Metabolic drugs in cardiological practice

October 12, 2021

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On the site you can find the necessary drugs to improve metabolism, designed to speed up metabolism. You can search by name, main component or manufacturer. For all medicines, upon request of the buyer, a certificate is provided along with the receipt.

Types of metabolic disorders, what medications are needed

Among the main factors causing metabolic disorders in the body are insufficient physical activity, unbalanced nutrition, and hormonal predisposition. Various acute and chronic diseases also affect human metabolism. Metabolics are drugs that correct metabolism and vital energy in the body, helping to speed up metabolism.

Types of violations in the digestibility and processing of elements occur in the main categories:

• protein metabolism;
• carbohydrate;
• fat metabolism;
• vitamins and minerals;
• water-mineral;
• acid-base;
• hormonal balance.

Proper metabolism and comprehensive weight loss are ensured by various fat-burning, tonic, and immunostimulating agents. The medications your doctor prescribes to improve your metabolism will differ in each of these cases. They are designed to regulate metabolic processes occurring in the body.

• Restore functionality at the cellular level and eliminate metabolic failures.
• The processes of processing useful components supplied with food are brought to a normal state.
• Restore complex biochemical reactions occurring in the human body.
• They establish the production of the necessary energy for normal life.

There is no one cure for all metabolic disorders in the body. In medical practice, different types of drugs are used to normalize the breakdown and processing of fats, the absorption of proteins, carbohydrates, minerals, vitamins, and the correct balance of hormones.

Modern view on the role of metabolic therapy in the treatment of diseases of the cardiovascular system

Lecture transcript

All-Russian Internet Congress of Specialists in Internal Diseases
00:00

Vladimir Trofimovich Ivashkin, Academician of the Russian Academy of Medical Sciences, Doctor of Medical Sciences:

– We have the next message. Professor Alexander Anatolyevich Simakov.

"Modern view on the role of metabolic therapy in the treatment of diseases of the cardiovascular system."

Please, Alexander Anatolyevich.

(Slide show).

Alexander Anatolyevich Simakov, professor, doctor of medical sciences:

– Thank you Vladimir Trofimovich.

(Slide show).

I want to start by saying that we all work in clinics and we all have our own patients. And most importantly, we all have our own students and graduate students with whom we work, from whom we grow our shift. When a patient comes to our clinic, a young doctor always turns to his mentor, usually with two questions: what do clinical recommendations say about this disease in this case, and how best to treat the patient.

The first question reflects the application of randomized clinical trials to real-world practice. And the second implies a specific patient with individual physical, mental, social and some other characteristics of the patient. And also, most importantly, the subjective opinion of experts. Although medicine purports to be a mixture of these concepts, they are in fact diametrically opposed to each other.

(Slide show).

I would even call it (you know, Vladimir Trofimovich, Oksana Mikhailovna) not so much “The Role of Metabolic Therapy”, but rather “What is medicine in general” from the position of relationships. This is science, art or certain rules, recommendations.

01:22

(Slide show).

Most clinical guidelines allow us to optimize treatment and standardize outcomes. The clinical opinion of the doctor should not be underestimated at all. A subjective study of the protocol and (inaudible, 01:40) of the doctor can sometimes provide better knowledge of the protocol.

There is, I want to say, such an example of BARI. It is not very well known, this study, in Russia. This study looked at the mortality rate of diabetic patients who underwent percutaneous angioplasty CABG after 7 years of treatment. It has been included in various recommendations. At the same time, mortality in percutaneous angioplasty was higher than in CABG, although in the BARI registry of this study it was just lower. This situation occurred with clinical trials.

In addition, this adherence to treatment is a reflection of the relationship between the patient and the doctor, the effect and the placebo, and the preference of the patient himself. By the way, this is very well illustrated by alternative medicine. For example, homeopathic, where these ingredients act as the main factors.

(Slide show).

What I want to do again is at the beginning. It is clinical research that is the basis for many doctors and many researchers as a way to treat patients. If a drug is not included for one reason or another, for example, in recommendations or in RCTs, doctors do not prescribe it. It is the recommendations, standards, and protocols that are the basis for not prescribing this drug.

But it is well known that healthcare systems and clinical practice differ significantly from country to country. All of this affects the outcomes of randomized trials (ECST studies). From a safety point of view: in randomized studies only experienced specialists should be taken into account (work), but in real practice this does not always happen, unfortunately.

(Slide show).

Another problem is patient selection. The CASE study (almost a classic): almost 17 thousand patients - of which only 780 patients were included. This is less than 5%. As a consequence of strict inclusion/exclusion, most patients are left out of clinical trials - the results obtained are not applicable to them.

According to the National Institutes of Health, the average exclusion rate in RCTs is 73%. I sometimes think when I read these studies, where did they recruit such patients into the study? Patients included differ from others in gender, age, nationality, severity of the disease, social class and, subsequently, in the characteristics of the outcome of this disease.

04:08

(Slide show).

A special period is the run-in period of randomization, which is necessary to select patients who meet the requirements of the protocol. In the case of an introductory period with active treatment, patients with side effects and treatment failure are not included in the main part. Thus, when using Carvedilol, 6–9% were excluded from the study for one reason or another.

(Slide show).

Sometimes only patients with a good response to treatment continue further participation. All this reduces the sharp validity of the results obtained.

There are such CONSORT recommendations. These are uniform requirements: when you publish in biomedical publications, be sure to include all exclusion criteria.

(Slide show).

This is the data I found in the National Library in Washington. The National Institutes of Health meets these requirements in only 63% of cases when publishing randomized clinical trials and in 19% of clinical recommendations.

(Slide show).

The same is true for reports of adverse events or abnormal laboratory values, especially if the sponsor is the manufacturer. Of the 192 RCT reports on adverse effects, only a third provided information on the frequency of adverse events and changes in laboratory parameters.

(Slide show).

There are also difficulties when using surrogate and combined points as treatment. In real clinical practice, the results obtained in RCTs are not always applicable.

05:40

(Slide show).

Surrogate points are not considered a valid end point. Only such hard ones, such as mortality, the incidence of heart attack, stroke, can be considered from a position of significance. But the patient may be interested in other indicators. They are interested in quality of life, emotional comfort, general tone, and cognitive functions. He may not live as long as according to other studies, but it is the quality of life that is extremely important to him. For example, in a patient who develops dementia, life expectancy is not an adequate effect for the patient.

(Slide show).

For all the reasons listed above, real-world data (obtained from registers) are often more applicable in everyday work. It is known that RCTs do not take into account the formation of a therapeutic relationship between doctor and patient and the preferences of their patient. They also cannot exclude unintentional errors, for example, when adjusting factors.

(Slide show).

Although randomized clinical trials are fundamental to determining the effectiveness of treatment, we must always be aware of the low external validity of the data obtained. This occurs in guidelines where direct extrapolation of RCT data to the general population occurs. If more than 70% were excluded during the selection process, then the results obtained cannot be used without correction for the individual characteristics of the patient. Moreover, the best strategy requires modification of clinical recommendations.

(Slide show).

It should be noted that the term “evidence-based medicine” has recently undergone significant transformation. If you look at Sacket's original definition, "evidence-based medicine" is the conscious, precise, intelligent use of the best evidenced methods to decide on a patient's treatment strategy.

(Slide show).

Even if a young specialist asks his experienced colleague what the recommendations say, he will always make allowances for a specific patient. All this makes it possible to draw the following conclusion: medicine is not just about following recommendations.

Light as a physical structure can (depending on the need and methodology) be described from two positions: corpuscular and wave. This is a good example of complementarity.

07:53

(Slide show).

The term “complementarity” is generally understood in science and in art as the concept of two opposites interconnected. Romanticism during the Renaissance appeared as a result of the rejection of scientific rationalism not only in literature, but also in science.

(Slide show).

In a broad sense, this came down to the unity and struggle of two opposites: day and night, rationalism and irrationalism, the general and the individual.

(Slide show).

We often classify medicine as a natural science, but each patient has its own unique characteristics. The complementary approach in medicine implies an individual approach to the suffering person. From this point of view, medicine is not only a science, but also an art. From this point of view, it is absolutely logical that we should use not only those drugs that are included in the recommendations, given their fairly large number of shortcomings, but also the specific patient.

From this position, I would like to continue the topic of what we have been doing in our clinic for 20 years - this is the so-called metabolic therapy. If we look at the recommendations of the Europeans, they are present there, in 2006 there was stable angina, an energy modulator is present, but only for stable angina.

When you talk about cytoprotectors, many people say: “They are not in the recommendations, and we will not use them.” Doctors have a jumble in their heads: what is a cytoprotector and metabolic drugs. They often say: “Something like this is happening in the heart muscle. It’s impossible to understand what’s happening there.”

09:25

(Slide show).

I labeled the next slide as follows: cytoprotectors are an underestimated opportunity. Yes, only for stable angina, an energy modulator is recommended in European guidelines. But when I was preparing the lecture, I still tried to understand what we classify as cytoprotectors. Three positions must correspond to them: cellular metabolism, ion homeostasis and influence the structure and function of cell membranes.

If a drug has a proven experimental clinical effect, it can be classified as a cytoprotector. Everything else is beyond this concept. For myself, as a doctor, I know only three such drugs: ranolazine, which was removed from the market due to the influence of some (inaudible, 10:04), Trimetazidine and the drug with which we have been working for more than 20 years – phosphogenic creatine or “Neoton”.

(Slide show).

This energy production shown at the top is normal. It is produced by glucose and free fatty acids. Beta oxidation produces 60–80% of ATP, but requires a lot of oxygen. Glucose. If there is a lack of oxygen, then at the level of the first act everything ends, and the pH of the cell changes.

(Slide show).

Phosphogenic creatine is a drug that has been studied for a very long time. It should be noted that it was Russian scientists (Academician Sachs, Professor Rudai, Shakhov) in Moscow who developed this drug in their time. Unfortunately, he left us for Italy, but soon, as far as I understand, the patent will return to us. This is a drug that satisfies all three positions: it affects the cell membrane, it changes the energy pool and changes the pH of the cell in terms of removing acidosis.

(Slide show).

These are four slides, they talk about how phosphogenic creatine or “Neoton” affects energy production.

(Slide show).

I won’t go into detail - these are more biochemical. This is Lochman's reaction.

(Slide show).

This is a diagram of the creative path. This beautiful slide shows where the source of fast energy (to which points) is applied. Here in words we have stated it. Cytoplasmic membrane. Mitochondria are charged. On the action of ions and myofibrils. This is where the energy of the cardiomyocyte is required for contraction.

11:45

(Slide show).

The energy consumption of cardiomyocytes is broken down here: 80% for contraction, 10–15% for excitability, and 5–10% for the passage of ATP channels.

(Slide show).

In heart failure, especially over a long period of time, and in CHF in particular, the process of transfer and utilization of ATP in cardiomyocytes is disrupted. The level of phosphogenic creatinine decreases by 70% already in the early stages. Chronic heart failure leads to depletion of energy resources.

(Slide show).

These are the indicators according to the New York classification. It is no coincidence that chronic heart failure (CHF) is considered an epidemic; more patients die from it than from oncology. Treatment of this situation is a hot topic.

(Slide show).

Here is the ratio of phosphocreatine in patients with CHF for three years showed that while preserving resources, the survival rate of these patients increases.

(Slide show).

The mechanisms of irreversible damage to cardiomyocytes are outlined on this slide. This is a metabolic product, a change in the structural membrane, destruction of the cell membrane and a massive entry of various calcium into it.

(Slide show).

All this leads to an irreversible decrease in cells.

(Slide show).

The mechanism of protective action is multifaceted.

(Slide show).

It includes these four positions, protects membranes, is somewhat reminiscent of an anti-aggregation drug - it gives aggregation inside the cell and inhibits nucleotides, which produce energy.

13:20

(Slide show).

This drug affects all three links that we mentioned:

— cell membrane (here it is outlined here);

(Slide show).

— stabilization occurs during the interaction of charges of the zwitterion molecule;

(Slide show).

- phospholipase is involved.

(Slide show).

Clinical manifestations in patients with myocardial infarction: heart rhythm disturbances are reduced precisely due to the cell membrane. It is not an antirhythmic drug, but by stabilizing the membrane, it prevents arrhythmia from occurring.

(Slide show).

Contractile functions of the heart in experiment and in the clinic (Grazioli conducted a study in 1992, and it completely satisfied evidence-based medicine).

(Slide show).

The addition of "Neoton" or exogenous phosphocreatines to heart failure reduced its class according to the New York classification.

(Slide show).

Ventricular arrhythmia of heart failure for the same reason.

(Slide show).

Here are separate groups that we have studied a lot - these are acute forms, metabolic drugs, cytoprotectors. This is myocardial infarction in particular.

(Slide show).

Where phosphogenic creatine (“Neoton”) was added to the cardio shift, both the size of myocardial infarction and its mass decreased (there are corresponding calculations based on gram equivalents).

(Slide show).

The dynamics of troponins occurred faster, the time of normalization of other cardiac-specific enzymes when using “Neoton” in different schemes. Moreover, this is a dose-dependent drug.

(Slide show).

For the same reason, there was a decrease in ventricular tachycardia. That is why, Vladimir Trofimovich, we had a very good effect with post-reperfusion arrhythmias. I have published almost 15 candidate and doctoral dissertations, where we used phosphogenic creatine or “Neoton” as the main drug.

In conclusion, I want to say that if the European recommendations include an energy modulator only for chronic forms, for stable angina, then according to our research they should also be used in acute forms of coronary artery disease. For myocardial infarction, unstable angina, during thrombolysis. There are very interesting works by cardiac surgeons on the use of this drug as plegic solutions.

This is what I wanted to say in the time you gave me. Thank you very much for your attention.

Vladimir Ivashkin: Thank you very much.

15:45

Drugs for lipid metabolism disorders

Violation of lipid metabolism occurs due to failures in the absorption and breakdown of lipids (fats) with the formation of accumulation and the appearance of excess weight or active processing and depletion. This directly affects human morbidity and the occurrence of severe pathologies of the gastrointestinal tract and blood vessels. Medicines to improve fat metabolism include different drugs:

• Enzymes;
• Metabolics;
• Antioxidants;
• Fibrates;
• Statins (lowering cholesterol);
• Combined metabolism correctors.

Vitamins for impaired lipid metabolism include Fish oil, Nicotinic acid, vitamin E (retinol acetate or palmitate).

Metabolic syndrome - symptoms and treatment

Treatment of metabolic syndrome should be divided into non-pharmacological and medicinal.

Non-drug treatment of Reaven syndrome is maintaining a healthy lifestyle, quitting smoking and alcohol abuse, optimal physical activity [14], balanced nutrition, as well as the reasonable use of natural and preformed physical healing factors (massage, underwater shower massage, hypoxic therapy and hypercapnia, hydrotherapy, thalassotherapy, balneo- and thermotherapy, internal intake of mineral waters, general magnetotherapeutic effects)[15], psychotherapeutic techniques and training programs.[13]

Drug treatment of metabolic syndrome, depending on the presence of certain of its components, may include lipid-lowering, antihypertensive drugs, medications to reduce insulin resistance, postprandial hyperglycemia and weight.

The main drugs used in the treatment of arterial hypertension in patients with Reaven syndrome and diabetes mellitus are angiotensin-converting enzyme inhibitors, sartans and imidazoline receptor agonists. However, achieving target blood pressure often requires a combination of different classes of medications, such as long-acting calcium channel blockers, highly selective beta-blockers, and thiazide-like diuretics (indapamide) in combination with first-line medications.[10]

To correct lipid metabolism disorders in metabolic syndrome, statins are initially used, possibly in combination with esetrole and fibrates. The main mechanism of action of statins is a decrease in intracellular OX synthesis due to reversible blocking of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase. It leads to an increase in the number of LDL-C receptors on the surface of the hepatocyte and a decrease in the concentration of LDL-C in the blood. In addition, statins have pleiotropic effects, such as antithrombogenic, anti-inflammatory, and improvement of endothelial function, which leads to stabilization of atherosclerotic plaque. Modern statins are capable of reducing LDL cholesterol by up to 55%, reducing triglycerides by up to 30% and increasing HDL cholesterol by up to 12%. At the same time, the key advantage of statin therapy is the reduction of cardiovascular complications and overall mortality[1]. It is most effective to use atorvastatin (10-80 mg/day) or rosuvastatin (5-40 mg/day).[11]

If statin monotherapy is ineffective, it is advisable to add ezetrol at a dose of 10 mg/day, which prevents the absorption of TC in the intestine and can enhance the reduction of LDL-C by 15-20%.

Fibrates are another class of lipid-lowering drugs. They break down triglyceride-rich fat particles, reduce the synthesis of free fatty acids and increase HDL-C by increasing the breakdown of LDL. This leads to a significant decrease in triglycerides (up to 50%), LDL-C (up to 20%) and an increase in HDL-C (up to 30%). Fibrates also have pleiotropic effects: they reduce the concentration of uric acid, fibrinogen and improve insulin sensitivity, but their positive effect on the prognosis of patients has not been proven. The most effective and safe drug in this group is fenofibrate 145 mg/day.

To reduce insulin resistance, the drug of choice is metformin, which has a proven positive effect on tissue insulin resistance through enhancing glucose uptake by target tissues. Metformin reduces the rate of absorption of carbohydrates in the small intestine, has a peripheral anorexigenic effect, reduces glucose production by the liver, and improves glucose transport within cells. The positive effects of metformin (1500-3000 mg/day) on endpoints are due to a decrease in insulin resistance, systemic metabolic effects (weight loss, lipid disorders, blood clotting factors, etc.).[9]

To reduce postprandial hyperglycemia, acarbose is used, which reversibly blocks glucoamylase, sucrose and maltase in the upper small intestine. As a result, undigested carbohydrates reach the lower intestines, and the absorption of carbohydrates is prolonged. However, acarbose has been shown to have additional effects. The STOP-NIDDM study (2002) in patients with metabolic syndrome taking acarbose at a dosage of 300 mg/day demonstrated a reduction in the development of diabetes mellitus by 36%, new cases of arterial hypertension by 34%, and the total rate of cardiovascular events by 46%[6 ].

If a patient with Reaven syndrome has type 2 diabetes mellitus, modern classes of antihyperglycemic drugs, such as glucagon-like peptide analogue-1, dipeptidyl peptidase-4 inhibitor, and sodium-glucose transporter type 2 inhibitor, can be used. A representative of the latter class, empagliflozin (Jardins), in the EMPA-REG OUTCOME study (2016) reduced cardiovascular mortality in patients with type 2 diabetes by 36%.

Drug correction of morbid obesity is indicated if non-drug treatment does not lead to a decrease in body weight by more than 5% of the initial one. Drugs for the treatment of obesity are divided into centrally acting anoretic drugs (sibutramine) and drugs that act on the gastrointestinal tract, such as orlistat (Xenical).

The appetite suppressant drug sibutramine has a lesser effect on dopamine and cholinergic processes, but reduces the consumption of fats and carbohydrates, which leads to weight loss and improves fat and carbohydrate metabolism. Blood pressure and heart rate increase by only 5%.

Orlistat is an inhibitor of gastric and pancreatic lipases, as a result of which a third of dietary triglycerides are not absorbed and their concentration in the blood decreases, which leads to a decrease in food calories and weight. In addition, blood pressure, glucose levels and insulin resistance are reduced.

In medical practice, treatment of metabolic syndrome depends on the presence and severity of its components. The table below shows the tactics for selecting therapy for the most common variants of Reaven syndrome.

Metabolism of vitamins, micro- and macroelements

Pharmacological drugs that help improve the metabolism of vitamins and minerals are prescribed in the following cases:

• lack of these elements in the body;
• excessive intake from food;
• failures in breakdown and digestibility;
• imbalance of vital systems.

As a result of hypovitaminosis or hypervitaminosis, deficiency of micro- and macroelements, a huge range of severe pathologies arises. An imbalance of these components causes illness, affects the condition of hair, skin, nails, and directly affects a person’s appearance.

For example, iodine deficiency leads to the development and progression of thyroid disease and an imbalance of thyroid hormones. Due to hormonal imbalance, weight changes occur. An excess of this microelement in the body is also dangerous; it can cause disruptions in the endocrine system. Therefore, it is recommended to use drugs as prescribed by a doctor.

A huge selection of multivitamin complexes with the rarest vitamins and microelements allows you to undergo a full course of treatment and restore the lost balance.

An exceptional correction of mineral metabolism is carried out with preparations containing iron, copper, zinc, phosphorus, calcium, chromium and others. Ferrum-LEK, rich in iron, allows you to replenish your body with this useful element. This complex is prescribed for iron deficiency anemia and pregnancy.

Protein metabolism disorders

Insufficient supply of protein and amino acids and metabolic disorders lead to exhaustion of the body, weakened immunity, and a decrease in the transport function for the delivery of nutrients. This deficiency causes protein-energy deficiency, which is eliminated by various drugs:

• anabolics;
• amino acids;
• vitamins and minerals;
• immunomodulators;
• general tonic compounds.

In case of insufficiency of endocrine regulation, adaptogens and general tonics are prescribed. Profound depletion and dysfunction resulting from the lack of protein in food are eliminated by drugs to improve metabolism for parenteral and enteral administration, respectively, by injection into a vein and through a tube.

Carbohydrate metabolism disorders

Diabetes mellitus, pancreatitis, arterial hypertension and other diseases occur against the background of carbohydrate metabolism disorders. The body is not able to independently process the main sources of energy resources, such as:

• glucose;
• fructose;
• galactose;
• glycogen.

Drug therapy includes drugs to improve metabolism, depending on the type of malfunction in the body. For this purpose, enzymes, anti-enzymes, hypoglycemic agents, drugs that regulate uric acid metabolism and others are used. The doctor prescribes Cocarboxylase, ATP, Vitrum Cardio Omega-3, and multivitamin complexes.

Drugs that can “switch” the metabolism of the cardiomyocyte under ischemic conditions from FA oxidation to glucose oxidation, which allows for more efficient use of residual oxygen, are called antianginal agents with a metabolic mechanism of action or myocardial cytoprotectors. There is no generally accepted classification of drugs with a metabolic mechanism of action. This class of drugs is heterogeneous both in chemical structure and in mechanisms of action, pharmacokinetics and pharmacodynamics of individual drugs.

A common feature of drugs of this class is their lack of significant effect on blood circulation parameters. They either do not affect myocardial contractility or are capable of enhancing it, increasing the ejection fraction.

Classification of metabolic drugs by mechanism of action

Glucose-insulin-potassium mixture

MECHANISM OF ACTION AND PHARMACOLOGICAL EFFECTS Insulin alone or in combination with glucose and potassium improves myocardial metabolism by increasing the supply of glucose to cardiomyocytes, as well as reducing the availability of fatty acids for cardiomyocytes. The use of the mixture should theoretically be accompanied by a decrease in myocardial oxygen demand, delay the development of acidosis and reduce free radical damage to cardiomyocytes.

INDICATIONS Despite encouraging results previously obtained in meta-analyses of a limited number of clinical trials, after completion of the largest trial to date examining the effect of a glucose-insulin-potassium mixture on the outcomes of AMI with ST elevation (CREATE-ECLA), it became clear that the use of this mixture did not reduce mortality, cardiac arrest, cardiogenic shock and recurrent myocardial infarction. Thus, it is currently believed that the use of a glucose-insulin-potassium mixture in acute MI is useless.

Perhexiline℘

MECHANISM OF ACTION AND PHARMACOLOGICAL EFFECTS Perhexiline℘ (carnitine palmitoyl transferase inhibitor) predominantly inhibits carnitine palmitoyl transferase 1 and, to a lesser extent, carnitine palmitoyl transferase 2, which ensures a shift in metabolism from FA oxidation towards oxidation glucose and lactate.

INDICATIONS • Treatment-resistant angina (as part of multicomponent regimens). • Waiting for revascularization. The use of perhexiline℘ requires mandatory re-evaluation of its concentration in the blood.

CONTRAINDICATIONS • Impaired liver or kidney function.

SIDE EFFECTS • Hepatotoxicity and peripheral neuropathy. They limit the use of the drug due to the development of phospholipidosis. A significant reduction in the frequency of hepatotoxic and neuropathic effects can be achieved by maintaining the concentration of the drug in the blood within 150 and 600 ng/ml, which requires constant evaluation. • Others: nausea, dizziness, hypoglycemia in patients with diabetes.

Etomoxir℘

MECHANISM OF ACTION AND PHARMACOLOGICAL EFFECTS Etomoxir℘ inhibits carnitine palmitoyl transferase 1, which ensures a metabolic shift from FA oxidation towards glucose and lactate oxidation. A study involving a small number of patients showed anti-ischemic and positive inotropic effects of the drug. Trimetazidine

The most studied and widely used antianginal drug with a metabolic mechanism of action.

MECHANISM OF ACTION AND PHARMACOLOGICAL EFFECTS Trimetazidine (an inhibitor of β-oxidation of FAs) reduces β-oxidation of FAs and increases the oxidation of glucose. In this case, the drug blocks the last enzyme in the β-oxidation chain of fatty acids - long-chain 3-ketoacyl-CoA thiolase. The drug enhances the synthesis of membrane phospholipids, which helps to increase the stability of the sarcolemma of cardiomyocytes, restore its barrier function, maintain ion homeostasis and reduce the accumulation of FAs in the cytoplasm. This reduces the cytotoxic effect of under-oxidized FAs, as well as their uncoupling effect on oxidative phosphorylation in mitochondria.

Clinical significance The drug reduces the average number of angina attacks per week, the severity of ST segment depression in FN, and the number of nitroglycerin tablets used, which is accompanied by an improvement in quality of life. In patients with stable angina in combination with LV systolic dysfunction, the addition of trimetazidine to conventional treatment was also associated with improved survival. In acute MI, in the early post-infarction period, there is not enough information on the use of trimetazidine. In CHF, treatment with trimetazidine may improve LV contractility, including in patients with diabetes and dilated cardiomyopathy.

PHARMACOKINETICS Trimetazidine sustained release has better pharmacokinetic properties; the required concentration of the drug in the blood is maintained for 24 hours compared to the short-acting form.

INDICATIONS • Angina pectoris (second-line drug, used as part of multicomponent regimens). Trimetazidine can be successfully combined with β-blockers, CCBs and nitrates, including in patients with diabetes.• LV systolic dysfunction and CHF. Dosing. A slow-release drug is prescribed at 35 mg 2 times a day, a short-acting drug is prescribed at 20 mg 3 times a day. A direct comparative trial showed significantly greater antianginal efficacy of the sustained-release dosage form than that of the short-acting dosage form.

CONTRAINDICATIONS • Age under 18 years. • Pregnancy and lactation.

SIDE EFFECTS • Nausea, epigastric pain, constipation. • Headache. They occur rarely, are mild and almost never require discontinuation of the drug.

Ranolazine℘

MECHANISM OF ACTION AND PHARMACOLOGICAL EFFECTS Ranolazine℘ (a piperazine derivative, an inhibitor of FA β-oxidation) appears to block 3-ketoacyl-CoA thiolase. The exact mechanism of action has not been established. According to RCT data, the drug reduces the frequency of angina attacks and the need for nitroglycerin, improves exercise tolerance, without affecting heart rate and blood pressure.

INDICATIONS • Angina pectoris (second-line drug). In Russia and Europe, indications for the use of the drug have not been defined. In the USA, the drug is approved for use by the FDA as part of combination therapy for angina pectoris when standard antianginal drugs are insufficiently effective at a dose of 750–1000 mg 2 times a day.

SIDE EFFECTS • Reversible increase in serum creatinine levels. • Increase in Q-Tc interval. The incidence of side effects increases in patients over 75 years of age.

INTERACTIONS Ranolazine℘ is a potent inhibitor of the cytochrome P-450 CYP3A isoenzyme, so its use with CCBs (especially diltiazem and verapamil), digoxin, simvastatin, azole antifungals, and tricyclic antidepressants requires special caution. The use of ranolazine℘ in combination with drugs that prolong the QT interval is contraindicated. Levocarnitine

MECHANISM OF ACTION AND PHARMACOLOGICAL EFFECTS Levocarnitine (stimulator of pyruvate dehydrogenase) accelerates the removal of acetyl-CoA from mitochondria, followed by increased activity of pyruvate dehydrogenase. An increase in the concentration of acetyl-CoA in the cytoplasm is accompanied by the formation of a large amount of malonyl-CoA, which inhibits carnitine palmitoyl transferase 1. The drug has an antianginal effect, improves the tolerability of FN, and also increases survival in patients with DCM and MI.

INDICATIONS In Russia and Europe, indications for the use of the drug have not been defined.

SIDE EFFECTS • Disorders of the gastrointestinal tract. • Mild symptoms of myasthenia gravis.

Mildronate♠

MECHANISM OF ACTION AND PHARMACOLOGICAL EFFECTS Mildronate♠, by blocking butyrobetaine hydroxylase, slows down the synthesis of carnitine in the liver, reducing its availability for cardiomyocytes, and also inhibits the reabsorption of carnitine in the kidneys and increases its excretion from the body, which is accompanied by a slowdown in the functioning of the “carnitine shuttle” with a decrease in intake FA into the mitochondrial matrix, reducing the intensity of FA oxidation and increasing glucose metabolism.

INDICATIONS There is no evidence base for most indications. Recommendations for the treatment of stable angina, MI and CHF do not mention the drug.

CONTRAINDICATIONS • LVH. • Organic lesions of the central nervous system. • Pregnancy, breastfeeding.

SIDE EFFECTS • Dyspepsia. • Agitation, sleep disturbance, tachycardia, arterial hypotension. • Skin itching. Coenzyme Q 10 ♠

MECHANISM OF ACTION AND PHARMACOLOGICAL EFFECTS Coenzyme Q10♠ (ubiquinone) is a powerful antioxidant that also ensures the maintenance of the antioxidant activity of α-tocopherol. Experimental studies have shown various effects of the drug: reducing LDL oxidation, improving endothelial function, reducing reperfusion damage, etc. According to clinical studies of varying methodological quality, the drug as part of combination therapy, when taken at a dose of 60–200 mg per day, provides a reduction in the amount of cardiovascular disease. vascular complications, cases of cardiac death, improves exercise tolerance and improves functional class in patients with CHF.

INDICATIONS The drug is not mentioned in modern European and American recommendations for the treatment of MI, angina pectoris and CHF. The drug is registered in the USA, Europe and Russia as a food additive.

SIDE EFFECTS Nausea occurs rarely and is mild.

OTHER DRUGS In our country, inosine, cocarboxylase, Mexicor♠, succinic acid and other drugs continue to be prescribed, the evidence base for the use of which in ischemic heart disease and/or heart failure is absent. The use of these drugs is not recommended by the All-Russian Scientific Society of Cardiology (VNOK) and the Society of Heart Failure Specialists (OSSN).

Other types of metabolic disorders

The appearance of metabolic failures in muscles provokes the development of severe neuromuscular diseases. This leads to disruption of the activity of the heart and blood vessels. In these cases, antioxidants, cardioprotectors, enzymes, antienzymes and other drugs are used.

Violation of water and mineral balance leads to the appearance of edema, kidney disease, pressure surges, the formation of excess fluid in tissues and other pathological processes. Antioxidants and acid-base regulators (ABC) are prescribed.

In each case, an individual scheme is recommended:

1. Prescribing and taking medications.
2. Special diet.
3. A radical lifestyle change.
4. Correction of physical activity.
5. Sleep patterns to improve brain function.

Weight changes due to metabolic disorders

An important condition in the treatment of obesity is the establishment of the very causes of the disease and excess weight. Before losing weight, metabolic disorders are first eliminated. These two phenomena are closely interrelated; in this case, it is better to consult a doctor.

The patient is prescribed laboratory tests of blood, urine, and other tests, and based on the results, corrective therapy is recommended.

• Medicines for disorders of lipoprotein metabolism with the addition of drugs that affect appetite, as well as enterosorbents.
• Special complexes for replenishing the deficiency of vitamins, micro- and macroelements in the form of tablets, dragees and solutions.

Modern single-dose medications and complex medications allow you to maintain your body in ideal shape and prevent the occurrence of failures and deficiency conditions.

Metabolic drugs in cardiological practice

Recently, interest in the metabolic direction in the treatment of stable forms of coronary artery disease has increased. Metabolically active drugs can potentially preserve the viability of the myocardium (hibernating myocardium) until surgery to restore coronary blood flow. Metabolic therapy is aimed at improving the efficiency of oxygen utilization by the myocardium under ischemic conditions. Normalization of energy metabolism in cardiomyocytes is an important and promising approach to the treatment of patients with coronary artery disease.

Possible pathways of cytoprotection:

• inhibition of the oxidation of free fatty acids (trimetazidine, ranolazine);
• increased flow of glucose into the myocardium (glucose-sodium-insulin solution);
• stimulation of glucose oxidation (L-Carnitine);
• replenishment of macroerg reserves (phosphocreatine);
• improvement of transmyocardial transport of NAD+/NADH (amino acids);
• opening of K+-ATP channels (Nicorandil).

Of the currently known myocardial cytoprotectors, the most studied drug with proven antianginal and anti-ischemic effects is trimetazidine, which exerts its effect at the cellular level and acts directly on ischemic cardiomyocytes. The high effectiveness of trimetazidine in the treatment of coronary artery disease is explained by its direct cytoprotective anti-ischemic effect. Trimetazidine, on the one hand, rearranges energy metabolism, increasing its efficiency, on the other hand, it reduces the formation of free radicals, blocking the oxidation of fatty acids [10, 13].

The mechanism of action of trimetazidine is related to:

• with inhibition of 3-ketoacyl-CoA thiolase, leading to a decrease in beta-oxidation of fatty acids and stimulation of glucose oxidation;
• optimization of myocardial function under ischemic conditions by reducing proton production and limiting intracellular accumulation of Na+ and Ca2+;
• accelerating the renewal of membrane phospholipids and protecting membranes from the damaging effects of long-chain acyl derivatives.

These processes help maintain the required level of ATP in cardiomyocytes, reduce intracellular acidosis and excessive accumulation of calcium ions.

Thus, the anti-ischemic effect of trimetazidine is carried out at the level of the myocardial cell due to changes in metabolic transformations, which allows the cell to increase the efficiency of oxygen use in conditions of reduced oxygen delivery and thus preserve the functions of the cardiomyocyte.

Trimetazidine on the Russian pharmaceutical market is represented by such drugs as Preductal (France), Trimetazid (Poland), Trimetazidine, Rimecor (Russia).

Numerous studies have convincingly demonstrated the high antianginal and anti-ischemic efficacy of trimetazidine in patients with coronary artery disease, both in monotherapy and in combination with other drugs [14, 17, 18]. The drug is no less effective in the treatment of stable angina than beta-blockers or calcium antagonists, but it is most effective in combination with basic hemodynamic antianginal drugs. The advantages of trimetazidine include the absence of hemodynamic effects, which allows the drug to be prescribed regardless of the level of blood pressure, heart rate characteristics and myocardial contractile function.

Trimetazidine can be prescribed at any stage of the treatment of angina pectoris as part of combination antianginal therapy to enhance the effectiveness of beta-blockers, calcium antagonists and nitrates in the following categories of patients:

• with newly diagnosed exertional angina;
• in whom it is not possible to achieve a therapeutic effect with hemodynamic antianginal drugs;
• in elderly people;
• with left ventricular dysfunction;
• with CHF;
• with diabetes mellitus;
• with sick sinus syndrome;
• in whom traditional antianginal drugs cause side effects;
• in persons with severe side effects during treatment with antianginal drugs.

Trimetazidine allows you to reduce the dose of drugs that have side effects, improving the overall tolerability of treatment.

Important points are the absence of contraindications, drug incompatibility, and its good tolerability. Adverse reactions occur very rarely and are always mild. This allows the drug to be used by elderly people with diabetes mellitus and other concomitant diseases.

There are no data yet on the effect of trimetazidine on long-term outcomes and cardiovascular mortality in patients with coronary artery disease, so the advisability of its use in the absence of angina or episodes of silent myocardial ischemia has not been established.

Normalization of energy metabolism in cardiomyocytes is an important and promising approach to the treatment of patients with CHF. Metabolic therapy in such patients should be aimed at improving the efficiency of oxygen utilization by the myocardium under ischemic conditions. However, there are very few studies devoted to studying the characteristics of the action of trimetazidine in patients with CHF [7, 11, 16].

In this regard, at the Department of Clinical Pharmacology and Pharmacotherapy of the FPPOV MMA named after. I.M. Sechenov conducted a study to determine the limits and capabilities of trimetazidine in the complex therapy of patients with CHF, which has complicated the course of coronary artery disease.

The study included 82 patients with NYHA functional classes II–III CHF, which complicated the course of coronary artery disease. Among them there were 67 men, 15 women, the average age was 62.2 ± 7.3 years. Before inclusion in the study, all patients achieved stabilization of their condition during therapy with cardiac glycosides, diuretics, and beta-blockers in individually selected doses. All patients were divided into two groups: the first (main) group included 40 patients, to whom trimetazidine at a dose of 60 mg/day and the ACE inhibitor enalapril at a dose of 5–10 mg/day were added to complex therapy; the second (control) group consisted of 42 patients who received only enalapril without trimetazidine to complex therapy. There were no significant differences between the groups in age, gender, duration of the disease, or functional class of CHF. The observation period was 16 weeks.

The clinical effectiveness of therapy was assessed by the dynamics of the functional class of CHF. All patients underwent Holter ECG monitoring with assessment of the average daily heart rate (HR), the total number of episodes of ST segment depression, and the maximum value of ST segment depression. ST segment trends were regarded as ischemic when it decreased horizontally by at least 1 mm relative to the J point for 1 minute or more. The anti-ischemic effect was considered significant if the number of episodes of myocardial ischemia decreased by 3 or more and/or total ST segment depression decreased by 50% or more. The nature of heart rhythm disturbances was also assessed: the number of isolated ventricular extrasystoles (VCs), paired VCs, supraventricular extrasystoles (VVCs), episodes of unsustained ventricular tachycardia (VT), runs of supraventricular tachycardia (SVT). The criteria for the antiarrhythmic effect were considered to be a reduction in isolated PVCs by 50%, paired PVCs by 90% with complete elimination of VT episodes.

To assess exercise tolerance, patients underwent a treadmill test. The criteria for a positive test were a typical attack of angina and/or persistent horizontal ST segment depression of 1 mm or more. When analyzing the results of the treadmill test, the maximum power of the load performed and the total duration of the load were assessed.

In order to assess the state of intracardiac hemodynamics, patients underwent an echocardiographic study with assessment of the following morphofunctional parameters of the heart: left atrium (LA) size, cm; end-diastolic size (EDD), cm; end-systolic size (ESR), cm; ejection fraction (EF) of the left ventricle, %.

Clinical and instrumental studies were carried out before and after 16 weeks of continuous therapy.

Statistical analysis of the obtained data was carried out using standard statistical methods, including calculation of the unpaired Student's t test. All data are presented as mean standard deviations (M ± m).

Analysis of the dynamics of the FC of CHF showed that after 16 weeks of treatment, 28% of patients in the first group and 26% of patients in the second group achieved an improvement in clinical condition and a transition to a lower FC of CHF. The number of patients with FC III decreased in the first group from 50 to 27.5%, in the second - from 64.3 to 30.9%. The number of patients with FC II increased to 67.5 and 66.7%, respectively. During treatment, patients with FC I appeared in both groups: 5% in the first group and 2.4% in the second. Overall, the FC of CHF decreased by 11% (p < 0.05) and 10% (p < 0.05), respectively (

).

According to Holter ECG monitoring at baseline, the following data were obtained in patients included in the study: NVEs were recorded in all patients in both groups; in 9 patients of the first group and in 7 patients of the second group, runs of NVT were recorded. In all patients, isolated PVCs were recorded, including potentially life-threatening PVCs of high grades: paired PVCs and episodes of unstable VT.

After 16 weeks of treatment in the first group, the number of paired VTs decreased by 57.6% (p < 0.05), in the second group - by 28.8% (p < 0.05), the number of episodes of unstable VT - by 58.3% (p < 0.05) and 36.8% (p < 0.05), respectively, the number of isolated PVCs - by 23.6% (p > 0.05) and 6.9% (p > 0.05), respectively , the number of NVEs - by 26.4% (p 0.05) and 10.8% (p > 0.05), respectively.

No new paired PVCs or episodes of nonsustained VT were reported in any patient receiving trimetazidine therapy.

According to Holter ECG monitoring, a significant decrease in the daily number of episodes of ST segment depression was noted in the first group by 55.5% (p < 0.05), in the second - by 23.3% (p < 0.05).

The improvement in the clinical condition of the patients was accompanied by an improvement in the morphofunctional parameters of the heart, which was more pronounced in patients of the first group who received trimetazidine. After 16 weeks of continuous treatment, there was a decrease in EDR in the first group by 4.7% (p < 0.05), in the second group - by 2.1% (p < 0.05); TFR - by 7.5% (p < 0.05) and 4.8% (p < 0.05), respectively; EF increased in the first group by 13.7% (p < 0.05), in the second group - by 10.4% (p < 0.05).

The results of the treadmill test provide objective confirmation of the high antianginal and anti-ischemic activity of trimetazidine: the maximum load power in patients of the first group increased by 12.3% (p < 0.05), in patients of the second group - by 6.7% (p < 0. 05), the total duration of the load increased by 16.8% (p < 0.05) and by 8.2% (p < 0.05), respectively.

Thus, a clear understanding of the pathophysiological mechanisms of damage to myocardial cells under conditions of ischemia and hypoxia, which are based on metabolic disorders, necessitates the inclusion of antioxidants and antihypoxants in the complex therapy of stable forms of IHD.

Normalization of energy metabolism in cardiomyocytes is also an extremely important and promising approach to the treatment of patients with coronary heart disease complicated by the development of chronic heart failure. Adding the metabolic drug trimetazidine to the traditional therapy of patients with CHF makes it possible to achieve more pronounced dynamics of clinical manifestations of the disease and a more pronounced improvement in the morphofunctional parameters of the heart. Along with antianginal and anti-ischemic effects, trimetazidine also has a positive effect on the contractile function of the left ventricular myocardium and reduces the ectopic activity of the heart by reducing the electrical instability of the ischemic myocardium.

To obtain evidence of the positive effect of metabolic agents on endpoints, the incidence of cardiovascular events, mortality and disease prognosis in patients with coronary artery disease, they need to be further studied in large-scale randomized trials.

For questions regarding literature, please contact the editor.

T. E. Morozova , Doctor of Medical Sciences, Professor of MMA named after. I. M. Sechenova , Moscow