sized vessels, which promotes the deposition of blood in it, reduces blood flow to the heart and preload on the heart. In large doses, molsidomine has a dilating effect on the arteries and arterioles, which helps reduce peripheral resistance, blood pressure and afterload. Unlike organic nitrates, which activate guanylate cyclase only after the formation of S-nitrosothiol, Sidnopharm stimulates the formation of cGMP without prior interaction with SH groups. Since the action of molsidomine does not depend on SH groups, tolerance to it does not develop, while depletion of SH groups causes the development of tolerance to nitrates. The resistance of the coronary arteries decreases and blood flow increases by 20%, which improves blood supply to ischemic areas of the myocardium. In this case, the phenomenon of myocardial stealing is not observed. Platelet aggregation decreases, thromboxane formation decreases, platelet adhesion to the vascular wall is suppressed, and the synthesis of prostaglandin (prostacyclin) increases, which inhibits platelet aggregation and has a vasodilatory effect [2,3]. The hemodynamic effects of SIN-1 include a decrease in left ventricular systolic and end-diastolic pressure, stroke volume, mean arterial pressure and systemic vascular resistance, an increase in heart rate and diastolic coronary blood flow [17]. In addition, SIN-1 inhibits intracoronary platelet aggregation in vitro [18] and upon intracoronary administration [19], and also promotes the release of prostacyclin, which also prevents thrombus formation [20]. At the same time, take molsidomine orally at a dose of 8 mg 3 times a day. did not significantly affect blood rheology in patients with coronary artery disease [21]. It is also possible that the molsidomine metabolite SIN-1C has immunomodulatory properties, which may have a beneficial effect on the course of immune processes in the focus of necrosis during myocardial infarction. With long-term use of sydnonimines, tolerance to them or to nitrates does not develop [16,22]. The effect of molsidomine appears after 15–20 minutes, the duration of action is from 1 to 6 hours (on average 4 hours). To prevent angina attacks, tablets of 2–4 mg are taken 2–3 times a day. after meals or use a prolonged-release form - 8 mg tablet (retard) 1 time / day. In more severe cases, you can use a 4 mg tablet (Forte) 3 times a day. or 8 mg (retard) 2 times/day. To stop the attacks of angina pectoris with poor tortoglycerin tolerance, you can take a sublingually 1-2 mg of molsidomin (1/2–1 tablet of 2 mg). The bioavailability of the drug when oral administration is 44–59%, the concentration in plasma reaches the maximum within 1-2 hours, further metabolism with the release of nitrogen oxide and the formation of metabolites is quickly; The half -life (T1/2) Sin -1 is 1-2 hours. The drug is not excreted in unchanged form, 90% of metabolites are excreted from the body with urine. In old age, with liver and heart failure, the effect of the first passage through the liver decreases, and the half -life increases [23]. In severe liver failure (an increase in bromisulfalein test to 20-50%), a slowdown in the excretion and an increase in the concentration of molsidomin in blood plasma was noted. The drug does not cumulates (including in patients with renal failure). Molsidomin expands the peripheral venous vessels, has an anti -aggregate, analgesic and anti -anginal effect. Its venuvial activity is due to the release of nitrogen oxide (No) after a series of metabolic transformations, which stimulates soluble guanilantcyclase, in connection with this, the malaxidomin is considered as the Donator of the NO. As a result of this, the accumulation of the CGMF, which helps to relax the smooth muscles of the vessel wall (to a greater extent - veins). A decrease in preloading even without a direct impact on the contractility of the myocardium leads to the restoration of the violation of the myocardium in oxygen and its receipt that violated during the IBS (the need for oxygen is reduced by 26%). The drug relieves coronary arteries spasm, improves collateral blood circulation, increases the tolerance of loads, reduces the number of angina attacks during physical exertion, suppresses the early phase of platelet aggregation, reduces the release and synthesis of serotonin, thromboxan and other pro -groups. In patients with chronic heart failure, mallicidomin, reducing preload, helps to reduce the size of the heart chambers. It reduces the pressure in the pulmonary artery, reduces the filling of the left ventricle and the tension of the myocardial wall, the stroke of the blood. The clinical efficiency of molsidomin under coronary heart disease is evaluated in a number of clinical studies. In particular, Messin R. et al. [24] conducted a multicenter randomized dual -blind -controlled 6 -weekly study of the effectiveness of conventional (4 mg) and retarded (8 mg) forms of the drug in 90 patients with stable angina pectoris. Against the background of therapy, a reliable increase in the load tolerance and a decrease in the depression of the ST segment during load samples, a decrease in the frequency of sore throat and need for nitroglycerin, and the prolonged form turned out to be somewhat more effective. In 1997, an Accord study was conducted in France, which studied the effect of gratonism on the lumen of the coronary arteries and the prognosis in 700 patients who underwent cylinder transluminal angioplasty. The drug comparison was diltiazem. As a primary point, a six -month mortality in comparison groups was monitored, the secondary points were the frequency of restenoses and a change in the lumen of the coronary arteries with repeated coronarography after six months. The study establishes that lincidomin and molsidomin are more increased by the lumen of the coronary arteries, reduce the frequency of restenoses compared to diltiazem, but do not affect the forecast of the life of coronary patients. This data is partly contrary to the results of a double blind placebo -controlled study conducted by Wohrle J., Hoher M. et al. [25]. The study included 166 patients after coronary angioplasty, receiving within 6 months. Molsidomin 8 mg/day. or placebo. Against the background of pharmacotherapy, the frequency of restenoses was the same as in the placebo group, but the functional class of angina pectoris was noticeably reduced. Along with nitrates, gatelessness can be used in patients with heart failure. So Spring A. et al. We studied the dynamics of changes in the ejection fraction in 30 patients with heart failure. Against the background of basic therapy (ACE inhibitors, diuretics, cardiac glycosides), the release fraction was 33.8%, and after 3 months. After adding mallicidomine (6 mg/day) to the therapy, it increased significantly (up to 44.8%). A comparison of the influence of a 24 -hour infusion of mallicidomine and isosorbide 5 -mononitrate (IS - 5 - 5 - MN) on the pressure level in the pulmonary artery in a randomized double -blind, controlled cross examination in 15 patients with NYHA II - III showed that the malliper to a greater extent Reduces pressure in the pulmonary artery. An interesting observation was made by Lee S. - D. et al. (2001), who described three patients with non -specific aortoarthterity and pulmonary hypertension, in which nitric oxide inhalation effectively reduced the pressure in the pulmonary artery and pulmonary vascular resistance. Molsidomin (unlike Nifedipine) at a dose of 4 mg had the same effect, reducing shortness of breath for a long time, improving hemodynamic parameters and increasing the load tolerance. Recently, data have also appeared about the possibility of using molsidomin in the treatment of primary pulmonary hypertension in newborns. Also, one of the indications for the use of molsidomin can be cirrhosis of the liver with phenomena of portal hypertension. It is known that the use of nitrates and B - blockers allows you to reduce the pressure in the system of the gate vein. Hori N. et al. In 1996, the results of an experimental study on rats were published, during which it was shown that the mallicidomine is more effective than propranolol, reduces the pressure in the porcine vein in experimental animals, and the combination of these drugs has a complete additive effect. The data obtained create the prerequisites for continuing the study of the effectiveness of molsidomin (vice -pharma) with pulmonary and portal hypertension. Thus, Siddhadarm (Molsidomin) can be used in the following clinical conditions. - Stable voltage angina pectoris - with angina of voltage II FC, the drug can be used episodically at a dose of 2–4 mg in 30-60 minutes. to physical activity (or other situation, stereotypically causing an attack of angina pectoris). With angina pectoris III - IV FC, the drug can be prescribed in a daily dose of 16 mg (4 mg 4 times/day). - Acute coronary syndrome - the use of chinfarm is advisable in cases of intolerance to organic nitrates or the rapid development of tolerance to them. Siddom should not be used in the presence of unstable hemodynamics. - Early postinfarct angina pectoris - Siddopharm no less effective than organic nitrates, reduces the number of angina attacks in a daily dose of 16 mg (simple or retarded forms). - stagnant heart failure - vice -power can be used as an addition to standard therapy (IAC, diuretics, cardiac glycosides, b - b -anxis) in cases of insufficient efficiency. In addition, Siddhadarm (Molsidomin) can be prescribed at night with the development of night attacks of heart asthma. Against the background of therapy with molsidomin, the development of side effects is possible, including arterial hypotension (especially with simultaneous intake of alcohol), headache at the beginning of treatment; Dizziness, nausea, allergic reactions in the form of skin rashes, bronchospasm are rarely observed. Possible headache, slowdown in the velocity of psychomotor reactions, nausea, loss of appetite, diarrhea. Contraindications to the use of the drug are cardiogenic shock; arterial hypotension; glaucoma (especially closed); I trimester of pregnancy and lactation; decrease in central venous pressure; hypersensitivity to the components of the drug. The simultaneous use of vascular, antihypertensive drugs and ethanol increases the severity of the antihypertensive effect. When Sidnofarm is used simultaneously with acetylsalicylic acid, its antiplatelet effect is enhanced. Thus, the advantages of the drug include proven effectiveness for coronary heart disease, stenard of stress and congestive heart failure, the best tolerance compared to nitrates and lack of tolerance to the drug with regular use for a long time. All this determines the broad prospects for the use in the wide clinical practice of the antianginal drug Molsidomin (Sidnopharm), especially in the conditions of an increase in the incidence of cardiovascular pathology, an increase in resistance to nitrates and often their poor tolerance.

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