agonists to imidazoline receptors

Spurs. Pharmacology. / agonists to imidazoline receptors

Imidazoline receptor agonists

Mechanism of action

Imidazoline receptors are localized both in the central nervous system (in the nuclei of the reticular formation, rostral ventrolateral region of the medulla oblongata) - subtype 1, and on the periphery (for example, in the kidneys, pancreas) - subtype 2. The latter are also found on mitochondria. Another type of receptor is described that does not belong to any of the mentioned types and is localized in sympathetic nerve endings. Their activation leads to a decrease in the production of norepinephrine.

Activation of imidazoline receptors leads to an increase in the synthesis of arachidonic acid and inhibition of Na+/H+ ion exchange channels. Activation of central I1 receptors leads to a decrease in blood pressure and a decrease in heart rate, due to a central suppressive effect on the peripheral sympathetic nervous system. Differences in the therapeutic and hemodynamic effect of centrally acting drugs are due to unequal affinities for different types of receptors. The first-generation centrally acting drug clonidine has an affinity for two types of receptors: central α-aderonoreceptors and imidazoline receptors. Its hypotensive effect is largely due to stimulation of imidazoline receptors, while the main side effects are mediated by cortical α1-adrenergic receptors.

Rilmenidine and moxonidine are highly selective for I1 receptors. Their affinity for I1 receptors is more than 100 times greater than their affinity for α2 adrenergic receptors. Both drugs are characterized by a pronounced hypotensive effect, sometimes accompanied by a slight sedative effect. The hypotensive effect of imidazoline receptor agonists and the resulting decrease in peripheral vascular resistance are associated with their pronounced peripheral sympatholytic activity. In this case, stimulation of I1 receptors causes only a slight decrease in heart rate (HR). It has been shown that bradycardia when using clonidine is largely associated with stimulation of α-adrenergic receptors.

Pharmacokinetics

Rilmenidine (1-2 mg/day once, Bioavailability 100% Plasma protein binding 10% T_ - about 8 hours, The main route of elimination is through the kidneys unchanged, Onset of action - after 1 -1.5 hours, Maximum - 2- 5 hours Duration - 24 hours, No withdrawal syndrome and orthostatic hypotension)

Moxonidine (0.2-0.4 mg/day once, Bioavailability 90% Plasma protein binding - 8%, half-life - 2-3 hours, Main route of elimination is renal excretion, Onset of action - 0.5 hours Maximum action - 2- 5 hours Duration - 24 hours, No tolerance with long-term use No withdrawal syndrome

Both I1 receptor agonists have similar pharmacokinetic characteristics. It should be noted that despite the relatively short half-life, the hypotensive effect of the drugs after a single dose persists throughout the day. The maximum decrease in diastolic blood pressure at the peak concentration was 30.9 mmM. Hg Art. A single dose of moxonidine, according to 24-hour blood pressure monitoring, while providing a long-term hypotensive effect, does not change the circadian rhythm of blood pressure [14]. The duration of the therapeutic effect of imidazoline agonists is associated with their accumulation in the nuclei of the brain.

Side effects, tolerability

The most common side effects of rilmenidine are dry mouth (4.9%), asthenia (4.1%), insomnia (4.5%). Their severity depends on the dose of the drug and decreases with long-term therapy. When using moxonidine, dry mouth was most often observed (in 12.9% of patients). However, in general, numerous registration and post-marketing studies indicate that moxonidine is very well tolerated - it caused dry mouth and sedation in less than 10% of patients, which is much less common than with other centrally acting antihypertensive drugs. In addition to dry mouth and sedation, insomnia (5-8%) and headache (6%) were observed with moxonidine use. The highest incidence of side effects was in patients of older age groups.

Metabolic syndrome - the basis of pathogenetic therapy

In 1948, the famous clinician E.M. Tareev wrote: “The idea of hypertension is most often associated with an obese hypersthenic, with a possible disorder of protein metabolism, with blood clogging with products of incomplete metamorphosis - cholesterol, uric acid...” Thus, more than 50 years ago the idea of metabolic syndrome (MS) was practically formed. In 1988, G. Reaven described a symptom complex including hyperinsulinemia, impaired glucose tolerance, low HDL cholesterol and arterial hypertension, giving it the name “syndrome X” and for the first time suggesting that insulin resistance (IR) with compensatory hyperinsulinemia. In 1989, J. Kaplan showed that an essential component of the “deadly quartet” is abdominal obesity. In the 90s the term “metabolic syndrome” appeared, proposed by M. Henefeld and W. Leonhardt. The prevalence of this symptom complex is becoming epidemic and in some countries, including Russia, reaches 25-35% among the adult population.

Generally accepted criteria for MS have not yet been developed, presumably due to the lack of common views on its pathogenesis. The ongoing discussion about the validity of using the terms “complete” and “incomplete” MS illustrates the underestimation of a single mechanism that determines the parallel development of all cascades of metabolic disorders in insulin resistance.

IR is a polygenic pathology, in the development of which mutations in the insulin receptor substrate genes (IRS-1 and IRS-2), β3-adrenergic receptors, uncoupling protein (UCP-1), as well as molecular defects in proteins of the insulin signaling pathway (glucose transporters) may play a role. . A special role is played by a decrease in insulin sensitivity in muscle, fat and liver tissues, as well as in the adrenal glands. In myocytes, the supply and utilization of glucose is impaired, and resistance to the antilipolytic action of insulin develops in adipose tissue. Intensive lipolysis in visceral adipocytes leads to the release of large amounts of free fatty acids (FFA) and glycerol into the portal circulation. Entering the liver, FFAs, on the one hand, become a substrate for the formation of atherogenic lipoproteins, and on the other hand, they prevent the binding of insulin to the hepatocyte, potentiating IR. Hepatocyte IR leads to a decrease in glycogen synthesis, activation of glycogenolysis and gluconeogenesis. For a long time, IR is compensated by excess insulin production, so the violation of glycemic control does not manifest itself immediately. But, as the function of pancreatic β-cells is depleted, decompensation of carbohydrate metabolism occurs, first in the form of impaired fasting glycemia and glucose tolerance (IGT), and then type 2 diabetes mellitus (T2DM). An additional decrease in insulin secretion in MS is caused by long-term exposure of β-cells to high concentrations of FFA (the so-called lipotoxic effect). With existing genetically determined defects in insulin secretion, the development of T2DM is significantly accelerated.

According to another hypothesis, abdominal adipose tissue plays a leading role in the development and progression of insulin resistance. A feature of visceral adipocytes is their high sensitivity to the lipolytic action of catecholamines and low sensitivity to the antilipolytic action of insulin.

In addition to substances that directly regulate lipid metabolism, the fat cell produces estrogens, cytokines, angiotensinogen, plasminogen activator inhibitor-1, lipoproten lipase, adipsin, adinopectin, interleukin-6, tumor necrosis factor-α (TNF-α), transforming growth factor B, leptin etc. It has been shown that TNF-α is able to act on the insulin receptor and glucose transporters, potentiating insulin resistance, and stimulating leptin secretion. Leptin (“the voice of adipose tissue”) regulates eating behavior by affecting the hypothalamic satiety center; increases the tone of the sympathetic nervous system; enhances thermogenesis in adipocytes; suppresses insulin synthesis; affects the cell's insulin receptor, reducing glucose transport. In obesity, leptin resistance is observed. It is believed that hyperleptinemia has a stimulating effect on some hypothalamic releasing factors (RF), in particular ACTH-RF. Thus, with MS, mild hypercortisolism is often observed, which plays a certain role in the pathogenesis of MS.

Particular attention should be paid to the mechanisms of development of arterial hypertension (AH) in MS; some of them were unknown until recently, which is why the pathogenetic approach to the treatment of MS was not fully developed.

There are numerous studies devoted to the study of the subtle mechanisms of the influence of insulin resistance and hyperinsulinemia on blood pressure levels.

Normally, insulin has a vascular protective effect due to the activation of phosphatidyl 3-kinase in endothelial cells and microvessels, which leads to expression of the endothelial NO synthase gene, release of NO by endothelial cells and insulin-mediated vasodilation.

Currently, the following mechanisms of the effect of chronic hyperinsulinemia on blood pressure have been established:

stimulation of the sympathoadrenal system (SAS);
stimulation of the renin-angiotensin-aldosterone system (RAAS);
blockade of transmembrane ion exchange mechanisms with an increase in the content of intracellular Na+ and Ca++, a decrease in K+ (increased sensitivity of the vascular wall to pressor influences);
increased reabsorption of Na+ in the proximal and distal tubules of the nephron (fluid retention with the development of hypervolemia), retention of Na+ and Ca++ in the walls of blood vessels with an increase in their sensitivity to pressor influences;
stimulation of proliferation of smooth muscle cells of the vascular wall (narrowing of arterioles and increasing vascular resistance).

Insulin is involved in regulating the activity of the sympathetic nervous system in response to food intake. Experimental studies have found that during fasting, SAS activity decreases, and when food is consumed, it increases (especially fats and carbohydrates).

It is assumed that insulin, passing through the blood-brain barrier, stimulates glucose uptake in regulatory cells associated with the ventromedial nuclei of the hypothalamus. This reduces their inhibitory effect on the centers of the sympathetic nervous system of the brain stem and increases the activity of the central sympathetic nervous system.

Under physiological conditions, this mechanism is regulatory, but with hyperinsulinemia it leads to persistent activation of the SAS and stabilization of hypertension.

Increased activity of the central parts of the SAS leads to peripheral hypersympathicotonia. In the kidneys, activation of JGA β-receptors is accompanied by the production of renin, and sodium and fluid retention increases. Persistent hypersympathicotonia in the periphery of skeletal muscles leads to disruption of the microvasculature, first with physiological sparseness of microvessels, and then to morphological changes, such as a decrease in the number of functioning capillaries. A decrease in the number of adequately supplied myocytes, which are the main consumer of glucose in the body, leads to an increase in insulin resistance and hyperinsulinemia. Thus, the vicious circle closes.

Insulin, through mitogen-activated protein kinase, enhances the damaging vascular effects due to the stimulation of various growth factors (platelet growth factor, insulin-like growth factor, transforming growth factor P, fibroblast growth factor, etc.), which leads to proliferation and migration of smooth muscle cells, proliferation of vascular fibroblasts walls, accumulation of extracellular matrix. These processes cause remodeling of the cardiovascular system, leading to loss of elasticity of the vascular wall, disruption of microcirculation, progression of atherogenesis and, ultimately, an increase in vascular resistance and stabilization of hypertension.

Some authors believe that endothelial dysfunction plays a major role in the pathogenesis of hypertension associated with metabolic disorders. In individuals with insulin resistance and hyperinsulinemia, there is a decreased response to vasodilation and an increased response to vasoconstrictor effects, which leads to cardiovascular complications.

Metabolic syndrome is characterized by hyperuricemia (according to various sources, it occurs in 22-60% of patients with MS).

It has now been shown that the concentration of uric acid in the blood correlates with triglyceridemia and the severity of abdominal obesity; This phenomenon is based on the fact that increased fatty acid synthesis activates the pentose pathway of glucose oxidation, promoting the formation of ribose-5-phosphate, from which the purine core is synthesized.

Taking into account all the aspects of the problem discussed above, a therapeutic algorithm for a pathogenetic approach to the treatment of metabolic syndrome should be formed.

Treatment of metabolic syndrome

The complex of treatment for metabolic syndrome includes the following equivalent items: lifestyle changes, treatment of obesity, treatment of carbohydrate metabolism disorders, treatment of arterial hypertension, treatment of dyslipidemia.

Lifestyle change

This aspect underlies the successful treatment of metabolic syndrome.

The doctor’s goal in this case is to form a stable motivation in the patient, aimed at long-term compliance with recommendations on nutrition, physical activity, and taking medications. A “success mindset” allows the patient to more easily endure the hardships that lifestyle changes require.

Changing your diet. The diet of a patient with metabolic syndrome should not only ensure weight loss, but also not cause metabolic disorders and provoke an increase in blood pressure. Fasting in syndrome X is contraindicated, since it is severe stress, and with existing metabolic disorders, it can lead to acute vascular complications, depression, and breakdown in a “food binge.” Meals should be frequent, food should be taken in small portions (usually three main meals and two or three intermediate meals) with a daily calorie content of no more than 1500 kcal. The last meal is an hour and a half before bedtime. The basis of nutrition is complex carbohydrates with a low glycemic index; they should account for up to 50–60% of the nutritional value. The glycemic index unit of a food is the change in glycemia after a meal equal to the change in glycemia after consuming 100 g of white bread. Most confectionery products, sweet drinks, baked goods, and small cereals have a high glycemic index; their consumption should be eliminated or reduced to a minimum. Low GI in whole grains, vegetables, fruits rich in dietary fiber. The total amount of fat should not exceed 30% of the total calorie content, saturated fat - 10%. Each meal should include an adequate amount of protein to stabilize glycemia and promote satiety. You should eat fish at least twice a week. Vegetables and fruits should be present in the diet at least five times a day. The permissible amount of sweet fruits depends on the degree of carbohydrate metabolism disorder; in the presence of type 2 diabetes mellitus, they should be sharply limited.

Table salt - no more than 6 g per day (one teaspoon).

Alcohol, as a source of “empty calories”, an appetite stimulant, and a glycemic destabilizer, should be excluded from the diet or reduced to a minimum. If it is impossible to give up alcohol, preference should be given to dry red wine, no more than 200 ml per day.

Patients are recommended to keep a food diary, where they record what, in what quantity and at what time was eaten and drunk.

Quitting smoking is necessary; this significantly reduces the risk of cardiovascular and cancer complications.

Physical activity. According to G. Reaven, insulin resistance can be found in 25% of people leading a sedentary lifestyle. Regular muscle activity itself leads to metabolic changes that reduce insulin resistance. To achieve a therapeutic effect, it is enough to practice 30 minutes of intense walking every day or 20-30 minutes of jogging three to four times a week.

Obesity treatment

In the treatment of metabolic syndrome, a satisfactory result can be considered a weight reduction of 10-15% in the first year of treatment, by 5-7% in the second year and the absence of relapses in body weight gain in the future.

Following a low-calorie diet and physical activity regimen is not always feasible for patients. In these cases, drug therapy for obesity is indicated.

Currently, the drugs orlistat and sibutramine are registered and recommended for long-term treatment of obesity in Russia. The mechanism of their action is fundamentally different, which makes it possible to select the optimal drug in each specific case, and in severe cases of obesity that are resistant to monotherapy, prescribe these drugs in a complex manner.

Treatment of carbohydrate metabolism disorders

The severity of carbohydrate metabolism disorders in metabolic syndrome ranges from minimal (impaired fasting glycemia and glucose tolerance (IGT)) to the development of type 2 diabetes mellitus.

In the case of metabolic syndrome, medications that affect carbohydrate metabolism should be prescribed not only in the presence of T2DM, but also in less severe (reversible!) disorders of carbohydrate metabolism. Hyperinsulinemia requires aggressive therapeutic tactics. There is evidence of the presence of complications characteristic of diabetes mellitus already at the stage of impaired glucose tolerance. This is believed to be due to frequent episodes of postprandial hyperglycemia.

A powerful arsenal of modern hypoglycemic agents allows you to choose the optimal therapy in each specific case.

Drugs that reduce insulin resistance

For metabolic syndrome - drugs of choice.

A. Biguanides

Currently, the only biguanide that reduces insulin resistance is metformin. According to the UKPDS results, treatment with metformin in T2DM reduces the risk of death from diabetes by 42%, myocardial infarction by 39%, and stroke by 41%.

Can be considered a first-line drug in the treatment of metabolic syndrome.

Mechanism of action: increasing tissue sensitivity to insulin; suppression of gluconeogenesis in the liver; changing the pharmacodynamics of insulin by reducing the ratio of bound to free insulin and increasing the ratio of insulin to proinsulin; suppression of fat oxidation and formation of free fatty acids, reduction of triglycerides and LDL, increase of HDL; according to some data - a hypotensive effect; stabilization or reduction of body weight. Reduces fasting hyperglycemia and postprandial hyperglycemia. Does not cause hypoglycemia.

It can be prescribed for IGT, which is especially important from the point of view of preventing the development of T2DM.

B. Thiazolidinediones (“glitazones”, insulin sensitizers)

Pioglitazone and rosiglitazone are approved for clinical use.

In Russia, this is a rarely used group of drugs, probably due to their relative novelty, known risk of acute liver failure, and high cost.

Mechanism of action: increase glucose uptake by peripheral tissues (activate GLUT-1 and GLUT-4, suppress the expression of tumor necrosis factor, which increases insulin resistance); reduce glucose production by the liver; reduce the concentration of free fatty acids and triglycerides in plasma by suppressing lipolysis (through increasing the activity of phosphodiesterase and lipoprotein lipase). They act only in the presence of endogenous insulin.

α-glucosidase inhibitors

Acarbose drug

Mechanism of action: competitively inhibits intestinal α-glucosidases (sucrase, maltase, glucoamylase) - enzymes that break down complex sugars. Prevents the absorption of simple carbohydrates in the small intestine, which leads to a decrease in postprandial hyperglycemia. Reduces body weight and, as a result, has a hypotensive effect.

Insulin secretogens

Drugs of this class are prescribed for metabolic syndrome in cases where it is not possible to achieve satisfactory glycemic control with the help of drugs that reduce insulin resistance and/or acarbose, as well as in the presence of contraindications to them. The risk of developing hypoglycemia and weight gain with long-term use requires a strictly differentiated approach when choosing a drug. Prescription for NTG is not practiced. The combination of insulin secretogens with biguanides is very effective.

A. Sulfonylureas

Clinical experience shows that monotherapy with some insulin secretogens (in particular, glibenclamide) in patients with metabolic syndrome usually turns out to be ineffective even in maximum doses due to increasing insulin resistance - the secretory capacity of β-cells is depleted and an insulin-requiring variant of T2DM is formed. Preference should be given to highly selective dosage forms that do not cause hypoglycemia. It is desirable that the drug can be taken once a day to increase treatment compliance.

These requirements are met by the second generation drug gliclazide in the pharmacological form of MV (modified release) and the third generation drug glimepiride.

Gliclazide is a highly selective drug (specific to the SUR1 subunit of ATP-sensitive potassium channels of β-cells), restores the physiological profile of insulin secretion; increases the sensitivity of peripheral tissues to insulin, causing post-transcriptional changes in GLUT-4 and activating the action of insulin on muscle glycogen synthetase; reduces the risk of thrombosis by inhibiting platelet aggregation and adhesion and increasing the activity of tissue plasminogen; reduces the level of lipid peroxides in plasma.

Glimepiride complexes with the sulfonylurea receptor SURX. Has a pronounced peripheral effect: increases the synthesis of glycogen and fat by activating the translocation of GLUT-1 and GLUT-4; reduces the rate of gluconeogenesis in the liver, increasing the content of fructose-6-biphosphate. It has lower glucagonotropic activity than other sulfonylurea drugs. Provides a low risk of hypoglycemia - causes a maximum decrease in blood glucose with minimal insulin secretion. It has antiaggregation and antiatherogenic effects, selectively inhibiting cyclooxygenase and reducing the conversion of arachidonic acid to thromboxane A2. It is complexed with caveolin in fat cells, which probably determines the specificity of the effect of glimepiride on the activation of glucose utilization in adipose tissue.

B. Prandial glycemic regulators (short-acting secretogens)

Fast-acting hypoglycemic drugs, amino acid derivatives. In Russia they are represented by repaglinide and nateglinide.

The mechanism of action is a rapid, short-term stimulation of insulin secretion by the β-cell due to rapid reversible interaction with specific ATP-sensitive potassium channel receptors.

It is believed that nateglinide is safer with respect to the development of hypoglycemia: insulin secretion caused by nateglinide depends on the level of glycemia and decreases as the level of glucose in the blood decreases. The possibility of using low doses of nateglinide for IGT in patients at high risk of cardiovascular complications is being studied (NAVIGATOR).

Insulin therapy

Early initiation of insulin therapy for metabolic syndrome (except in cases of decompensated diabetes) seems undesirable, as it is likely to aggravate the clinical manifestations of hyperinsulinism. However, it should be noted that, in order to avoid complications of diabetes mellitus, compensation of carbohydrate metabolism must be achieved at any cost. If the effect of the previously listed types of treatment is unsatisfactory, insulin therapy should be prescribed, possibly in acceptable combinations with oral hypoglycemic drugs. In the absence of contraindications, combination with biguanides is preferable.

Treatment of arterial hypertension

The target blood pressure level for the development of type 2 diabetes mellitus is <130/85 mm Hg. Art.; with impaired renal function - < 125/75 mm Hg. Art.

An ideal antihypertensive drug in this clinical situation should have a proven effect on cardiovascular end points, not have negative metabolic effects, affect the pathogenetic links of hypertension in insulin resistance and have a number of protective effects (cardio-, nephro-, vasoprotection) with a beneficial effect on endothelial function, platelet-vascular hemostasis and fibrinolysis.

ACE inhibitors

ACE inhibitors are the drugs of choice in the clinical group under discussion. This is due, firstly, to the pathogenetic validity of their use (activation of the RAAS in IR) and, secondly, to a number of advantages of drugs of this class:

reducing insulin resistance and improving glycemic control;
no negative effect on lipid and purine metabolism (FASET, ABCD, CAPPP, HOPE, UKPDS);
vasoprotective effect - regression of vascular remodeling; anti-atherosclerotic effect (SECURE - HOPE-substudy);
nephroprotective effect in diabetic and non-diabetic forms of nephropathy (FACET, MICRO-HOPE, REIN, EUCLID, AIPRI, BRILLIANT);
correction of endothelial dysfunction, beneficial effect on platelet hemostasis and fibrinolysis: ↑NO, ↑prostacyclin, ↓endothelin, ↑endothelium-dependent hyperpolarization factor, ↓procoagulant potential, ↑tissue plasminogen activator, ↓platelet aggregation (TREND).

Thus, ACE inhibitors meet all the requirements for an antihypertensive drug for patients with metabolic syndrome.

β-blockers

Prescribing β-blockers to patients with metabolic syndrome has an undeniable pathogenetic advantage due to the presence of hypersympathocotonia, the mechanisms of which were discussed above. However, for a long time in this clinical group, these drugs were prescribed taking into account a number of restrictions; it was also believed that they were contraindicated for patients with diabetes mellitus due to their negative effect on carbohydrate and lipid metabolism.

However, the results of UKPDS and other studies have proven the effectiveness and safety of the use of selective beta-blockers in patients with metabolic disorders and type 2 diabetes. All adverse side effects were mainly associated with the use of non-selective and low-selective β-blockers.

Thus, in patients with metabolic syndrome, it is possible to use highly selective β-blockers (betaxolol, bisoprolol, nebivolol, etc.) as part of combination therapy in small doses.

Diuretics

Along with β-blockers, thiazide and thiazide-like diuretics are considered first-line drugs for long-term treatment of patients with uncomplicated hypertension. However, as in the case of β-blockers, the use of drugs in this group has a number of limitations due to the development of side effects: decreased sensitivity of peripheral tissues to insulin with compensatory hyperinsulinemia, increased glycemia, adverse effects on the lipid profile (increased triglycerides in the blood , total cholesterol, low-density lipoprotein cholesterol), impaired uric acid metabolism (hyperuricemia).

Many multicenter prospective studies have noted a high incidence of diabetes mellitus in patients with hypertension when treated with thiazide and thiazide-like diuretics. The thiazide-like diuretic indapamide, which combines the properties of a diuretic and a vasodilator, has a lesser effect on metabolic risk factors. According to the literature, with long-term therapy, indapamide does not have a negative effect on carbohydrate and lipid metabolism and does not worsen renal hemodynamics, which makes it the drug of choice in this clinical group.

Calcium antagonists

Currently, many years of discussion about the effectiveness and safety of calcium antagonists have been summed up.

Numerous multicenter studies have proven a reduction in the risk of cardiovascular complications (STOP-2, NORDIL, INSIGHT, VHAT, NICS-EH, HOT, ALLHAT) during therapy with these drugs. In addition, calcium antagonists have a number of advantages that justify their use in patients with metabolic syndrome:

decreased insulin resistance, decreased basal and glucose-stimulated insulin levels;
no negative impact on carbohydrate and lipid purine metabolism;
vasoprotective effect - regression of vascular remodeling, anti-atherosclerotic effect (INSIGHT, MIDAS, ELSA);
nephroprotective effect (proven for non-hydropyridine drugs);
correction of endothelial dysfunction - increase in NO due to antioxidant mechanisms (↑superoxide dismutase activity, ↓NO destruction), improvement of platelet-vascular and fibrinolytic components of hemostasis (↓platelet aggregation, ↓thrombomodulin).

Preference should be given to long-acting non-hydropyridine and dihydropyridine drugs due to the ability of short-acting calcium antagonists, prescribed in large doses, to increase the risk of cardiovascular complications.

AT1-angiotensin receptor blockers

At the present stage, this group of drugs is one of the most actively studied.

A reduction in the risk of cardiovascular complications in patients with hypertension during treatment with losartan was shown in the LIFE study. Proven nephroprotective effect for diabetic nephropathy in T2DM (RENALL, IDNT, CALM). In addition, the ability of AT1-angiotensin receptor blockers to reduce uric acid levels (losartan) has been shown.

The influence of AT1-angiotensin receptor blockers on the pathogenetic links of hypertension in metabolic syndrome and the absence of a negative effect on carbohydrate and lipid metabolism make these drugs promising in this clinical group. A multicenter study evaluating the effect of valsartan on cardiovascular events in patients with impaired carbohydrate tolerance (NAVIGATOR) is currently underway. Further study of this group of drugs may place them on par with ACE inhibitors when it comes to the treatment of metabolic syndrome.

α1-blockers

Until the interim analysis of the ALLHAT trial, which found an increase in cardiovascular events, particularly new cases of heart failure, with doxazosin, drugs in this group were considered among the most promising drugs used to treat patients with metabolic syndrome. This is due to the ability of α-blockers to increase tissue sensitivity to insulin and, as a result, improve glycemic control, correct the lipid profile, and have a beneficial effect on hemostasis and endothelial function.

However, at this stage, α1-blockers can only be used as additional drugs in the combination therapy of hypertension, including metabolic syndrome.

I1-imidazoline receptor agonists

Drugs of this group occupy a special place in the treatment of metabolic syndrome due to the correction of one of the main links in the pathogenesis of hypertension - central hypersympathicotonia. These drugs, by reducing central sympathetic impulses, increase the sensitivity of peripheral tissues to insulin, improve glycemic control and reduce the activity of the RAAS.

Unfortunately, there is no data on the effect of I1-imidazoline receptor agonists on the prognosis of patients with hypertension, which does not allow recommending drugs of this class as first-line agents in the treatment of hypertension. However, they can be successfully used in combination therapy.

Treatment of dyslipidemia

Lipid-lowering therapy must be carried out in patients with MS and combined with therapeutic effects on IR and glycemia.

Statins are undoubtedly the first-line drugs in the treatment of dyslipidemia in patients with metabolic syndrome due to their good clinical efficacy (25-61% reduction in LDL, reduction in triglycerides) and good tolerability.

For isolated hypertriglyceridemia or severe hypertriglyceridemia, the drugs of choice are fibrates, which are inferior to statins in their effect on LDL, are less well tolerated and interact with a large number of drugs. The DAIS and VA HIT studies also demonstrated the beneficial effects of fibrates on cardiovascular risk in T2DM.

Conclusion

Thus, considering MS as a “generalized cardiovascular-metabolic disease” (LM Resnick’s term), we propose to focus on pathogenetic approaches to its treatment. It is also important to develop uniform diagnostic criteria and include the diagnosis of “metabolic syndrome” in the list of Medical Economic Standards. From the point of view of evidence-based medicine, it is desirable to conduct targeted multicenter studies of drugs used to treat metabolic syndrome.

T. V. Adasheva, Candidate of Medical Sciences, Associate Professor O. Yu. Demicheva Moscow State Medical and Dental University City Clinical Hospital No. 11

Buy Moxonidine SZ tablets 0.4 mg No. 28 in pharmacies

Instructions for use

Moxonidine-SZ tab. 0.4 mg No. 28

Dosage forms

tablets 0.4 mg Synonyms Moxarel Moxonidine Canon Moxonitex Tenzotran Physiotens Group Antihypertensive - imidazoline receptor agonists International nonproprietary name Moxonidine Composition Active ingredient - Moxonidine. Manufacturers North Star (Russia)

Pharmacological action Antihypertensive. It is an agonist of pre- and postsynaptic alpha2-adrenergic receptors. Quickly and almost completely absorbed from the gastrointestinal tract. It is excreted unchanged in the urine. The interval between reaching the maximum concentration and a pronounced decrease in blood pressure is 2-4 hours. The duration of action is more than 12 hours (it is slowly eliminated from the central nervous system and reduces the concentration of adrenaline in plasma for a long time). Reduces left ventricular myocardial hypertrophy, eliminates signs of myocardial fibrosis, microarteriopathy, and normalizes capillary blood supply to the myocardium. Reduces total peripheral vascular resistance, pulmonary vascular resistance, blood levels of renin and angiotensin II, adrenaline and norepinephrine at rest and during exercise, atrial natriuretic factor (with exercise), and aldosterone. Reduces tissue resistance to insulin, stimulates the release of growth hormone. Side effects Dry mouth (at the beginning of treatment), fatigue, weakness, headaches, dizziness, central nervous system depression, peripheral edema. Indications for use Arterial hypertension; metabolic syndrome. Contraindications Hypersensitivity, sick sinus syndrome, impaired sinoatrial and AV conduction II-III degree, bradycardia less than 50 beats per minute, severe cardiac arrhythmias, heart failure (NYHA functional class IV), unstable angina, severe liver and kidney dysfunction, peripheral circulatory disorders (obliterating atherosclerosis of the vessels of the lower extremities with intermittent claudication syndrome, Raynaud's disease), Parkinson's disease, depressive states, epilepsy, glaucoma, pregnancy, breastfeeding (stopped during treatment), adolescence (up to 16 years). Method of administration and dosage: Orally, during or after meals, with a small amount of liquid - 0.2 mg 1 time per day (in the morning). If there is no effect (after 3 weeks) - 0.4 mg once (in the morning) or 0.2 mg 2 times a day (morning and evening). A single dose should not exceed 0.4 mg, a daily dose of 0.6 mg, in case of renal failure a single dose should not exceed 0.2 mg, a daily dose of 0.4 mg. Overdose Symptoms: hypotension, dry mouth, palpitations, weakness, drowsiness. Treatment: symptomatic. Idazoxan (an imidazoline antagonist) is administered as a specific antidote. Interaction Strengthens (mutually) the effect of other antihypertensive drugs, depressants (alcohol, tranquilizers, barbiturates, antipsychotics). Special instructions Use with caution in renal failure. During treatment, alcohol consumption is excluded; it is not recommended (especially at the beginning of treatment) to work with mechanisms that require increased attention and speed of reaction. Storage conditions List B. At room temperature.

Features of antihypertensive therapy for obesity

S.V. FAILURE

, Doctor of Medical Sciences,
A.S.
SALASYUK ,
I.N.
BARYKINA ,
V.V.
TsOMA ,
E.V.
CHUMACHEK ,
V.Yu.
KHRIPAEVA ,
Volgograd State Medical University
Currently, obesity is one of the most important interdisciplinary medical problems. It is one of the main reasons for increased blood pressure. Thus, according to the Framingham study, obesity probably plays a major role in the development of hypertension in 78% of men and 65% of women [10]. At the same time, the fat cells themselves play an important role in the development of arterial hypertension, since they produce a variety of biologically active substances, some of which have pressor and proinflammatory effects. Particularly important in this regard is leptin, which, through activation of the sympathetic nervous system and a direct effect on the kidneys (increased sodium reabsorption), contributes to an increase in blood pressure. In addition, obesity itself negatively affects the structure of renal tissue and increases the risk of developing renal failure and progression of arterial hypertension. Also, adipose tissue, having its own renin-angiotensin system, can actively produce angiotensin.

The main factors for the development of arterial hypertension against the background of obesity are hyperinsulinemia, hyperleptinemia, hypercortisolemia, renal dysfunction, altered vascular structure and function, increased activity of the sympathetic and renin-angiotensin systems, and decreased activity of natriuretic hormone [12].

The main mechanisms of the formation of arterial hypertension in obesity:

• changes in renal hemodynamics, • structural changes in the kidneys, • activation of the sympathetic-adrenal nervous system, • insulin resistance, • free fatty acids (FFA), • leptin.

Let us consider the listed mechanisms in more detail.

Changes in renal hemodynamics.

A direct relationship has been identified between increased body weight and sodium retention. The main mechanism of sodium and fluid retention in arterial hypertension associated with obesity is activation of the renin-angiotensin system (RAS), sympathoadrenal system (SAS) and hyperinsulinemia [7]. At the initial stage, a compensatory decrease in renal vascular resistance develops, an increase in plasma flow through the kidneys and renal filtration rate occurs, which partially prevents increased sodium reabsorption. However, subsequently, against this background, the production of angiotensin II and cytokines in combination with activation of the SAS increases. Obese patients have an inappropriately low natriuretic response. These changes increase the “stress” of the glomerular walls against the background of other risk factors (hyperlipidemia and hyperglycemia) and quickly lead to the development of glomerulosclerosis, proteinuria, microalbuminuria and functional failure of nephrons. Early renal hyperfiltration in obesity is similar to that in type 1 diabetes mellitus.

Structural changes in the kidneys.

Against the background of obesity, a special variant of glomerulopathy develops with focal segmental glomerulosclerosis and enlargement of the glomeruli themselves (retrospective study with 6,800 kidney biopsies). Interestingly, against the background of such focal glomerulosclerosis, there is a lower incidence of nephrotic syndrome, less pronounced manifestations of segmental sclerosis and a larger glomerular size. It is believed that these changes are also caused by concomitant pathology (primarily arterial hypertension and dyslipidemia). The German WHO MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) study showed that the increase in the incidence of microalbuminuria was significantly higher in individuals with a large waist/hip ratio. Increased intrarenal pressure plays an important role in sodium retention, mainly by slowing the rate of tubular flow. Numerous studies have shown that obesity increases the weight of the kidneys, which is associated with the proliferation of endothelial cells, the accumulation of intrarenal lipids and the deposition of hyaluronic acid salts in the matrix and medulla of the kidneys. These deposits in the tightly encapsulated kidney lead to a mechanical increase in intrarenal pressure. Increased pressure and volume cause parenchymal prolapse and obstruction of urine outflow, leading to a slower intrarenal flow and increased renal sodium reabsorption. Particularly important is the increase in sodium reabsorption in the loop of Henle, which leads to compensatory vasodilation in the kidneys, increased glomerular filtration rate and stimulation of the RAS [8]. However, increasing the volume of fluid only for a short period can ensure the maintenance of normal sodium concentration in the blood. Subsequently, constant glomerular hyperfiltration in combination with impaired glucose tolerance, hyperlipidemia and hypertension quickly leads to the development of glomerulosclerosis and renal failure.

Activation of the sympathetic-adrenal nervous system.

The mechanisms and consequences of hyperactivation of the SAS are diverse - insulin resistance, increased afferent innervation of the kidneys with increased intrarenal pressure, leading to activation of renal mechanoreceptors, increased levels of free fatty acids, angiotensin II, leptin, potentiation of the sensitivity of central chemoreceptors and impaired baroreflex regulation [5]. Activation of the SAS in muscles and kidneys during obesity was confirmed by microneurographic method. Interestingly, drugs that suppress central sympathetic activity cause a greater reduction in blood pressure in obese patients than in nonobese patients.

Insulin resistance.

Currently, hyperinsulinemia is considered a key factor in the development of arterial hypertension in obesity. It is known that in obesity, insulin levels significantly increase, which is due to the need to maintain the metabolism of carbohydrates and fatty acids at a higher level, and this occurs against the background of insulin resistance of peripheral tissues [11]. Currently available data suggest that insulin resistance impairs insulin-mediated vasodilation, which contributes to an increase in blood pressure [9].

Free fatty acids (FFA).

It is believed that high levels of FFA increase blood pressure due to an increase in sympathetic activity, or vasospathic effect, realized through α-adrenergic receptors. With visceral obesity, too much FFA enters the liver, which activates hepatic afferent pathways, increases the activity of the SAS and contributes to the development of insulin resistance. In obesity, the level of FFA is approximately 2 times higher than in people without obesity.

Leptin

is a peptide consisting of 167 amino acids and plays an important role in both the pathogenesis of obesity and arterial hypertension, which is associated with the presence of various mechanisms of pressor effect [9]. Leptin is secreted by white adipocytes and its level directly correlates with the amount of adipose tissue and is always elevated in obese people. Women have higher leptin levels than men. Leptin crosses the blood-brain barrier into the CNS via endocytosis, where it binds to receptors (Ob-R) in the lateral and medial hypothalamus. The binding of leptin to receptors causes their activation, which ensures the regulation of energy balance through a decrease in appetite and an increase in energy expenditure due to stimulation of the SAS. Evidence that leptin reduces food intake and regulates body weight is supported by both experimental and clinical data. With an impaired ability to synthesize leptin or existing mutations in leptin receptors, severe obesity always develops. The hypertensive effect of leptin is enhanced by endothelial dysfunction, which almost always occurs in obesity. The pressor effect of leptin almost completely disappears against the background of α- and β-adrenergic blockade [17].

Adipose tissue and renin-angiotensin system activity

In obesity, activation of the RAS occurs against the background of increased fluid volume and sodium retention. A distinctive feature is a significant increase in aldosterone levels [15], which may be associated with the release of a specific hepatic factor (possibly a fatty acid), which has a stimulating effect on its synthesis. There is also a relationship between the level of plasma angiotensin (Ang II), renin activity (ARA) and plasma ACE with BMI [6].

It is known that adipose tissue has its own RAS, which plays an important role in the functioning of adipose tissue. Adipocytes are capable of synthesizing all components of the RAS. They also stimulate Ang II receptors, increasing their affinity for paracrine Ang II. It is possible that local Ang may be a factor in the growth of fat cells. It has been shown that with elevated levels of 11β-hydroxysteroid dehydrogenase, which is involved in the formation of cortisol, arterial hypertension develops with all the signs of metabolic syndrome. In obese women, overexpression of the gene encoding renin, ACE and receptors for Ang II type 1 in subcutaneous abdominal adipose tissue was detected. It is important to note that elevated Ang II levels occur primarily due to excess adipose tissue mass, leading to increased blood pressure.

Naturally, all the humoral disorders described above in arterial hypertension and obesity lead to changes in the cardiovascular system:

• vascular changes; • changes in the heart; • change in microcirculation; • markers of inflammation.

Vascular changes.

In obesity, changes occur at the cellular and molecular levels, leading to increased vascular tone [18]. Normally, insulin has vasodilator properties due to its ability to suppress the voltage-dependent flow of Ca2+ ions. This leads to stimulation of glucose transport and its phosphorylation to form glucose-6-phosphate, which then activates the transcription of Ca-ATPase and ultimately reduces intracellular calcium levels and vascular resistance. In case of obesity against the background of insulin resistance, these mechanisms are disrupted and this leads to an increase in vascular resistance.

A decrease in the elasticity of large vessels was revealed according to nuclear magnetic resonance, which directly correlated with an increase in the mass of abdominal visceral fat. It is important to note that weight loss in obesity is accompanied by a pronounced decrease in vascular resistance and mean blood pressure.

Changes in the heart.

Arterial hypertension without obesity most often leads to concentric hypertrophy of the left ventricle, while with a combination of arterial hypertension and obesity, its eccentric hypertrophy predominantly develops. It is known that with concentric LVH, cardiac dilatation occurs late, in contrast to eccentric hypertrophy [13]. The combination of increased blood pressure and obesity can also lead to a mixed type of cardiac hypertrophy caused by an increase in pre-load (a direct consequence of obesity) and afterload (a consequence of activation of the SAS and increased blood pressure). After adjusting and standardizing patients for major risk factors, it is clear that for every unit increase in BMI, the risk of developing heart failure increases by 5% in men and 7% in women. With severe obesity, the risk of developing chronic heart failure is increased by 2 times. A Mayo Clinic analysis of autopsy data found that the average heart weight in obese patients with hypertension was 467 g, compared with 367 g in obese patients without heart disease and 272 g in nonobese patients. Since LVH is an independent risk factor for sudden death and death due to decompensated cardiac disease, it may partly explain the high cardiovascular morbidity and mortality in obesity.

Infiltration of mononuclear cells in the area of the sinoatrial node and deposition of fat cells in the conduction system are other typical changes in the heart in obesity. Lipomatous hypertrophy in the interatrial septum is also very often detected in obesity. Therefore, the state of the myocardium in obesity is an “ideal” background for the development of arrhythmias and sudden death.

Changes in microcirculation. An increased risk of thrombosis can make a significant contribution to the worsening prognosis of cardiovascular pathology due to excess body weight. In obesity, polycythemia often occurs. Epidemiological data show that hypercoagulability and impaired fibrinolysis are directly associated with increased body weight or waist/hip ratio. In obesity, the levels of factor VII, fibrinogen, plasminogen, plasminogen activator inhibitor (PAI-1) and a number of other factors that increase the risk of developing cardiovascular complications are increased [18]. The production of leptin or inflammatory mediators by adipose tissue also increases the risk of thrombosis.

Markers of inflammation.

Adipocytes produce inflammatory cytokines: tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP) and PAI-1. In fact, obesity can be considered a state of “chronic inflammation” [3]. There is no doubt that the existing relationship between obesity and an increased risk of cardiovascular complications is largely determined by the high level of inflammatory mediators [4].

Antihypertensive pharmacotherapy

Currently, it is possible to quite accurately formulate the requirements [1] for antihypertensive therapy for obesity:

Standard goals:

• Achieving target blood pressure. • Improved prognosis. • Slowdown of conversion to diabetes. • Organoprotection.

Specific goals:

• Reducing insulin resistance. • Positive effect on adipocytes (leptin, ghrelin, resistin, adiponectin). • Stabilization/loss of body weight. • Correction of metabolic disorders. • Reduced hyperactivation of the SAS and RAAS. • Positive effect on prothrombogenic status and inflammation. • Reducing hypervolemia. • Reduced episodes of CHOA.

Naturally, it is very important for a practicing physician to know which classes of antihypertensive drugs are most effective in patients with a combination of arterial hypertension and obesity. But the paradox of the situation lies in the fact that no international or national guidelines provide recommendations on the choice of treatment in this clinical situation (naturally, the concept of metabolic syndrome is not synonymous with obesity). One explanation for this gap is the very small number of studies on antihypertensive therapy in obesity. Meta-analysis data ( Fig. 1

) do not clearly identify the antihypertensive drug of choice for the clinical situation discussed. True, they analyzed not antihypertensive effectiveness, but the effect of antihypertensive drugs on the weight of patients [16].

The same authors noted a significant increase in the weight of patients when using propranolol, atenolol and metoprolol, which led to talk about the possible antilipolytic effect of the “old” beta-blockers. It is believed that the “older” beta-blockers contribute to a gain of 1.2 kg/year due to a decrease in resting energy expenditure and a decrease in thermogenesis (up to 10% in some RCTs). According to the same meta-analysis, ACE inhibitors are able to reduce patient weight from 0.3 to 5.3 kg.

The latest 2013 European guidelines for the treatment of arterial hypertension (ESH/ESC Guidelines for the management of arterial hypertension) declare that “since metabolic syndrome is often regarded as a “prediabetic” condition, preference is given to blockers of the renin-angiotensin system and calcium antagonists because they may potentially improve, or at least not worsen, insulin sensitivity, while beta-blockers (except beta-blockers with vasodilating properties) and diuretics should be considered as additional drugs, preferably used in low doses. They also state in the section “Drugs of choice in certain situations” that ACEIs, angiotensin II receptor blockers (ARBs), and calcium antagonists are the drugs of choice for metabolic syndrome. This is also important for choosing a drug for a combination of arterial hypertension and obesity, since the latter is an obligatory component of the metabolic syndrome [2].

Among the existing studies on antihypertensive therapy for obesity, the most significant are the following:

The Treatment in Obese Patients with Hypertension (TROPHY) study.

Comparison of the effectiveness of lisinopril and HCTZ over 12 weeks. treatment in 232 patients with obesity and arterial hypertension with a BMI of 28–40 kg/m2 in men and 27–40 kg/m2 in women and DBP of 90–109 mm Hg. Art. found that in the lisinopril group (10 mg/day) there were 57% responders, while there were 29% responders on the low dose HCTZ dose (12.5 mg/day) and 46% responders on the high dose HCTZ dose (50 mg/day ). Naturally, the last treatment regimen showed the negative metabolic effects of the classic thiazide diuretic.

Study “Candesartan Role on Obesity and on Sympathetic System” (CROSS study)

. Comparison of the effectiveness of candesartan (8-16 mg) and HCTZ (25-50 mg) over 12 weeks. treatment in 127 patients with obesity and arterial hypertension (BMI >30 kg/m2) revealed the same hypotensive effect in the groups. However, the decrease in muscle nervous sympathetic activity was significant only in the candesartan group (20.7% (p < 0.05) versus 3.1% (p > 0.05) on HCTZ) and the increase in insulin sensitivity in the candesartan group by 24. 7% (p < 0.05) versus its decrease in the HCTZ group - by 9.2% (p > 0.05).

Study “A comparison of Telmisartan plus HCTZ with amlodipine plus HCTZ in Older patients with predominantly Systolic hypertension” (SMOOTH)

. Comparison of the effectiveness of the combination of telmisartan/HCTZ (80/12.5 mg/day) versus valsartan/HCTZ (160/12.5 mg/day) for 10 weeks. treatment in 840 patients with obesity (BMI > 27 kg/m2) and arterial hypertension (SBP 140–179 mm Hg and DBP 95–109 mm Hg) revealed that the combination of telmisartan/HCTZ reduced SBP and DBP more , than valsartan/HCTZ by 3.9 and 2.0 mmHg. Art. (<0.001).

Study “Patients with Metabolic Syndrome - Efficacy and Tolerability of Arifon Retard in the Treatment of Hypertension” (Minotaur).

During therapy with the atypical diuretic Arifon retard, a target blood pressure level of 64% was achieved versus 41% with conventional therapy, weight loss after a year by 3.2 kg versus 3.0 kg with conventional therapy, and an improvement in the lipid spectrum and glycemic profile.

An open-label multicenter study of the efficacy and safety of trandolapril in patients with arterial hypertension and overweight

(BMI ≥ 25 kg/m2) revealed that after 3 months. treatment, 84.7% of patients achieved target blood pressure. Similar results were obtained in an open multicenter study of the efficacy and safety of trandolapril in patients with arterial hypertension and overweight in Turkey. Such a high effectiveness of trandolapril in this category of patients may be associated with its highest lipophilicity and duration of antihypertensive effect among all ACE inhibitors.

The Hypertension-Obesity-Sibutramine Study (HOS)

. This multicenter, prospective, double-blind, randomized, placebo-controlled study included 171 patients aged 20 to 65 years with a combination of obesity and hypertension (BMI 27 to 45 kg/m2 and SBP 140 to 160 mmHg and/or DBP from 90 to 100 mm Hg) After a 2-week run-in period, patients were randomized to one of three combination antihypertensive therapy options: felodipine 5 mg/ramipril 5 mg (57 patients), verapamil 180 mg/ trandolapril 2 mg (55 patients) and metoprolol succinate 95 mg/hydrochlorothiazide 12.5 mg (59 patients). In each of these groups, patients were also randomized to receive sibutramine (15 mg). At the same time, it was found that the reduction in weight and degree of visceral obesity, improvement in carbohydrate and lipid metabolism, associated with taking sibutramine, was minimal in the group of patients treated with metoprolol/hydrochlorothiazide 12.5 mg when compared with other antihypertensive therapy regimens. The ACE inhibitor ramipril had the most favorable effect on all analyzed parameters.

Direct comparative study of ACE inhibitors and sartans in overweight individuals

[14]. This clinical study included 120 patients (61 men and 59 women) aged 18 to 60 years inclusive and with a body mass index (BMI) >27 kg/m2. Impaired glucose tolerance was defined as fasting plasma glucose levels <7 mmol/L and after oral administration of 75 mg glucose >7.8 and <11.1 mmol/L. Systolic blood pressure (SBP), determined by the Korotkoff method, according to the inclusion criteria, had to be > 140 mm Hg in the sitting position. Art. and <160 mm Hg. Art. and/or diastolic blood pressure (DBP) > 90 mm Hg. Art. and <100 mm Hg. Art. Patients were randomized by the “envelope method” into 4 groups: Group I took perindopril (Prestarium “A”, ) in a daily dose of 10 mg, Group II took enalapril (Renitek, ) in a daily dose of 20 mg, Group III took losartan (Cozaar, ) at a daily dose of 100 mg, group IV took telmisartan (Mikardis, ) 80 mg for 24 weeks.

All patients initially and after a course of therapy underwent 24-hour blood pressure monitoring (ABPM), echocardiography, vascular elasticity testing and laboratory examination.

The results of the study allow us to make an unambiguous conclusion that there are significant differences between antihypertensive drugs both within the same class and between these classes. Moreover, these differences concern the entire spectrum of pharmacodynamic effects - from the degree of blood pressure reduction to organ protection and metabolic effects. The fact that therapy with perindopril (Prestarium “A”) allowed us to achieve significantly better blood pressure control is not surprising, since it is known that at a daily dose of 10 mg it is the most effective ACE inhibitor in patients who do not respond to therapy with other inhibitors ACE or angiotensin receptor antagonists. In addition, the high effectiveness of perindopril was confirmed in the Russian PREMIYA study, where 70% of patients were overweight, and a study in France, where a third of patients were obese. An important clinical aspect is that during perindopril therapy there is no activation of the SAS. Moreover, data from spectral analysis of heart rhythm indicate normalization of sympathetic activity. Confirmation that the drug, by reducing insulin resistance, is able to reduce heart rate (an indicator that in real clinical practice is an indirect marker of SAS hyperactivation) are the results of the PREMIUM study, in which a decrease in heart rate of 6.1 beats/min was noted during perindopril therapy. The powerful cardio-, angio- and nephroprotective effect of perindopril is well proven, and its advantages over other drugs in the study are obvious, but they can only partly be associated with better blood pressure control when using it. A significant contribution to organoprotection is made by the drug’s effect on metabolic parameters, each of which in itself (hyperlipidemia, hyperglycemia, hyperuricemia, hyperleptinemia) is a powerful risk factor for vascular lesions.

An improvement in the blood lipid spectrum and especially triglycerides cannot be considered a random artifact, since other studies have noted an increase in HDL by 0.16 mmol/l during one-year therapy in patients with arterial hypertension and type 2 diabetes mellitus and a decrease in triglycerides by 0 .6 mmol/l in the treatment of patients with arterial hypertension according to the results of a double-blind RCT.

Perindopril also had a beneficial effect on purine metabolism. In addition, it has a beneficial effect [1] on key obesity hormones and insulin resistance ( Fig. 2

Rice. 2. The influence of various classes of antihypertensive drugs on the main links in the pathogenesis of obesity

If we analyze the possibilities of using individual classes of antihypertensive drugs for obesity and high blood pressure, we can state that, in addition to the preference for the use of individual classes (ACE inhibitors, sartans, imidazoline receptor agonists), there are large intraclass differences within the classes themselves.

Diuretics

One of the main mechanisms of increased blood pressure in arterial hypertension due to obesity is hypervolemia, which occurs as a result of increased reabsorption of sodium and water in the proximal renal tubules against the background of hyperinsulinemia and increased vascular resistance. Therefore, diuretics could become one of the main classes of antihypertensive drugs used for this pathology. However, the undoubted advantages of classical thiazide diuretics are clearly insufficient to compensate for their negative effects (primarily metabolic - hypokalemia, deterioration of carbohydrate, lipid and purine metabolism).

According to the results of clinical observations, all thiazide diuretics worsen carbohydrate metabolism, even at a daily dose of 12.5 mg. Moreover, the higher the initial level of glycemia, the more it increases with their use. In young people, impaired glucose tolerance develops on average after 5 years of continuous use of thiazide diuretics, and in older people - 1-2 years after the start of their use. In the case of concomitant diabetes mellitus, glycemic control worsens within the first few days of starting thiazide diuretics. In addition to the adverse effect on carbohydrate metabolism, thiazide diuretics can have a negative effect on lipid and purine metabolism.

Indapamide retard (Arifon retard) stands apart among diuretics, which, unlike classical thiazide diuretics, does not have a negative effect on the metabolism of glucose, lipids and uric acid. It must be borne in mind that indapamide retard (Arifon retard) has a proven and pronounced cardio-, angio- and nephroprotective effect, which makes it the drug of choice from the group of diuretics for the treatment of patients with obesity and disorders of carbohydrate and lipid metabolism, both in monotherapy, and with combination therapy.

Beta blockers

Increased activity of the SAS in obese patients dictates the need for the use of β-blockers for normalization in this category of patients. However, non-selective β-blockers (atenolol, propranolol) negatively affect carbohydrate and lipid metabolism. In addition, β-blockers (including selective β1-blockers in high doses), by blocking β-adrenergic receptors of the pancreas, inhibit the release of insulin. Since β-blockers cause the development of IGT and weight gain, their use in uncomplicated hypertension and obesity is not recommended as first-line therapy. However, this group of drugs can be used for obesity and arterial hypertension in cases where it is not possible to achieve the target blood pressure level due to pronounced activation of the SAS and tachycardia.

“New” highly selective β1-blockers (bisoprolol, carvedilol, nebivolol) are practically free of those adverse side effects that limited their widespread use in patients with impaired carbohydrate and lipid metabolism. In addition, nebivilol has a number of unique properties that can significantly expand the possibilities of its clinical use (improving endothelial and erectile function, increasing testosterone levels in men).

Calcium antagonists

As is known, this group includes dihydropyridine (nifedipidine, amlodipine, felodipine, lacidipine) and non-dihydropyridine (verapamil and diltiazem) calcium antagonists. Representatives of the first subgroup, against the background of a decrease in blood pressure, which develops due to peripheral vasodilation, can increase the heart rate (HR) and contribute to the activation of the SAS. Representatives of the second group, while maintaining pronounced antihypertensive activity, have a significantly less pronounced peripheral vasodilating effect than dihydropyridine calcium antagonists. Moreover, they are able to reduce heart rate (by suppressing the activity of sinus node automaticity) and reduce the activity of the SAS (data from the VAMPHYR study), which is important for obese patients.

Angiotensin-converting enzyme inhibitors (ACEIs)

Perindopril, ramipril and trandolapril, due to their high lipophilicity and high affinity for ACE in plasma and tissues, can significantly reduce insulin resistance.

Angiotensin II receptor antagonists (ARA II)

Since the effect of this class of drugs is associated with the suppression of RAS activity, they have many common features with ACE inhibitors (the presence of pronounced cardio-, angio- and nephroprotective properties), but they are better tolerated.

Lipophilic ARA II (telmisartan, irbesartan) have the additional property of improving tissue sensitivity to insulin, carbohydrate and lipid metabolism. Losartan reduces uric acid levels and is the drug of choice for hyperuricemia associated with obesity. Valsartan improves erectile function and increases testosterone levels in men.

Imidazoline receptor agonists

A prerequisite for prescribing I2-imidazoline receptor (AIR) agonists to patients with obesity and arterial hypertension is their ability to improve tissue sensitivity to insulin and carbohydrate metabolism. At the same time, according to the Russian multicenter study ALMAZ and two other international studies, in patients with metabolic syndrome and obesity, moxonidine therapy significantly improved lipid and carbohydrate metabolism, tissue sensitivity to insulin, contributed to a decrease in body weight and leptin levels in the blood and improved endothelial function vessels.

Alpha blockers

Alpha-blockers retain their therapeutic potential, despite the results of the ALLHAT study, in the treatment of arterial hypertension in obese patients due to their ability to reduce insulin resistance, improve carbohydrate and lipid metabolism and have a positive effect on renal hemodynamics. However, use should be limited to use only in combination with other antihypertensive agents.

For a practicing physician, we can suggest the following algorithm for antihypertensive therapy in obese patients ( Fig. 3

). In general, an analysis of the available literature indicates that ACEI or ARB II should be a mandatory component of antihypertensive therapy for a combination of arterial hypertension and obesity. But to break the “vicious” circle of arterial hypertension and obesity, almost all patients require combination antihypertensive therapy along with the prescription of drugs for weight loss.

Literature

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Source:

Medical Council, No. 17, 2014