Antihypertensive drugs: principles of therapy, groups, list of representatives. Antihypertensive therapy is

Catad_tema Arterial hypertension - articles

Place of combined antihypertensive therapy in modern treatment of arterial hypertension

Zh. D. Kobalava
Peoples' Friendship University of Russia

CLINICAL PHARMACOLOGY AND THERAPY, 2001, 10(3)

It is well known that the normalization of blood pressure in arterial hypertension is achieved very rarely. The best performance achieved in the US and France is 27% and 33% respectively. In most other regions, the figure fluctuates between 5-10%. Back in 1989, data from the Glasgow Blood Pressure Clinic study confirmed the dominant role of blood pressure levels achieved as a result of treatment in the prognosis of arterial hypertension (AH) and clearly demonstrated high rates of cardiovascular mortality and morbidity with an insufficient degree of its reduction. These assumptions were later confirmed in the HOT study. A combined scheme for the use of antihypertensive drugs as a tool for normalizing elevated blood pressure has always been present in the pharmacotherapeutic arsenal of hypertension. However, views on the place of combination therapy in the treatment of hypertension have been repeatedly revised. The first fixed combinations of antihypertensive drugs (reserpine + hydralazine + hydrochlorothiazide; alpha-methyldopa + hydrochlorothiazide; hydrochlorothiazide + potassium-sparing diuretics) appeared in the early 1960s. In the 1970s and 1980s, combinations of a diuretic, usually at a high dose, with beta-blockers or centrally acting drugs took the lead. However, soon, due to the emergence of new classes of drugs, the popularity of combination therapy decreased significantly. It was replaced by the tactics of a differentiated choice of drugs using them in maximum doses in the Monotherapy mode. Monotherapy with high doses of antihypertensive drugs often led to the activation of counterregulatory mechanisms that increase blood pressure and / or the development of adverse events. In this regard, it is not surprising that in the next decade, hopes for a higher antihypertensive activity of angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists did not materialize, and the pendulum of attitudes towards combination therapy returned to its original position, i.e. it was recognized as necessary for most patients with hypertension. A new round in the evolution of this approach is associated with the emergence of fixed low-dose combinations of antihypertensive drugs in the late 90s. These were combinations that did not contain a diuretic (calcium antagonist + ACE inhibitor; dihydropyridine calcium antagonist + beta-blocker) or containing it in low doses. Already in 1997, 29 fixed combinations were presented in the list of antihypertensive drugs in the report of the US Joint National Committee (VI). The feasibility of low-dose combined rational antihypertensive therapy, especially in patients with a high risk of developing cardiovascular complications, was confirmed in the latest recommendations of the WHO / International Society for Arterial Hypertension (1999) and DAH-1 (2000) .

Thus, the following stages can be distinguished in the history of combined antihypertensive therapy: I - the use of combinations containing rauwolfia derivatives and/or components in high doses; II - the use of combinations of diuretics in high or medium doses with beta-blockers, potassium-sparing diuretics, ACE inhibitors and III - the predominant use of fixed combinations without diuretics (beta-blocker + dihydropyridine calcium antagonist; calcium antagonist + ACE inhibitor) or containing diuretics in low doses (hydrochlorothiazide 6.25-12.5 mg; indapamide 0.625 mg)

Significant variability in the antihypertensive effect of different drugs has been repeatedly confirmed in cross-sectional and longitudinal clinical studies. However, the search for reliable criteria for individual choice of drugs was unsuccessful. At the same time, the effectiveness of Monotherapy with antihypertensive drugs of different classes is generally comparable: 40-50% of patients respond to treatment. The return to combination therapy is often associated with the results of the HOT mega-study, which confirmed the necessity of achieving the target level of blood pressure for a real reduction in cardiovascular risk. To solve this problem, combination therapy was required in 2/3 of the patients. Similar data were obtained from a retrospective analysis of most of the cited studies on hypertension (Fig. 1). The lower the required target pressure level (for example, in patients with diabetes mellitus and renal insufficiency), the more drugs the patient needs. Thus, the rationale for the relevance of combined antihypertensive therapy can be the following provisions: the effect of drugs of various classes on different physiological systems involved in the regulation of blood pressure, and a proven increase in the number of patients responding to treatment, up to 70-80%; neutralization of counterregulatory mechanisms aimed at increasing blood pressure; reducing the number of required visits; the possibility of more rapid normalization of blood pressure without increasing the frequency of adverse events (often it decreases); frequent need for rapid and well-tolerated reduction in blood pressure and / or achievement of low blood pressure targets in high-risk groups; the possibility of expanding indications for appointment.

Rational combination therapy must meet a number of prerequisites: safety and efficacy of the components; the contribution of each of them to the expected result; different but complementary mechanisms of action; higher efficiency compared to that of monotherapy with each of the components; balance of components in terms of bioavailability and duration of action; strengthening of organoprotective properties; impact on the universal (most frequent) mechanisms of increasing blood pressure; reducing the number of adverse events and improving tolerability. In table. Table 1 shows the undesirable consequences of the use of the main classes of drugs and the possibility of their elimination by adding a second drug.

TABLE 1. Adverse events of antihypertensive drugs and options for their management

Preparation A	Possible effects of drug A	Corrective drug
Dihydropyridine AK	SNS activation, heartbeat	Beta blocker
Dihydropyridine AK	Peripheral edema	ACE inhibitors
diuretic	Hypokalemia, hypomagnesemia, insulin resistance (?), RAS and/or SNS activation	ACE inhibitors, AT 1 receptor blockers
Antiadrenergic drugs	Fluid retention, edema, pseudo-resistance	diuretic
diuretic	Dyslipidemia	Alpha blocker
Beta blocker	Sodium retention, decreased cardiac output and renal blood flow	diuretic
Beta blocker	Peripheral vasospasm	calcium antagonist
Alpha blocker	Vasodilation, first-dose hypotension, postural hypotension	Beta blocker
Note: AK - calcium antagonist, RAS - renin-angiotensin system, SNS - sympathetic nervous system

The use of a combination of two drugs with similar pharmacodynamic properties can lead to different consequences in terms of quantitative interaction parameters: sensitization (0+1=1.5); additive action (1+1=1.75); summation (1+1=2) and effect potentiation (1+1=3). In this regard, it is rather conditionally possible to single out rational and irrational combinations of antihypertensive drugs (Table 2).

TABLE 2. Possible combinations of antihypertensive drugs

Established rational combinations

Possible rational combinations

Possible but less rational combinations

Irrational combinations

Combinations whose rationality requires clarification

Combination therapy does not always mean an increase in the antihypertensive effect and may lead to an increase in adverse events (Table 3).

TABLE 3. Adverse effects of the combined use of antihypertensive drugs

Preparation A	Drug B	Adverse effects exacerbated by drug B
diuretic	Vasodilators	hypokalemia
Non-dihydropyridine AAs	Beta blocker	Atrioventricular block, bradycardia
Alpha blocker	diuretic	First-dose hypotension, postural hypotension
ACE inhibitor	diuretic	Decreased glomerular filtration rate
ACE inhibitor	Potassium-sparing diuretic	Hyperkalemia
diuretic	Beta blocker	Hyperglycemia, dyslipidemia
Hydralazine	Dihydropyridine AK	Palpitations, myocardial ischemia
Dihydropyridine AK	alpha blocker	Hypotension
ACE inhibitor	Alpha blocker	Hypotension

There are different ways to use combination therapy. Two, three drugs or more can be prescribed sequentially, gradually titrating the doses of the components. After reaching the target blood pressure, the selected combination can be used for long-term maintenance therapy. Very valuable for rational treatment are fixed combined preparations, for the creation of which improved dosage forms are used. The advantages of low-dose combined antihypertensive drugs include the following: simplicity and ease of administration for the patient; facilitating dose titration; ease of prescribing the drug; increased patient adherence; reducing the frequency of adverse events by reducing the doses of the components; reducing the risk of using irrational combinations; confidence in the optimal and safe dose regimen; price reduction. The disadvantages are fixed doses of components, difficulties in identifying the cause of adverse events, lack of confidence in the need for all the components used. Additional requirements for combined drugs are the absence of unpredictable pharmacokinetic interactions and the optimal ratio of residual and maximum effects. Rational selection of components creates the prerequisites for prescribing drugs once a day, which, with Monotherapy, have to be used two or even three times a day (some beta-blockers, ACE inhibitors and calcium antagonists).

Thiazide diuretic + potassium sparing diuretic: amiloride + hydrochlorothiazide, spironolactone + hydrochlorothiazide, triamterene + hydrochlorothiazide (Triampur). This combination helps to prevent the loss of potassium and magnesium, but is currently practically not used, given the presence of ACE inhibitors, which can not only effectively prevent hypokalemia and hypomagnesemia, but are also better tolerated.

Thiazide diuretic + beta-blocker: Tenoretik (atenolol 50 or 100 mg + chlorthalidone 25 mg), Lopressor (metoprolol 50 or 100 mg + hydrochlorothiazide 25 or 50 mg) and Inderid (propranolol 40 or 80 mg + hydrochlorothiazide 25 mg). A combination of two of the most well-studied classes of antihypertensive agents. Beta-blocker modulates the following possible consequences of the use of a diuretic: tachycardia, hypokalemia and activation of the renin-angiotensin system. A diuretic is able to eliminate sodium retention caused by a beta-blocker. There is evidence that this combination provides control of blood pressure in 75% of cases. However, it is necessary to clarify the consequences of long-term use of this combination due to the possible adverse effects of the components on lipid, carbohydrate, purine metabolism, as well as sexual activity.

Diuretic + ACE inhibitor or AT-receptor blocker. Highly effective combinations that provide an impact on the two main pathophysiological mechanisms of hypertension: sodium and water retention and activation of the renin-angiotensing system. The effectiveness of such combinations has been demonstrated in low-, normo- and high-renin hypertension, including in patients who do not respond to blockers of the renin-angiotensin system (for example, in African Americans). The frequency of hypertension control increases to 80%. Blockers of the renin-angiotensin system eliminate hypokalemia, hypomagnesemia, dyslipidemia, carbohydrate metabolism disorders that can develop with monotherapy with diuretics. The use of the AT 1 blocker losartan helps to reduce the level of uric acid. Such combinations are very promising in patients with left ventricular hypertrophy and diabetic nephropathy. The most well-known combination drugs of this composition are Capozid (captopril 25 or 50 mg + hydrochlorothiazide 15 or 25 mg), Co-Renitec (enalapril 10 mg + hydrochlorothiazide 12.5 mg), Gizaar (losartan 50 mg + hydrochlorothiazide 12.5 mg). Additional beneficial potential has Noliprel, which is a combination of perindopril 2 mg with a metabolically neutral diuretic indapamide 0.625 mg.

ACE inhibitor + calcium antagonist. ACE inhibitors neutralize the possible activation of the sympathoadrenal system under the action of calcium antagonists. According to the ability to activate this system, calcium antagonists are arranged in the following order (in descending order): short-acting dihydropyridines, long-acting dihydropyridines, non-dihydropyridine calcium antagonists. Possessing venodilating properties, ACE inhibitors reduce the incidence of peripheral edema that develops as a result of arteriolar dilatation under the influence of calcium antagonists. On the other hand, the natriuretic effect of calcium antagonists creates a negative sodium balance and enhances the hypotensive effect of ACE inhibitors. There is encouraging clinical experience with such combinations. In particular, in the FACET study, the best rates of cardiovascular morbidity and mortality were achieved in the group of patients treated with fosinopril and amlodipine. In the HOT study, the calcium antagonist felodipine was supplemented with a low-dose ACE inhibitor as early as the second step. It was this largest study, which examined the effect of combined antihypertensive therapy on the risk of adverse outcomes, that demonstrated the possibility of achieving target diastolic blood pressure in more than 90% of patients. Last year, the results of the HOPE study have been widely discussed, which are of great interest in terms of the effectiveness of combination therapy for hypertension in high-risk groups. BP was elevated in 47% of patients included in this study; most of them also suffered from coronary artery disease. The frequency of combined use of ramipril with calcium antagonists was 47%, with beta-blockers - 40%, diuretics - 25%. The combination of a calcium antagonist and an ACE inhibitor is attractive from the point of view of enhancing not only the cardioprotective, but also the nephroprotective effect. Currently, there are several fixed combinations of drugs of these classes: Lotrel (amlodipine 2.5 or 5 mg + benazepril 10 or 20 mg), Tarka (verapamil ER + trandolapril in the following doses in mg - 180/2, 240/1, 240 / 2, 240/4), Lexel (felodipine 5 mg + enalapril 5 mg).

Calcium antagonist (dihydropyridine) + beta-blocker. This combination is rational in terms of hemodynamic and metabolic interactions. Numerous data testify not only to the theoretical validity, but also to the practical value of the combination of the highly vasoselective dihydropyridine calcium antagonist felodipine and the cardioselective (3-blocker metoprolol at doses of 5 and 50 mg (Logimax)). The components are well studied in multicenter clinical studies. In the HAPPPY, MAPHY studies , MERIT HF demonstrated the following effects of metoprolol and metoprolol SR: a significant reduction in total and cardiovascular mortality, including heart failure, a pronounced cardioprotective effect in the treatment and prevention of myocardial infarction, no effect on carbohydrate and lipid metabolism. database occupies one of the leading positions not only in its class of drugs, but also among all antihypertensive drugs.In clinical studies of HOT, V-HeFT, STOP-HYPERTENSTON-2, the following effects of felodipine were established: a decrease in total peripheral vascular resistance and load on the myocardium; increased cardiac output at rest and during exercise; increased tolerance to physical activity; a significant decrease in left ventricular hypertrophy; improvement of rheological properties of blood; 24-hour blood pressure control with a single use per day; high efficiency and good tolerability in all stages of hypertension, regardless of age; effectiveness in often concomitant hypertension conditions, such as coronary artery disease, diabetes mellitus, obliterating endarteritis; the absence of contraindications (except for hypersensitivity) and, most importantly, a clear favorable effect on cardiovascular morbidity and mortality, including in high-risk groups (in elderly people with diabetes mellitus). The possibility of using metoprolol and felodipine in relatively low doses allows the components of Logimax to fully show cardioselective and vasoselective properties. Logimax is a unique dosage form that provides a controlled release of active drugs for 24 hours. Felodipine is a gel matrix containing metoprolol microcapsules. After contact with the liquid medium, the formation of a gel shell occurs, with the gradual destruction of which the release of felodipine and microcapsules with metoprolol occurs.

Place of combination therapy in modern treatment of arterial hypertension

The initial choice of tactics of drug treatment of hypertension often plays a critical role in the future fate of the patient. A successful choice is the key to high adherence to treatment, an unsuccessful choice means a lack of BP control and / or failure to comply with doctor's prescriptions. The choice of the initial scheme of drug correction of hypertension remains empirical. In accordance with the traditional algorithm, treatment is considered appropriate to start with one drug in the minimum dose. Subsequently, the dose is increased or a second drug is added. However, this approach can hardly be considered always justified. Modern drugs intended for the basic therapy of hypertension show their full potential in 4-6 weeks, so the selection of antihypertensive therapy can stretch for many months, requiring repeated visits, and often additional examinations. Certain indications for the predominant prescription of drugs (Table 5) do not allow to reduce this period due to variable individual tolerability.

TABLE 5. Established indications for preferential use of certain antihypertensive drugs

Previously, long-term monotherapy was strongly recommended for patients with so-called "mild" hypertension. Taking into account the current clinical interpretation of hypertension in terms of risk level, such a recommendation can be extended only to a small group of patients with a low level of cardiovascular risk. In high- and very high-risk patients, fixed combinations should be used more frequently as early as the first stage of treatment. Of no small importance is the estimated adherence of patients to the treatment of hypertension (Table 6). If it is low, then the use of fixed combinations should also be more actively recommended.

TABLE 6. Factors affecting treatment adherence

Thus, at present, we can use two principal approaches to the pharmacological treatment of hypertension: sequential monotherapy until the choice of an effective and well-tolerated agent, or combination therapy in a regimen of sequential prescription of drugs or the use of fixed combinations of antihypertensive agents. Both approaches have advantages and disadvantages. Modern understanding of the pathogenesis of hypertension draws attention to fixed low-dose combinations that can increase the effectiveness of treatment, reduce the risk of adverse events and increase patient adherence to treatment and, therefore, optimize therapy in a large number of patients. However, further large-scale controlled studies are needed to investigate the effect of these relatively new drugs on meaningful intermediates and long-term prognosis.

Literature

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6. Hansson L., Zanchetti A., Carruthers S. et al. Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet, 1998, 351, 1755-1762.
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Federal State Budgetary Institution "Educational and Scientific Medical Center" of the Administration of the President of the Russian Federation, Moscow

The review of the literature presents current ideas about the relationship of cognitive dysfunction with major risk factors and adverse cardiovascular outcomes. The main approaches to antihypertensive therapy for primary and secondary prevention of stroke, as well as the prevention of vascular dementia, are analyzed. The effectiveness of the angiotensin receptor blocker olmesartan in the treatment of arterial hypertension is considered in detail. Evidence of its angioprotective and cerebroprotective properties is presented. They make it possible to recommend the drug primarily for the treatment of elderly patients with arterial hypertension, for whom the task of maintaining cognitive functions is one of the priorities.
Keywords Key words: olmesartan, arterial hypertension, cognitive functions, dementia, stroke.

Rational Antihypertensive Treatment as Basis for Cerebral Protection and Cognitive Decline Prevention

L.O. Minushkina

Educational and Science Medicine Center of RF President Administration Department for Property Management, Moscow

The review of literature presents modern concepts of the relationship between cognitive decline and major cardiovascular risk factors, adverse cardiovascular outcomes. Basic approaches to antihypertensive therapy for primary and secondary prevention of stroke and vascular dementia are described. The article details the effectiveness of angiotensin receptor blocker called olmesartan in the treatment of hypertension. The drug presents vascular and cerebral protective properties; so olmesartan should be used primarily in elderly patients with hypertension in order to maintain cognition.
keywords: olmesartan, hypertension, cognition, dementia, stroke.

Cognitive decline is a very significant risk factor for adverse outcomes. In a large study that included more than 30,000 patients followed up for about 5 years, it was shown that the presence of dementia is associated with the risk of stroke, heart failure, and cardiovascular mortality. A reduction in Mini Mental Status Assessment (MMSE) scores below 24 was similar to previous stroke in terms of effect on the risk of recurring events. The association of cognitive dysfunction with other adverse outcomes is that dementia may be a marker of the severity of target organ damage. In addition, patients with dementia are characterized by low adherence to treatment. Patients with cognitive decline have lifestyle features associated with the limitation of physical activity, the nature of nutrition, and the frequent development of mental depression. All this contributes to the progression of vascular diseases. Arterial hypertension (AH) is one of the leading risk factors for the development of progressive forms of cerebrovascular pathology and the formation of cognitive impairment.

Antihypertensive therapy is the basis of stroke prevention

For most patients, a reduction in the risk of complications is achieved by lowering blood pressure (BP) to 140/90 mm Hg. Art. The same level of blood pressure is considered as a target for secondary prevention of strokes. Achieving lower BP levels does not improve prognosis in these patients. For elderly patients with hypertension, even a higher level of systolic blood pressure - 150 mm Hg is considered as a target. With a decrease in blood pressure in these groups of patients, it is especially important to consider the tolerability of treatment.

In a meta-analysis of the largest studies on secondary prevention of stroke in patients with ischemic, hemorrhagic stroke or transient ischemic attack, it turned out that the success of secondary prevention depends primarily on the level of systolic blood pressure achieved during treatment. The overall reduction in the risk of recurrent strokes was 24%. At the same time, there were differences in the effectiveness of different classes of antihypertensive drugs. The use of thiazide diuretics, and especially the combination of the latter with ACE inhibitors, made it possible to more significantly reduce the risk of adverse outcomes than antihypertensive therapy with beta-blockers. One of the most well-known studies demonstrating the effectiveness of antihypertensive therapy in the secondary prevention of stroke was the PROGRESS study (Perindopril protection against recurrent stroke study), which showed a 28% reduction in the risk of recurrent stroke in the active treatment group (patients received perindopril as monotherapy). and in combination with indapamide). In the group receiving only perindopril, blood pressure decreased by 5/3 mm Hg. st, and there was no significant reduction in the risk of stroke compared with the placebo group. In patients receiving combined therapy with perindopril and indapamide, the decrease in blood pressure was more significant - 12/5 mm Hg. Art., and the risk of stroke decreased by 46%, which was significant compared with placebo. The effectiveness of antihypertensive therapy in the secondary prevention of stroke was also shown in a number of other studies, such as PATS, ACCESS.

In the primary prevention of stroke in patients with arterial hypertension, the degree of reduction in blood pressure is also the most significant for the prognosis. Upon reaching the target values of blood pressure, the reduction in the risk of stroke reaches 40%. In patients with a predominant increase in diastolic blood pressure, its decrease by 5-6 mm Hg. Art. leads to a 40% reduction in the risk of stroke. In patients with isolated systolic arterial hypertension, a decrease in systolic blood pressure reduces the risk of cerebrovascular accidents by 30%. Significant factors also include the use of statins, therapy with ACE inhibitors, endarterectomy in patients with hemodynamically significant stenosis of the coronary arteries. The use of aspirin leads to a decrease in the risk of stroke in patients with high cardiovascular risk. In patients with low and moderate risk of complications, the use of aspirin did not lead to a decrease in the risk of stroke.

Until recently, the question of the effectiveness of antihypertensive therapy in patients of older age groups remained open. Specifically designed to evaluate the effectiveness of treatment in patients with arterial hypertension older than 80 years, the HYVET study showed that combination antihypertensive therapy reduced the risk of stroke by 39%.

There is evidence of possible cerebroprotective properties of angiotensin receptor blockers. Thus, in the SCOPE study, it was shown that in patients with arterial hypertension over the age of 70 years, therapy with the angiotensin receptor blocker candesartan significantly reduced the risk of non-fatal strokes. Particularly significant was the reduction in the risk of stroke in the treatment of angiotensin receptor blockers in patients with isolated systolic hypertension. This was confirmed by the results of the LIFE study, where losartan reduced the risk of stroke by 40% in patients with ISAH, and the SCOPE study, where a 42% reduction in the risk of stroke was achieved in this subgroup.

The mechanism by which angiotensin receptor blockers have cerebroprotective properties is associated with the effect of stimulation of type 2 angiotensin receptors. It is this type of receptor that is expressed in the central nervous system. Their stimulation leads to a significant increase in cerebral blood flow. When treated with selective angiotensin type 1 receptor blockers, there is an increase in the plasma level of angiotensin II, which, acting on type 2 receptors, creates conditions for cerebroprotection.

Prevention of vascular dementia

One of the most common manifestations of chronic cerebrovascular disease is vascular dementia. At the same time, data on the relationship between the progression of vascular dementia and the level of blood pressure and the effectiveness of antihypertensive therapy are contradictory. An increase in blood pressure is a factor contributing to the progression of atherosclerotic vascular lesions, causing prothrombotic shifts, and on the other hand, it is a compensatory reaction associated with impaired autoregulation of cerebral circulation. The relationship between the progression of vascular dementia and the level of blood pressure is non-linear. In addition, the severity of cognitive impairment is also affected by the presence of other concomitant diseases and conditions - dyslipidemia, diabetes mellitus. It should be noted that stroke itself is one of the most significant factors leading to the development of dementia. It is fixed in 10% of patients after the first stroke and in 30% of patients with repeated strokes. This raises the importance of stroke prevention as an opportunity to prevent the onset of severe cognitive impairment.

The effectiveness of antihypertensive therapy in relation to the prevention of cognitive impairment has been studied in several large randomized trials. In the Syst-Euro study, nitrendipine therapy was shown to reduce the incidence of vascular dementia by 50%. In the PROGRESS study, the incidence of vascular dementia in the group treated with perindopril (as monotherapy and in combination with indapamide) decreased by 19%. On the other hand, in studies such as SHEP, SCOPE, HYVET-COG, therapy did not affect the incidence of cognitive impairment.

Angiotensin receptor blockers help prevent the development of cognitive dysfunction. This was shown in a large meta-analysis that included data from the ONTARGET and TRANSDENT studies. Treatment with this group of drugs made it possible to achieve a 10% reduction in the risk of developing vascular dementia with long-term treatment.

It is interesting to note that, according to meta-analyzes, with a small decrease in blood pressure (by 4.6/2.7 mmHg), there is an improvement in short-term memory test scores. In studies that achieved a more significant reduction in blood pressure (by 17/10 mmHg), test scores worsened.

Tactics of lowering blood pressure for the prevention of cerebrovascular complications

It should be noted that the choice of a particular drug is most often not fundamentally important. In most patients, in order to achieve the target values of blood pressure, it is necessary to resort to the appointment of a combination therapy with two, three or more drugs from different groups. Monotherapy can be justified as a start in patients with grade 1 hypertension and a low or moderate risk of complications. In patients with grade 2–3 hypertension who have a high or very high additional risk of complications, treatment can be started immediately using combination therapy.

It should be noted that patients with cerebrovascular disease, elderly patients do not always tolerate such a decrease in blood pressure. When selecting therapy, it is necessary to take into account individual tolerance and avoid episodes of hypotension. In this case, it is necessary to take into account age-related features, in particular, the optimal value of systolic blood pressure for the elderly is usually 135–150 mm Hg. Art., its further decrease leads to an aggravation of the clinical picture of cognitive dysfunction and an increased risk of ischemic stroke. Particular care should be taken to reduce blood pressure in patients with hemodynamically significant atherosclerosis of the carotid arteries. As one of the methods of control that facilitates the selection of therapy, daily monitoring of blood pressure can be used. This method allows you to control blood pressure at night, the rate and magnitude of the morning rise in blood pressure, the presence of episodes of excessive hypotension. When analyzing all parameters of 24-hour BP monitoring, it turned out that the highest predictive value in relation to the risk of stroke is the level of systolic BP at night.

For the prevention of cerebrovascular events, the ability of drugs to influence the state of the vascular wall and influence central pressure is also essential. The significance of these effects was demonstrated in the CAFE study conducted by the ASCOT project. The combination of amlodipine and perindopril has been shown to reduce central aortic pressure to a greater extent than treatment with atenolol and bendroflumethiazide. As is known, central blood pressure is closely related to the stiffness/elasticity of the vascular wall and pulse wave velocity, which, in turn, can affect the occurrence of cardiovascular events, especially stroke.

The combination of a blocker of the renin-angiotensin system (ACE inhibitor or angiotensin receptor blocker) with a calcium antagonist or thiazide diuretic seems to be the most rational and pathogenetically justified today. The combination of two drugs in full doses does not normalize blood pressure in 10-20% of patients. If necessary, a combination of three antihypertensive agents is preferably a combination of a blocker of the renin-angiotensin system, a thiazide diuretic, or a calcium antagonist.

In elderly patients, drugs from the group of angiotensin receptor blockers have certain advantages. This group of antihypertensive drugs is characterized by cerebroprotective properties, as well as very good tolerability, low risk of side effects, which leads to good adherence of patients to treatment. One of the drugs in this group is olmesartan (CardosalR, Berlin-Chemie/A.Menarini), which has shown good efficacy in elderly patients, angio- and cerebroprotective properties.

Efficacy of olmesartan in the elderly

Olmesartan medoxomil is rapidly absorbed from the gastrointestinal tract after oral administration. The bioavailability of the drug is 26-28%, 35-50% of the dose is excreted unchanged by the kidneys, the rest - with bile. The pharmacokinetics of olmesartan in elderly and young patients does not differ significantly. In the treatment of hypertension, the drug is prescribed at a dose of 10–40 mg per day in a single regimen.

A meta-analysis of randomized studies using angiotensin receptor blockers, which included 4892 patients treated with olmesartan, showed that the decrease in blood pressure during olmesartan therapy was more significant than during therapy with losartan and valsartan. At the same time, the tolerance of olmesartan is not worse than that of other sartans.

The efficacy of olmesaratan in elderly patients was evaluated in two similarly designed studies. A total of 1646 patients over 65 years of age participated in them. In one of the studies, the efficacy of olmesartan was evaluated in patients with isolated systolic hypertension, in another - with systolic-diastolic hypertension. Olmesartan was prescribed at a dose of 20–40 mg/day. In patients with isolated systolic hypertension, after 12 weeks of therapy, systolic blood pressure decreased by 30 mm Hg. Art. with a slight change in diastolic blood pressure. After 24 weeks of therapy, blood pressure returned to normal in 62.5% of patients. The drug was well tolerated in patients aged 65-74 years, and in patients older than 75 years.

In a meta-analysis of 2 randomized trials comparing the efficacy of ramipril and olmesartan, data on the treatment of 1400 patients with grade 1 and 2 hypertension over the age of 65 years were analyzed. It turned out that olmesartan is more effective in reducing blood pressure. Therapy with olmesartan creates a more stable antihypertensive effect throughout the day, independent of the time of eating. Both drugs were well tolerated.

Two identically designed studies (European and Italian) compared the efficacy of ramipril and olmesartan in elderly patients. The dose of ramipril was titrated from 2.5 to 10 mg, olmesartan from 10 to 40 mg. A total of 1453 patients participated in the studies. In 715 of them, control over the effectiveness of therapy was carried out using daily monitoring of blood pressure. The decrease in blood pressure was more pronounced during olmesartan therapy - the difference in the achieved level of systolic blood pressure was 2.2 mm Hg. Art., diastolic blood pressure - 1.3 mm Hg. Art. Olmesartan created a significantly more pronounced decrease in blood pressure in the last 6 hours before taking the next dose. The smoothness index of BP reduction was also higher in the olmesartan group. Only in the treatment with this drug was there a significant decrease in the rate of the morning increase in blood pressure, in the ramipril group there was no such dynamics. Thus, olmesartan was more effective in the elderly. It has been shown that during long-term therapy in patients with hypertension, olmesartan not only leads to a persistent decrease in blood pressure, but also helps to reduce pressure variability and improves the state of autonomic regulation of vascular tone.

The 735 patients in this study had metabolic syndrome and were analyzed separately for drug efficacy. In general, in the group, normalization of blood pressure was achieved in 46% of patients in the olmesartan group and in 35.8% of patients in the ramipril group. The same regularities could be traced in groups of patients with both the presence and absence of the metabolic syndrome. Among elderly patients with metabolic syndrome during olmesartan therapy, the average daily systolic blood pressure decreased by 10.2 mm Hg. Art. and diastolic blood pressure - by 6.6 mm Hg. Art., and against the background of the appointment of ramipril - by 8.7 and 4.5 mm Hg. Art. respectively. The incidence of side effects was similar with both drugs.

Olmesartan is also effective in combination therapy. The Japanese study of olmesartan in the elderly (Miyazaki Olmesartan Therapy for Hypertension in the EldeRly - MOTHER) compared the efficacy of olmesartan in patients with hypertension in combination with a calcium antagonist and a thiazide diuretic. The combination with a calcium antagonist was somewhat more effective in patients with normal body weight, and the combination with a thiazide diuretic had little benefit in overweight patients. The blood creatinine level remained stable throughout the 6 months of treatment. In the group of patients with normal body weight, regardless of the type of treatment, there was a significant decrease in blood aldosterone activity, which was not found in patients with obesity.

Elderly patients showed good efficacy of the combination of olmesartan and hypothiazide. The antihypertensive efficacy of a combination of 40 mg of olmesartan and 25 mg of hypothiazide was studied in a group of 176 hypertensive patients over 65 years of age. 116 patients had grade 1 hypertension, 60 patients had grade 2 hypertension, 98 patients had isolated systolic hypertension. Titration of antihypertensive therapy was carried out according to the scheme of olmesartan 20 mg per day, then 40 mg per day, combination with hypothiazide 12.5 mg, then 25 mg. Combination therapy was required in 159 patients. Normalization of blood pressure during treatment was achieved in 88% of patients with grade 1 hypertension, in 56% of patients with grade 2 hypertension, and in 73% of patients with isolated systolic hypertension. Daily monitoring of blood pressure showed a sufficient duration of antihypertensive action when taking the combination once a day. The frequency of side effects associated with hypotension did not exceed 3%.

Angioprotective effects of olmesartan

Olmesartan is able to inhibit the progression of atherosclerotic vascular lesions, which was shown in a large randomized study MORE (The Multicentre Olmesartan atherosclerosis Regression Evaluation study). The study compared the effects of olmesartan and atenolol on carotid intima-media thickness and atherosclerotic plaque volume. Olmesartan was prescribed at a dose of 20–40 mg/day, atenolol – 50–100 mg/day. Examination of the carotid arteries using 2D and 3D ultrasound was performed at 28, 52 and 104 weeks of treatment. The thickness of the carotid intima-media complex decreased in both groups, there were no significant intergroup differences. The decrease in the volume of atherosclerotic plaques was more significant during olmesartan therapy, and in the group of patients with an initial lesion volume greater than the median of the group, differences in the effectiveness of the drugs were significant.

The angioprotective effect of olmesartan was also shown in a comparative study with the dihydropyridine calcium antagonist amlodipine. Patients with hypertension and diabetes received either 20 mg of olmesartan or 5 mg of amlodipine for a year. With the same antihypertensive effect, olmesartan also contributed to a significant decrease in the cardio-ankle index, which reflects the severity of arterial stiffness. The authors of the study attribute the angioprotective effect of olmesartan to its antioxidant properties.

A decrease in central pressure has also been shown during treatment with olmesartan. The combination of olmesartan with dihydropyridine calcium antagonists is especially effective. In a randomized trial compared the effect of two combinations on the level of central blood pressure. 486 patients were allocated to treatment with olmesartan and amlodipine 40/10 mg or perindopril and amlodipine 8/10 mg. Central systolic pressure while taking the first combination decreased by 14.5 mm Hg, and when using the second combination by 10.4 mm Hg. Art. Differences between groups were significant. In the olmesartan group, normalization of blood pressure was achieved in 75.4% of patients, in the treatment with perindopril - in 57.5%. .

In combination therapy, the combination of olmesartan with a dihydropyridine calcium antagonist is more effective in reducing central aortic pressure than the combination of olmesartan and a thiazide diuretic. The decrease in pressure on the brachial artery was the same.

The basis of the angioprotective action of olmesartan may be its effect on the processes of peroxidation, the function of the vascular endothelium, the level of inflammatory mediators, and some biomarkers. The antioxidant effect of olmesartan was shown in a small study where 20 patients with hypertension received olmesartan therapy at a dose of 20 mg / day for 6 months. The drug was effective and allowed to normalize blood pressure in all patients. At the same time, the level of markers of oxidative stress and oxidized lipoproteins, as well as markers of inflammation, significantly decreased.

In a comparative study on a group of 31 patients with hypertension compared the efficacy of olmesartan and amlodipine. Both drugs were equally effective in lowering blood pressure, but only with the use of olmesartan were signs of improvement in endothelial function revealed. Only treatment with olmesartan improved the degree of reactive hyperemia. In the same group, a decrease in the level of albuminuria and a decrease in C-reactive protein were registered. Increased urine antioxidant levels. The dynamics of the plasma level of superoxide disumutase was not revealed, however, there was a correlation between the level of this antioxidant defense enzyme and the degree of endothelium-dependent vasodilation.

In a group of 30 patients with hypertension, the effects of long-term (6 months) therapy with olmesartan at a dose of 20 mg/day were evaluated. Olmesartan effectively reduced blood pressure, contributed to a significant decrease in the cardio-ankle index, which reflects the stiffness of the arterial wall. The level of C-reactive protein and the protein that binds fatty acids of adipocytes significantly decreased.

All these angioprotective properties create the prerequisites for the effectiveness of olmesartan in the prevention of vascular dementia and cerebral stroke.

Cerebroprotective properties of olmesartan

The basis of the cerebroprotective effect of olmesartan may be its effect on the state of cerebral blood flow. This was shown in a study where a group of elderly hypertensive patients with no history of CNS involvement received olmesartan for 24 months. Initially, a decrease in regional blood flow in the frontal, parietal, temporal, and occipital lobes by 11–20% was shown compared with the control group, which included persons comparable in age but without AH. Initially, in the group of patients with hypertension, the mean blood pressure was 156/88 mm Hg. Art., and against the background of treatment with olmesartan - 136/78 mm Hg. Art. At the same time, at the end of treatment, the indices of regional cerebral blood flow did not differ from those in the control group.

In the group of patients who had a stroke, the efficacy of olmesartan therapy at a dose of 10–20 mg per day for 8 weeks was evaluated. During treatment, patients showed a significant improvement in the state of regional cerebral blood flow. The increase in cerebral blood flow in the affected area was 11.2%, in the contralateral zone - 8.9%. The state of autoregulation of the tone of cerebral vessels improved. As a result, this led to an improvement in the processes of rehabilitation of patients after a stroke and a decrease in neurological deficit. An improvement in the condition of patients according to the Bartels index and the MMSE scale was registered. When comparing the effectiveness of olmesartan and amlodipine therapy in patients after stroke, it turned out that with the same effect on peripheral blood pressure, only olmesartan therapy improved cerebral blood flow. Only in the group treated with olmesartan after a stroke, there was an increase in cerebral blood flow both from the side of the lesion and in the healthy hemisphere, as well as an increase in cerebrovascular reserve. The range of motion in the hand increased by 30%, the arm – by 40%, and the leg – by 100%. At the same time, the increase in movements in the arm and leg was significantly greater than during amlodipine therapy. The Bartels index and MMSE also increased.

Thus, olmesartan has not only good antihypertensive efficacy, the ability to reduce arterial stiffness, improve vascular endothelial function, but also has cerebroprotective properties. This allows us to recommend the drug primarily for the treatment of elderly patients with hypertension, for whom the task of maintaining cognitive functions is one of the priorities.

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These are the decisions of experts of the All-Russian Scientific Society of Cardiology (VNOK) in 2004 on the adoption of target levels of blood pressure. Combined regimen for the use of antihypertensive drugs as a tool for normalizing high blood pressure. Analysis of the history and data of ongoing research.

Profequarrels V.S. Zadionchenko, Ph.D. G.G. Shekhyan, N.Yu. Timofeeva, A.M. Shchikota, Ph.D. A.A. Yalymov

MGMSU

Many studies completed in recent years have clearly demonstrated that only "strict" control of blood pressure (BP) can significantly reduce the incidence of cardiovascular complications (CVS) - myocardial infarction (MI), acute cerebrovascular accident (ACV), chronic heart failure ( CHF) in patients with arterial hypertension (AH). Based on the results of these studies, desirable target levels of blood pressure were determined. According to the recommendations of experts from the World Health Organization (WHO) and the International Society of Hypertension (ISHA) (1999), the target level of blood pressure for young and middle-aged people, as well as patients with diabetes mellitus (DM), is recognized as values not exceeding 130/85 mm Hg. Art., for the elderly - 140/90 mm Hg. Art. In 2003, the European Society of Hypertension (ESH), together with the European Society of Cardiology (ESC), adopted recommendations for the management of patients with hypertension and published the 7th report of the American Joint National Committee (JNC) on the prevention, detection, detection and treatment of high blood pressure. . In these documents, values no higher than 140/90 mm Hg are also taken as the target level of blood pressure. Art., and for patients with diabetes and kidney damage - no higher than 130/80 mm Hg. Art. Experts of the All-Russian Scientific Society of Cardiology (VNOK) in 2004 adopted similar target levels of blood pressure.

Achieving target levels of blood pressure with a single antihypertensive drug (AHP) is possible only in 5-50% of patients with 1 and 2 severity of hypertension, and in patients with 3 severity of hypertension, in the presence of target organ damage, diabetes, signs of CVE, monotherapy is effective only in rare cases. Back in 1989, data from the Glasgow Blood Pressure Clinic study confirmed the dominant role of blood pressure levels achieved as a result of treatment in the prognosis of hypertension and clearly demonstrated high rates of cardiovascular mortality and morbidity with an insufficient degree of its reduction. Later, these provisions were confirmed in the HOT study. Similar data were obtained from a retrospective analysis of most of the cited studies on hypertension (Fig. 1).

The combined regimen for the use of antihypertensive drugs as a tool for normalizing elevated blood pressure has always been present in the pharmacotherapeutic arsenal of hypertension, however, views on the place of combination therapy in the treatment of hypertension have been reconsidered. In case of ineffectiveness of combination therapy, they switch to the drugs that are part of the used combination at a full dose, or add a third drug at a low dosage. If this therapy does not lead to the achievement of target levels of blood pressure, then a combination of 2-3 drugs is prescribed in the usual effective doses. The question of which patients can be prescribed combination therapy at the first stage of treatment is still open.

To make it easier to make a decision on how to treat a patient with hypertension who came to an appointment for the first time or again, we suggest that doctors use the algorithm shown in Figure 2.

Even if the patient came for the first time, we have the opportunity to measure blood pressure and preliminarily assess the degree of cardiovascular risk. If the risk is low or moderate, we can start with recommendations for lifestyle changes and the yellow side of the algorithm, if the risk is high or very high, medical treatment should be started immediately, going on the red side. The advantage of the algorithm is that, by helping to make a decision quickly, it leaves the doctor complete freedom of choice in the treatment of a patient with hypertension.

History reference

As early as the beginning of the 20th century. it became known about the influence of neurohumoral factors on the development of hypertension. In the 1930s discovered a substance now called angiotensin II. In the 1950s it was proved that it directly stimulates the synthesis of aldosterone, and after 10 years the role of angiotensin-converting enzyme (ACE) in the neurohumoral regulation of blood pressure was studied, and the concept of the functioning of the renin-angiotensin-aldosterone system (RAAS) was formulated. The search for substances capable of acting at this level began. The first drug - an angiotensin II receptor antagonist was synthesized in 1969, it was saralazine. The drug had a powerful, but extremely poorly predictable antihypertensive effect; at the same dose, it could cause a collapse or, conversely, lead to a sharp increase in blood pressure.

Despite the failure, work in this direction continued, and in 1971 the world's first ACE inhibitor, teprotide, was synthesized. The history of its creation is interesting: in 1965, the Brazilian scientist Ferreira, while studying rattlesnake venom, discovered its ability to stabilize bradykinin. A drug isolated from snake venom has been used in clinical practice for a very short time. The reasons for this were the high toxicity of the drug, the short duration of the effect and the need for intravenous administration.

Continuing research into the mechanism of functioning of the RAAS led to the creation of the first tableted ACE inhibitor, captopril, in 1975. This was a revolutionary discovery that started a new era in the treatment of hypertension and heart failure.

In 1980, enalapril was synthesized by Merck employees. The duration of his clinical effect was about 12–24 hours. For several decades, the drug has been actively used in clinical practice and continues to be an effective means of controlling blood pressure.

Diuretics are the oldest class of antihypertensive drugs, having been used since the 1950s. (Table 1). Despite the active introduction of new classes of antihypertensive drugs, primarily calcium antagonists and ACE inhibitors, interest in the class of diuretics has by no means diminished. First, in modern large clinical trials in the field of hypertension, a thiazide diuretic is usually used as a standard comparator with proven efficacy. Secondly, in modern international guidelines for hypertension, a diuretic is an obligatory component of combined antihypertensive therapy, which is used already at the initial stage of treatment of patients with hypertension. Thirdly, the tactics of using diuretics for long-term treatment of hypertension has been significantly revised in order to improve long-term safety.

The first fixed combinations of antihypertensive drugs (reserpine + hydralazine + hydrochlorothiazide; α-methyldopa + hydrochlorothiazide; hydrochlorothiazide + potassium-sparing diuretics) appeared in the early 1960s. In the 1970s and 1980s the leading place was taken by diuretic combinations, usually in high doses, with β-blockers or drugs of central action. However, soon, due to the emergence of new classes of drugs, the popularity of combination therapy decreased significantly. It was replaced by the tactics of a differentiated choice of drugs with their use in maximum doses in monotherapy.

Monotherapy with high doses of antihypertensive drugs often led to the activation of counterregulatory mechanisms that increase blood pressure and / or the development of adverse events. In this regard, it is not surprising that in the next decade, hopes for a higher antihypertensive activity of ACE inhibitors did not materialize, and the pendulum of attitudes towards combination therapy returned to its original position, i.e. it was recognized as necessary for most patients with hypertension.

In the late 1990s fixed low-dose combinations of antihypertensive drugs appeared: not containing a diuretic (calcium antagonist + ACE inhibitor; dihydropyridine calcium antagonist + β-blocker) or containing it in low doses. Already in 1997, 29 fixed combinations were presented in the list of antihypertensive drugs in the report of the US Joint National Committee. The feasibility of low-dose combined rational antihypertensive therapy, especially in patients with a high risk of developing CVD, was confirmed in the latest recommendations of the WHO / International Society for Arterial Hypertension (1999) and DAH-1 (2000).

Rational combination therapy must meet a number of mandatory conditions, such as:

the safety and efficacy of the components;

the contribution of each of them to the expected result;

different but complementary mechanisms of action;

higher efficiency compared to that of monotherapy with each of the components; balance of components in terms of bioavailability and duration of action; strengthening of organoprotective properties;

impact on the universal (most frequent) mechanisms of increasing blood pressure;

reducing the number of adverse events and improving tolerability.

Table 2 shows the undesirable effects of the main classes of drugs and the possibility of their elimination by adding a second drug.

Combination drugs consisting of an ACE inhibitor and a thiazide diuretic have been used in clinical practice for a long time and are currently one of the most commonly used groups of drugs for the treatment of hypertension, heart failure and coronary heart disease (CHD). In the pathogenesis of these conditions, an important role is played by the activation of two neurohumoral systems of the body: RAAS and sympathetic-adrenal (SAS). The activation process is caused by such unfavorable factors as a decrease in cardiac output, organ ischemia, loss of sodium and water, a significant change in pH, etc. As a result, angiotensin II is formed.- a biologically active substance, which is a powerful vasoconstrictor, stimulates the release of aldosterone, and also increases the activity of the SAS (stimulates the release of norepinephrine). Norepinephrine, in turn, can activate the RAAS (stimulates the synthesis of renin).

Ultimately, an increase in the activity of these two systems of the body, causing a powerful vasoconstriction, an increase in heart rate, cardiac output, maintains the function of blood circulation at an optimal level, maintains homeostasis of the body. Normally, the activation of the body's pressor systems (RAAS and SAS) is "resisted" by the action of the depressor system (kallikrein-kinin: the key link is bradykinin), which causes systemic vasodilation. However, with prolonged action of various pathological factors described above, normal regulation is disturbed, and as a result, the effects of pressor systems predominate. ACE inhibitors inhibit the effects of pressor systems and simultaneously activate depressor systems.

The main effects of ACE inhibitors (enalapril) are due to the blockade of angiotensin-converting enzyme: elimination of the vasopressor, antidiuretic and antinatriuretic effects of angiotensin II, increased vasodilating, diuretic and natriuretic effects of bradykinin and other endogenous vasodilators (prostaglandins J2 and E2, natriuretic peptide, endothelial relaxation factor), as well as mediated blockade of SAS activity by inhibiting the synthesis of norepinephrine. The antihypertensive effect of the thiazide diuretic - indapamide is due, on the one hand, to the natriuretic effect, which eliminates the overload of the vascular wall with sodium and reduces its hyperreactivity to various vasopressor agents (catecholamines, angiotensin II, etc.), on the other hand, by direct vasodilating action due to blocking of slow calcium channels. in smooth muscle cells of the vascular wall, increased synthesis of prostacyclin in the vascular wall and prostaglandin E2 (PGE2) in the kidneys and suppression of the synthesis of endothelium-dependent vasoconstrictor factor.

FaRmacokinetics of the combined drug Enziks ®

Enalapril: after oral administration, about 60% is absorbed from the gastrointestinal tract, the bioavailability of the drug isbets 40%. Enalapril is rapidly and completely hydrolyzed in the liver to form activemetabolite - enalaprilat, which is a more active ACE inhibitor than enalapril. Enalaprilat easily passes through the blood-tissue barriers, excluding the blood-brain barrier (BBB), a small amount crosses the placenta and into breast milk. T1 / 2 of enalaprilat - about 11 hours. Enalapril is excreted mainly by the kidneys - 60% (20% - in the form of enalapril and40% - in the form of enalaprilat), through the intestines - 33% (6% - in the form of enalapril and 27% - in the form of enalaprilat).

Indapamide: after oral administration, it is rapidly and completely absorbed from the gastrointestinal tract; bioavailability - 93%. Indapamide passes through histohematic barriers (including placental), passes into breast milk, and is metabolized in the liver. T1 / 2 of the drug - 14-18 hours. 60-80% is excreted by the kidneys in the form of metabolites (in unchanged form - about 5%), through the intestines - 20%. In patients with chronic renal failure (CRF), pharmacokinetics do not change and do not accumulate.

Rational combination therapy allows to achieve a good antihypertensive effect, which is combined with excellent tolerability and safety of treatment. Due to the fact that combination therapy is becoming one of the main directions in the treatment of patients with hypertension, fixed combinations of antihypertensive drugs containing two drugs in one tablet are widely used. Their use allows to obtain a stable antihypertensive effect with a minimum number of side effects. Of course, combination therapy is necessary to achieve and maintain the target level of blood pressure, but it should be remembered that this therapy is the intake of at least two drugs, the frequency of which may be different.

Therefore, the use of drugs in the form of combination therapy must meet the following conditions:

drugs should have a complementary effect;
an improvement in the result should be achieved when they are used together;
organoprotective properties should be enhanced;
drugs should have close pharmacodynamic and pharmacokinetic parameters, which is especially important for fixed combinations.

Combination therapy does not always mean an increase in the antihypertensive effect and may lead to an increase in adverse events (Table 4).

The advantages of low-dose combined antihypertensive drugs include the following:

simplicity and convenience of reception for the patient;
facilitating dose titration;
ease of prescribing the drug;
increasing patient adherence to treatment;
reducing the frequency of adverse events by reducing the doses of the components;
reducing the risk of using irrational combinations; confidence in the optimal and safe dose regimen; price reduction.

The disadvantages are:

fixed doses of components;
difficulties in identifying the cause of adverse events;
lack of confidence in the need for all the components used.

Additional requirements for combined drugs are the absence of unpredictable pharmacokinetic interactions and the optimal ratio of residual and maximum effects. Rational selection of components creates the prerequisites for prescribing drugs once a day, which, when monotherapy has to be used two or even three times a day (some β-blockers, ACE inhibitors and calcium antagonists).

Thiazide diuretic + ACE inhibitor is a highly effective combination that provides an impact on the two main pathophysiological mechanisms of hypertension: sodium and water retention and activation of the RAAS. The effectiveness of such combinations has been demonstrated in low-, normo- and high-renin hypertension, including in patients who do not respond to blockers of the renin-angiotensin system (for example, in African Americans). The frequency of hypertension control increases to 80%. ACE inhibitors eliminate hypokalemia, hypomagnesemia, dyslipidemia, carbohydrate metabolism disorders that can develop with diuretic monotherapy. Such combinations are very promising in patients with left ventricular hypertrophy (LVH) and diabetic nephropathy. Potentially a useful combination drug of this composition is Enziks® ( Shtada) (enalapril 10 mg + indapamide 2.5 mg). Indications for the primary use of Enziks® are shown in Table 5.

Of no small importance is the estimated adherence of patients to the treatment of hypertension (Table 6). If it is low, then the use of fixed combinations should also be more actively recommended.

Organoprotective effects of the combined drug Enziks® To a radioprotective effect

The cardioprotective effect is provided by the influence of the Enzix drug on LVH - the prevention of its development or the possible regression of LVH. The LIVE multicenter study (Left ventricle hypertrophy: Indapamide Versus Enalapril) investigated the effect of indapamide and enalapril therapy on regression of left ventricular myocardial mass (LVMM).

Therapy with indapamide led to a significant decrease in LVMM (p<0,001). Индапамид также в большей степени снижал выраженность гипертрофии левого желудочка (ГЛЖ), чем эналаприл (p<0,049).

In a study by Bocker W., it was found that indapamide reduces LVMM, inhibits plasma aldosterone activity and ACE activity in plasma and myocardium.

A number of studies have proven the ability of long-term therapy with enalapril and indapami home to improve the life prognosis of patients with hypertension (TOMSH, STOP–Hypertension 2, ABCD, ANBP2). The TOMHS randomized, double-blind, placebo-controlled, parallel-group study compared acebutolol, amlodipine, chlorthalidone, doxazosin, enalapril, and placebo. BP decreased in all groups, but significantly more in the active therapy groups than in the placebo group. Mortality and major cardiovascular events were not significantly higher in the placebo group, there were no significant differences between active therapy groups.

In a randomized, open-ended, blinded, prospective STOP-Hyper ten-sion 2 study, the use of β-blockers in combination with diuretics (2213 b-x: metoprolol, atenolol or pindolol in combination with hydrochlorothiazide and amiloride), calcium blockers (2196 b-x: felodipine or isradipine) and ACE inhibitors (2205 b-x: enalapril or lisinopril). Significant differences in the frequency of fatal cardiovascular events, stroke, heart attack and other vascular mortality have not been obtained.

The randomized, open-label, blinded endpoint study of ANBP2 (6083 patients, duration 4.1 years) compared the use of enalapril and diuretics found that the risk of cardiovascular events or death in patients treated with ACE inhibitors was 11% lower than those taking diuretics (p=0.05). The ability of enalapril to reduce the risk of complications and death was especially pronounced in men in relation to the risk of myocardial infarction.

In many clinical studies on the treatment of hypertension, the ability of enalapril, in addition to lowering blood pressure, to provide a cardioprotective effect was revealed (CATCH, PRESERVE). In a 5-year study that studied the effect of enalapril on the severity of LVH and the dispersion of the QT interval in patients with hypertension with LVH against the background of achieving and maintaining a normal level of blood pressure, a significant decrease in LVML by 39% was found (p<0,001), улучшение сократительной способности миокарда ЛЖ в виде увеличения ФВ (p<0,05) и достоверное уменьшение дисперсии интервала QT, что, помимо снижения риска развития ХСН, может сопровождаться снижением риска развития желудочковых аритмий и улучшением прогноза.

In a randomized, double-blind, placebo-controlled, parallel-group comparison study of ABCD (Appropriate Blood pressure Control in Diabetes), which studied the effect of a 5-year intensive and moderate reduction in blood pressure with nisoldipine and enalapril in patients with type 2 diabetes with hypertension (n=470) compared with normotensive patients with type 2 diabetes (n=480), a significant decrease in the incidence of MI was shown in the enalapril group (5 versus 25 cases, p=0.001) compared with the nisoldipine group with the same decrease in blood pressure, glucose and blood lipids.

The randomized, double-blind, parallel-group HANE study compared hydrochlorothiazide (215 patients), atenolol (215 patients), nitrendipine (218 patients) and enalapril (220 patients). Target blood pressure achieved by the 8th week: in the atenolol group - in 63.7%, in the enalapril group - in 50%, in the hydrochlorothiazide and nitrendipine groups - in 44.5%. By the 48th week, the effectiveness was 48.0%, 42.7%, 35.4% and 32.9%, respectively. Significantly more often, patients discontinued the use of nitrendipine (28 patients, p=0.001).

The SLIP randomized, parallel-group trial compared verapamil SR with enalapril. Monotherapy was sufficient in 65.1% of cases. Both drugs significantly reduced blood pressure and levels of total cholesterol, triglycerides, and low-density lipoproteins. The effectiveness of enalapril in patients with CHF stage II-IV is confirmed by the data of a number of placebo-controlled studies conducted double-blind (American Heart Association, 1984; Finland, 1986). The results obtained showed that the use of enalapril provides a long-term improvement in hemodynamics, expressed in a decrease in the size of the left ventricle (according to echocardiography), a significant increase in ejection fraction (according to radionuclide ventriculography), a decrease in filling pressure and an increase in the systolic index. In addition, there was a steady relief of symptoms (according to subjective assessmentspatients) and a significant increase in exercise tolerance (assessed byduration of exercises on a bicycle ergometer).

Data obtained during the CONSENSUS research program, which ended in 1987, indicated that enalapril at a dose of up to 40 mg / day. in combination with therapy with cardiac glycosides and diuretics when taken for 6 months. reduced the risk of death in patients with stage IV CHF by 40%, and when taken for 12 months. - 31% compared to placebo. After 1 year, all patients were transferred to enalapril.

In 1999, an analysis was made of the fate of all patients participating in this study. Data collected over 10 years show that the risk of death from CHF in the study group was 30% lower than the average for the population. The study showed that enalapril increases the life expectancy of patients with CHF by an average of 1.5 times. The use of enalapril leads to an increase in the quality of life of the patient.

Antianginal effect of enalapril at a dosage of 10 mg / day. (both single and fractional in two doses) was tested in a series of double-blind, randomized, placebo-controlled studies (Klinische Pharmakologie, Universität Frankfurt am Main, 1988; Institute of Cardiology, University of Cagliari, Italy, 1990) in patients with confirmed coronary artery disease and normal blood pressure. Efficiency was monitored by the dynamics of changes in the ECG caused by physical activity. Already after the first dose, there was a 22 percent improvement in terms of reducing the ST interval, after a 15-day course, the improvement was 35%. In addition, the use of enalapril significantly increased the threshold for angina and increased the duration of exercise. At the same time, the level of blood pressure did not change significantly, that is, the observed effect was presumably associated with an improvement in coronary blood flow.

Nephroprotective effect

ACE inhibitors are currently successfully used in nephrological practice. The nephroprotective effect of this group of drugs, associated with the elimination of non-immune mechanisms of the progression of renal pathology, remains maximum in comparison with other drugs. The use of ACE inhibitors is shown both in primary renal diseases (glomerulonephritis of various origins), and in secondary nephropathies (especially in diabetic). The nephroprotective effect of ACE inhibitors is manifested at all stages of kidney damage. There are data from a clinical study that included 30 patients with stage I-II AH (14 men and 16 women, mean age 55.7±2.1 years), with AH duration of 12.4±1.8 years without impaired renal function, which revealed corrective effect of 12-week therapy with enalapril at a dose of 10-20 mg / day. on the glomerular filtration rate (GFR) calculated in the Rehberg test. In patients, blood pressure significantly decreased: from 157.4±2.3/93.6±1.7 to 132.6±6.5/85.5±2.0 mm Hg. Art. (p<0,001) с достижением целевого АД у 60% больных. Через 1 мес. терапии в целом достоверно увеличилась СКФ: с 82±3,5 до 110,8±9,0 мл/мин (p<0,05), оставаясь на этом уровне после 3 мес. лечения (111,2±10,2 мл/мин). Исходно сниженная СКФ увеличилась с 72,9±3,6% до 105,5±10,8% (p<0,01); нормальная СКФ не изменилась (97,1±3,6% против 96,3±6,0%). Разнонаправленная динамика СКФ у больных с исходно нормальной и сниженной СКФ свидетельствует об улучшении функционального состояния почек и нефро-протективном эффекте эналаприла.

ACE inhibitors are successfully used in the treatment of renovascular hypertension, but are contraindicated in the presence of bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney due to the risk of reducing the total glomerular filtration rate and the development of azotemia.

Of undoubted interest are studies of the effectiveness of enalapril in patients with hypertension and diabetic nephropathy. Ravid M. et al. found that long-term use of enalapril prevents the development of kidney dysfunction in patients with type 2 diabetes with microalbuminuria (MAU).

A targeted analysis of the spectrum of ACE inhibitors used by patients with diabetes with preserved kidney function and the absence of progression of diabetic nephropathy revealed that in patients who receivedenalapril, there was no progression of renal pathology during follow-up periods of 15 years and more.

The nephroprotective effect of antihypertensive drugs is to prevent the development of chronic renal failure. Markers of the nephroprotective effect are microproteinuria - the earliest sign of impaired renal function, creatinine clearance and albuminuria / creatinine index (IAI> 3.4). AAI is 3 times higher in patients with AH and 9 times higher in patients with DM and, like microproteinuria, is a risk factor for cardiovascular events. The nephroprotective effect of indapamide was studied in the NESTOR study. In 570 patients with hypertension and type 2 diabetes, the effect of indapamide and enalapril on MAU was compared during 1 year of treatment. There were no differences in antihypertensive efficacy between the drugs: the degree of reduction in SBP/DBP was 23.8/13 mm Hg. Art. in the indapamide group and 21/12.1 mm Hg. Art. – in the Enala-prila group. The AAI in patients included in the study was 6.16, and the rate of albumin excretion was 58 μm/min, while there was no violation of creatinine clearance. After 1 year of treatment, there was a decrease in AAI to 4.03 (by 35%) in the indapamide group and to 3.74 (by 39%) in the enalapril group, and the rate of albumin excretion decreased by 37% and 45%, respectively. Thus, the nephroprotective effect of indapamide was comparable to that of enalapril.

Effects on endothelial dysfunction and microcirculation

Data on the ability of enalapril therapy to improve endothelial function (EF) in hypertension were obtained in an open comparative randomized crossover study lasting 12 weeks, which included 30 men aged 30-65 years with mild to moderate hypertension. The efficacy of enalapril (10–20 mg/day) was compared with the non-dihydropyridine calcium antagonist diltiazem (180–360 mg/day). Evaluation of EF was carried out on the basis of endothelium-dependent vasodilation (EDVD) of the brachial artery (cuff test) and biochemical markers - stable NO metabolites in blood serum, expression and activity of the eNOS enzyme in cell culture.

The study found almost the same antihypertensive efficacy of diltiazem and enalapril. Improvement in EF was also revealed during treatment with both drugs. The increase in EDVD during treatment with diltiazem was 4.5±1.2%, and during treatment with enalapril it was 6.5±1.0%. In both cases, the increase in EDVD compared with the baseline was significant (p<0,005). Улучшение ЭФ на фоне лечения обоими препаратами подтверждалось динамикой биохимических маркеров ЭФ, однако механизм влияния этих препаратов на ЭФ различался: дилтиазем улучшал ЭФ за счет увеличения активности еNOS, тогда как эналаприл – за счет увеличения экспрессии еNOS. Показатель ЭЗВД после лечения эналаприлом был сопоставим с уровнем, который отмечался у обследованных без факторов риска. Таким образом, на фоне лечения эналаприлом происходило выраженное улучшение ЭФ. Возможно, свойство эналаприла улучшать ЭФ (что, по сути, означает дополнительный антиатерогенный эффект) обеспечивало более эффективное уменьшение осложнений в группе пациентов, получавших указанный препарат в исследовании АВСD. При изучении влияния препаратов на метаболические показатели (общего холестерина, триглицеридов, холестерина липопротеидов высокой плотности и глюкозу крови) не было выявлено достоверной динамики, что свидетельствует об их метаболической нейтральности.

There are data from another clinical study that revealed the corrective effect of 12-week therapy with enalapril at a dose of 10-20 mg / day. on microcirculation (MCC) in patients with hypertension. The study included 30 patients with AH I-II degree: 14 men and 16 women aged 24-73 years (mean age 55.7±2.1 years) with duration of AH 12.4±1.8 years. The state of the MCC was studied by laser Doppler flowmetry. In patients, blood pressure significantly decreased: from 157.4±2.3/93.6±1.7 to 132.6±6.5/85.5±2.0 mm Hg. Art. (p<0,001) с достижением целевого АД у 60% больных. Выявлено корригирующее действие эналаприла на все диагностированные патологические типы МКЦ за счет уменьшения спазма и разгрузки венулярного звена микроциркуляторного русла, что сопровождает by improving tissue perfusion.

Thus, enalapril therapy has not only an adequate antihypertensive effect with normalization of blood pressure in 60% of patients with AH I-II degree, but also a corrective effect on the state of the MCC system by reducing spasm and unloading the venular link of the microvasculature. The data obtained indicate an angioprotective effect of therapy based on the improvement of tissue perfusion.

M e tabolic effects

Enziks® does not adversely affect carbohydrate metabolism, blood lipid composition and uric acid concentration, i.e. does not activate risk factors for coronary artery disease, therefore it is indicated for long-term therapy of hypertension in patients with risk factors.

Impact on quality of life

An open uncontrolled study of the effect of enalapril on the quality of life of AH patients included 244 patients with AH I-II degree aged 25 to 76 years (mean age 55.0±2.27 years). During the 1 week before the start of the study, patients did not take antihypertensive drugs. Then they were prescribed enalapril at a dose of 5-10 mg 1 time / day. within 60 days. The quality of life was assessed according to the main indicators given in the General Well–Being Question naire questionnaire: physical well-being, working capacity, psychological well-being, sexual abilities. Normalization of blood pressure occurred in 62.9% of patients who received enalapril at a dose of 10 mg / day, and in 55.3% of patients who received 5 mg / day. Thus, a good and very good therapeutic effect was achieved in 81.17–90.56% of patients (depending on the dose of the drug). In addition, enalapril therapy led to an improvement in the quality of life in 51.5-59.7% of patients (depending on the dose of the drug).

Side effects of Enzix combination drug

Enziks® is contraindicated during pregnancy (belongs to category C drugs in the first trimester and to category D - in the second and third) due to teratogenic effects on the fetus, as well as during breastfeeding (penetrates into breast milk). For newborns and infants who have been exposed to ACE inhibitors in utero, it is recommended to conduct careful monitoring for the timely detection of a pronounced decrease in blood pressure, oliguria, hyperkalemia and neurological disorders, possible due to a decrease in renal and cerebral blood flow. Oliguria requires maintenance of blood pressure and renal perfusion by administration of appropriate fluids and vasoconstrictor drugs. In general, according to the results of clinical studies, the drug is well tolerated.

However, due to the clinical effects of Enzix®, associated with its effect on ACE metabolism and leading to a decrease in blood pressure, there are a number of pathological conditions in which it should be used with caution due to the risk of dangerous side effects. So, care must be taken when prescribing the drug to patients with a reduced volume of circulating blood (with restriction of salt intake, hemodialysis, diarrhea and vomiting). This is due to the high risk of a sudden and pronounced decrease in blood pressure after even the initial dose of Enzix®, which, in turn, can lead to loss of consciousness and ischemia of the internal organs.

While taking the drug, care should also be taken when performing physical exercises and in hot weather due to the risk of dehydration and a concomitant decrease in BCC.

When taking the drug Enziks® in patients with an indication of the development of angioedema in history (hereditary, idiopathic or on the background of therapy with ACE inhibitors), there is an increased risk of its development.

The use of the drug Enziks® in a small percentage of cases can cause a cough due to enalapril, which is part of the composition. The cough is usually unproductive, persistent, andstops after the end of treatment.

During the period of treatment, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions (dizziness is possible, especially after taking the initial dose.

Perkey

Enziks® (Stada) is a modern antihypertensive drug that provides not only effective control of blood pressure, but also improves the life prognosis of patients with hypertension due to the proven protective effect on all target organs.

In modern conditions of limited funding for health care, when choosing antihypertensive therapy, not only clinical aspects, but also economic ones are taken into account. The study of the cost-effectiveness of the use of antihypertensive drugs allows us to identify their economic benefits. Thus, in a retrospective pharmacoeconomic analysis of several large clinical trials, Enzix® showed the best cost-effectiveness ratios in assessing both the degree of BP reduction and regression of LVH and MAU in comparison with the most commonly prescribed antihypertensive drugs from different classes.

Thus, Enziks® is a representative of modern combined antihypertensive drugs, has a favorable efficacy and safety profile, proven in large clinical trials.

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Different doctors may have their own treatment regimen. However, there are general concepts based on statistics and research.

At the initial stage

In uncomplicated cases, drug antihypertensive therapy is often started with the use of proven "conventional" drugs: beta-blockers and diuretics. In large-scale studies involving patients, it has been shown that the use of diuretics, beta-blockers reduces the risk of cerebrovascular accident, sudden death, and myocardial infarction.

An alternative option is the use of captopril. According to new data, the incidence of heart attacks, strokes, deaths with conventional treatment or with captopril is almost the same. Moreover, in a special group of patients who have not previously been treated with antihypertensive drugs, captopril shows a clear advantage over conventional therapy, significantly reducing the relative risk of cardiovascular events by 46%.

Long-term use of fosinopril in patients with diabetes, as well as arterial hypertension, is also associated with a significant reduction in the risk of death, myocardial infarction, stroke, exacerbation of angina pectoris.

Therapy for left ventricular hypertrophy

As an antihypertensive therapy, many doctors practice the use of angiotensin-converting enzyme (ACE) inhibitors. These drugs have cardioprotective properties and lead to a decrease in the mass of the LV myocardium (left ventricle). When studying the degree of influence of various drugs on the LV myocardium, it was revealed that the reverse degree of development of its hypertrophy is most pronounced in ACE inhibitors, since antiotensin-2 controls the growth, hypertrophy of cardiomyocytes and their division. In addition to cardioprotective effects, ACE inhibitors have a nephroprotective effect. This is important, because despite all the successes of antihypertensive therapy, the number of patients who develop terminal renal failure is growing (4 times compared to the "eighties").

Therapy with calcium antagonists

Increasingly, calcium antagonists are being used as first-line drugs. For example, long-acting dihydropyridine calcium channel blockers are effective in isolated systemic arterial hypertension (AH). A four-year study of 5000 patients showed a significant effect of nitrendipine on the incidence of cerebral stroke. In another study, the base drug was a long-acting calcium antagonist, felodipine. Patients were followed up for four years. As blood pressure (blood pressure) decreased, beneficial effects increased, there was a significant decrease in the risk of developing cardiovascular complications, and the frequency of sudden death did not increase. The SystEur study, which included 10 Russian centers, also showed a 42% reduction in the incidence of stroke with nisoldipine.

Calcium antagonists are also effective in pulmonary arterial hypertension (this is systemic hypertension that occurs in patients with obstructive pulmonary disease). Pulmonogenic hypertension develops several years after the onset of a pulmonary disease, and there is a clear connection between the exacerbation of the pulmonary process and pressure rises. An advantage of calcium antagonists in pulmonary hypertension is that they reduce calcium-mediated hypoxic vasoconstriction. The delivery of oxygen to tissues increases, hypoxia of the kidneys and vasomotor center decreases, blood pressure decreases, as well as afterload and myocardial oxygen demand. In addition, calcium antagonists reduce the synthesis of histamine, kinin, serotonin in tissues, swelling of the bronchial mucosa and bronchial obstruction. An additional advantage of calcium antagonists (in particular, isradipine) is their ability to change metabolic processes in hypertensive patients. By normalizing or lowering blood pressure, these drugs can prevent the development of dyslipidemia, glucose and insulin tolerance.

Calcium antagonists showed a clear relationship between dose, plasma concentration and pharmacological hypotensive effect. By increasing the dose of the drug, it is possible, as it were, to control the hypotensive effect, increasing or decreasing it. For long-term treatment of hypertension, long-acting drugs with a low absorption rate (amlodipine, a long-acting gastrointestinal form of nifedipine, or osmoadolat, a long-acting form of felodipine) are preferred. When using these drugs, smooth vasodilation occurs without reflex activation of the sympathetic-adrenal system, release of catecholamines, reflex tachycardia and increased myocardial oxygen demand.

Myotropic vasodilators, central alpha-2-adrenergic agonists, and peripheral adrenergic agonists are not recommended as first-choice drugs, taking into account tolerability.

Antihypertensive drugs: principles of therapy, groups, list of representatives

Antihypertensive drugs (antihypertensives) include a wide range of medicines designed to lower blood pressure. Since about the middle of the last century, they began to be produced in large volumes and massively used in patients with hypertension. Until that time, doctors had only recommended diet, lifestyle changes, and sedatives.

Arterial hypertension (AH) is the most frequently diagnosed disease of the cardiovascular system. According to statistics, approximately every second inhabitant of the planet of advanced age has signs of high blood pressure, which requires its timely and correct correction.

To prescribe drugs that reduce blood pressure (BP), it is necessary to establish the very fact of the presence of hypertension, assess the possible risks for the patient, contraindications to specific drugs and the feasibility of treatment in principle. The priority of antihypertensive therapy is to effectively reduce pressure and prevent possible complications of a dangerous disease, such as stroke, myocardial infarction, and renal failure.

The use of antihypertensive drugs has reduced mortality from severe forms of hypertension over the past 20 years by almost half. The optimal level of pressure to be achieved through treatment is considered to be a figure not exceeding 140/90 mm Hg. Art. Of course, in each case, the question of the need for therapy is decided individually, but with prolonged high blood pressure, the presence of damage to the heart, kidneys, retina, it should be started immediately.

According to the recommendation of the World Health Organization, an absolute indication for antihypertensive therapy is a diastolic pressure of 90 mm Hg or more. Art., especially if such a figure holds for several months or six months. Usually, drugs are prescribed for an indefinite period, for most patients - for life. This is due to the fact that when therapy is discontinued, three-quarters of patients again experience manifestations of hypertension.

Many patients are afraid of long-term or even lifelong medication, and often the latter are prescribed in combinations that include several items. Of course, the fears are understandable, because any medicine has side effects. Numerous studies have shown that there is no health risk with long-term use of antihypertensive drugs, side effects are minimal if the dose and regimen are correctly selected. In each case, the doctor individually determines the features of treatment, taking into account the form and course of hypertension, contraindications, comorbidities in the patient, but it is still necessary to warn about possible consequences.

Principles of prescribing antihypertensive therapy

Thanks to many years of clinical studies involving thousands of patients, the main principles of drug treatment of arterial hypertension were formulated:

Treatment begins with the smallest doses of the drug, using a drug with a minimum of side effects, that is, choosing the safest remedy.
If the minimum dose is well tolerated, but the pressure level is still high, then the amount of the drug is gradually increased to the amount necessary to maintain normal blood pressure.
To achieve the best effect, it is recommended to use combinations of drugs, prescribing each of them in the lowest possible dosages. Currently, standard regimens for the combined treatment of hypertension have been developed.
If the second prescribed drug does not give the desired result, or its administration is accompanied by side effects, then it is worth trying a remedy from another group without changing the dosage and regimen of the first drug.
Long-acting drugs are preferred, which allow maintaining normal blood pressure throughout the day, without allowing fluctuations in which the risk of complications increases.

Antihypertensive drugs: groups, properties, features

Many drugs have antihypertensive properties, but not all of them can be used to treat patients with hypertension due to the need for long-term use and the possibility of side effects. Today, five main groups of antihypertensive drugs are used:

Angiotensin-converting enzyme inhibitors (ACE inhibitors).
Angiotensin II receptor blockers.
Diuretics.
calcium antagonists.
Beta blockers.

Medicines from these groups are effective in arterial hypertension, can be prescribed as initial treatment or maintenance therapy, alone or in various combinations. Choosing specific antihypertensive drugs, the specialist is based on the patient's pressure indicators, the characteristics of the course of the disease, the presence of lesions of target organs, comorbidities, especially those of the cardiovascular system. The overall likely side effect, the possibility of combining drugs from different groups, as well as the existing experience in the treatment of hypertension in a particular patient, is always evaluated.

Unfortunately, many effective drugs are not cheap, which makes them inaccessible to the general population. The cost of the drug may become one of the conditions under which the patient will be forced to abandon it in favor of another, cheaper analogue.

Angiotensin-converting enzyme inhibitors (ACE inhibitors)

ACE inhibitors are quite popular and are widely prescribed for a wide variety of patients with high blood pressure. The list of ACE inhibitors includes such drugs as: captopril, enalapril, lisinopril, prestarium, etc.

As you know, the level of blood pressure is regulated by the kidneys, in particular, by the renin-angiotensin-aldosterone system, the correct operation of which determines the tone of the vascular walls and the final level of pressure. With an excess of angiotensin II, a spasm of the vessels of the arterial type of the systemic circulation occurs, which leads to an increase in the total peripheral vascular resistance. To ensure adequate blood flow in the internal organs, the heart begins to work with an excessive load, forcing blood into the vessels under high pressure.

In order to slow down the formation of angiotensin II from the precursor (angiotensin I), it was proposed to use drugs that block the enzyme involved in this stage of biochemical transformations. In addition, ACE inhibitors reduce the release of calcium, which is involved in the contraction of the vascular walls, thereby reducing their spasm.

mechanism of action of ACE inhibitors in CHF

The appointment of ACE inhibitors reduces the likelihood of cardiovascular complications (stroke, myocardial infarction, severe heart failure, etc.), the degree of damage to target organs, especially the heart and kidneys. If the patient already suffers from chronic heart failure, then the prognosis of the disease when taking funds from the ACE inhibitor group improves.

Based on the characteristics of the action, it is most rational to prescribe ACE inhibitors to patients with kidney pathology and chronic heart failure, with arrhythmias, after a heart attack, they are safe for use by the elderly and diabetes mellitus, and in some cases can be used even by pregnant women.

The disadvantage of ACE inhibitors is considered the most frequent adverse reactions in the form of dry cough associated with a change in the metabolism of bradykinin. In addition, in some cases, the formation of angiotensin II occurs without a special enzyme, outside the kidneys, so the effectiveness of ACE inhibitors is sharply reduced, and treatment involves choosing another drug.

Absolute contraindications to the appointment of ACE inhibitors are:

Pregnancy;
A significant increase in the level of potassium in the blood;
Sharp stenosis of both renal arteries;
Quincke's edema with the use of ACE inhibitors in the past.

Angiotensin II receptor blockers (ARBs)

The drugs from the ARB group are the most modern and effective. Like ACE inhibitors, they reduce the action of angiotensin II, but, unlike the latter, their point of application is not limited to a single enzyme. ARBs act more widely, providing a powerful antihypertensive effect by disrupting the binding of angiotensin to receptors on cells of various organs. Thanks to this targeted action, relaxation of the vascular walls is achieved, and the excretion of excess fluid and salt by the kidneys is also enhanced.

The most popular ARBs are losartan, valsartan, irbesartan, and others.

Like ACE inhibitors, agents from the group of angiotensin II receptor antagonists show high efficacy in the pathology of the kidneys and heart. In addition, they are practically devoid of adverse reactions and are well tolerated in long-term administration, which allows them to be widely used. Contraindications to ARBs are similar to those for ACE inhibitors - pregnancy, hyperkalemia, renal artery stenosis, allergic reactions.

Diuretics

Diuretics are not only the most extensive, but also the most long-used group of drugs. They help to remove excess fluid and salt from the body, thereby reducing the volume of circulating blood, the load on the heart and blood vessels, which eventually relax. The classification implies the allocation of groups of potassium-sparing, thiazide and loop diuretics.

Thiazide diuretics, among which are hypothiazide, indapamide, chlorthalidone, are not inferior in effectiveness to ACE inhibitors, beta-blockers and other groups of antihypertensive drugs. High concentrations of them can lead to changes in electrolyte metabolism, lipid and carbohydrate metabolism, but low dosages of these drugs are considered safe even with long-term use.

Thiazide diuretics are used in combination therapy along with ACE inhibitors and angiotensin II receptor antagonists. It is possible to prescribe them to elderly patients, people suffering from diabetes, various metabolic disorders. Gout is considered an absolute contraindication to taking these drugs.

Potassium-sparing diuretics are milder than other diuretics. The mechanism of action is based on blocking the effects of aldosterone (an antidiuretic hormone that retains fluid). Pressure reduction is achieved by removing liquid and salt, but potassium, magnesium, calcium ions are not lost.

Potassium-sparing diuretics include spironolactone, amiloride, eplerenone, etc. They can be prescribed to patients with chronic heart failure, severe edema of cardiac origin. These drugs are effective in refractory hypertension, which is difficult to treat with other groups of drugs.

Due to their action on renal aldosterone receptors and the risk of hyperkalemia, these substances are contraindicated in acute and chronic renal failure.

Loop diuretics (lasix, edecrin) are the most aggressive, but at the same time, they can reduce blood pressure faster than others. For long-term use, they are not recommended, since there is a high risk of metabolic disorders due to the excretion of electrolytes along with the liquid, but these drugs are successfully used for the treatment of hypertensive crises.

calcium antagonists

The contraction of muscle fibers occurs with the participation of calcium. Vascular walls are no exception. Preparations of the group of calcium antagonists carry out their action by reducing the penetration of calcium ions into the smooth muscle cells of blood vessels. The sensitivity of vessels to vasopressor substances that cause vascular spasm (adrenaline, for example) also decreases.

The list of calcium antagonists includes drugs of three main groups:

Dihydropyridines (amlodipine, felodipine).
Benzothiazepine calcium antagonists (diltiazem).
Phenylalkylamines (verapamil).

The drugs of these groups differ in the nature of the effect on the walls of blood vessels, the myocardium, the conduction system of the heart. So, amlodipine, felodipine act mainly on the vessels, reducing their tone, while the work of the heart does not change. Verapamil, diltiazem, in addition to the hypotensive effect, affect the work of the heart, causing a decrease in heart rate and its normalization, therefore, they are successfully used for arrhythmias. By reducing the need of the heart muscle for oxygen, verapamil reduces pain in angina pectoris.

In the case of the appointment of non-dihydropyridine diuretics, it is necessary to take into account the possible bradycardia and other types of bradyarrhythmias. These drugs are contraindicated in severe heart failure, atrioventricular blockade, and simultaneously with intravenous administration of beta-blockers.

Calcium antagonists do not affect metabolic processes, reduce the degree of left ventricular hypertrophy in hypertension, and reduce the likelihood of stroke.

Beta blockers

Beta-blockers (atenolol, bisoprolol, nebivolol) have a hypotensive effect by reducing cardiac output and the formation of renin in the kidneys, causing vascular spasm. Due to their ability to regulate the heart rate and have an antianginal effect, beta-blockers are preferred for lowering blood pressure in patients suffering from coronary heart disease (angina pectoris, cardiosclerosis), as well as in chronic heart failure.

Beta-blockers change carbohydrate, fat metabolism, can provoke weight gain, so they are not recommended for diabetes and other metabolic disorders.

Substances with adrenoblocking properties cause bronchospasm and slow heart rate, and therefore they are contraindicated in asthmatics, with severe arrhythmias, in particular, atrioventricular block II-III degree.

Other antihypertensive drugs

In addition to the described groups of pharmacological agents for the treatment of arterial hypertension, additional drugs are also successfully used - imidazoline receptor agonists (moxonidine), direct renin inhibitors (aliskiren), alpha-blockers (prazosin, cardura).

Imidazoline receptor agonists act on nerve centers in the medulla oblongata, reducing the activity of sympathetic vascular stimulation. Unlike drugs from other groups, which at best do not affect carbohydrate and fat metabolism, moxonidine is able to improve metabolic processes, increase tissue sensitivity to insulin, and reduce triglycerides and fatty acids in the blood. Taking moxonidine in overweight patients promotes weight loss.

Direct renin inhibitors are represented by the drug aliskiren. Aliskiren helps to reduce the concentration of renin, angiotensin, angiotensin-converting enzyme in the blood serum, providing hypotensive, as well as cardioprotective and nephroprotective effects. Aliskiren can be combined with calcium antagonists, diuretics, beta-blockers, but the simultaneous use with ACE inhibitors and angiotensin receptor antagonists is fraught with impaired renal function due to the similarity of the pharmacological action.

Alpha-blockers are not considered drugs of choice, they are prescribed as part of combined treatment as a third or fourth additional antihypertensive agent. Medicines of this group improve fat and carbohydrate metabolism, increase blood flow in the kidneys, but are contraindicated in diabetic neuropathy.

The pharmaceutical industry does not stand still, scientists are constantly developing new and safe drugs to reduce pressure. Aliskiren (rasilez), olmesartan from the group of angiotensin II receptor antagonists can be considered drugs of the latest generation. Among diuretics, torasemide has proven itself well, which is suitable for long-term use, safe for elderly patients and patients with diabetes mellitus.

Combined preparations are also widely used, including representatives of different groups “in one tablet”, for example, the equator, combining amlodipine and lisinopril.

Folk antihypertensives?

The described drugs have a persistent hypotensive effect, but require long-term use and constant monitoring of the pressure level. Fearing side effects, many hypertensive patients, especially elderly people suffering from other diseases, prefer herbal remedies and traditional medicine to taking pills.

Hypotensive herbs have a right to exist, many really have a good effect, and their action is associated mostly with sedative and vasodilating properties. So, the most popular are hawthorn, motherwort, peppermint, valerian and others.

There are ready-made fees that can be bought in the form of tea bags at a pharmacy. Evalar Bio tea containing lemon balm, mint, hawthorn and other herbal ingredients, Traviata is the most famous representatives of herbal antihypertensive drugs. Hypotensive monastic tea has also proven itself well. At the initial stage of the disease, it has a general strengthening and calming effect on patients.

Of course, herbal preparations can be effective, especially in emotionally labile subjects, but it should be emphasized that self-treatment of hypertension is unacceptable. If the patient is elderly, suffers from heart disease, diabetes, atherosclerosis, then the effectiveness of traditional medicine alone is doubtful. In such cases, drug therapy is required.

In order for the drug treatment to be more effective, and the dosages of drugs to be minimal, the doctor will advise patients with arterial hypertension to first change their lifestyle. Recommendations include quitting smoking, normalizing weight, and limiting salt, fluid, and alcohol intake. Adequate physical activity and the fight against physical inactivity are important. Non-pharmacological measures to reduce pressure can reduce the need for drugs and increase their effectiveness.

Treatment of hypertension

A well-known main risk factor for the development of the most formidable vascular diseases (stroke and myocardial infarction) is hypertension. The main way to treat hypertension is antihypertensive therapy, i.e. lowering elevated blood pressure values with the help of drugs without affecting the underlying cause of hypertension. Now there are many modern drugs that help lower blood pressure. All these drugs are divided into classes depending on the mechanism of their action.

Diuretics (diuretics) stimulate the excretory function of the kidneys, thereby helping the body get rid of excess fluid. These include arifon, hydrochlorothiazide, brinaldix, diuver, veroshpiron.

Adrenoblockers (alpha-blockers and beta-blockers) reduce the effect of adrenaline on nerve receptors, thereby reducing the effect of stress factors on blood vessels. Among them are prazosin, doxazosin (alpha-blockers) and atenolol, propranalol, nadolol, concor (beta-blockers).

The drugs prestarium, captopril, enalapril, losartan and valsartan, inhibit the action of angiotensin-converting enzyme, which causes an increase in pressure. Centrally acting drugs (clophelin, cint) and calcium antagonists (nifedipine, nimodipine, verapamil) can also lower blood pressure.

Unfortunately, all antihypertensive drugs have contraindications and side effects, therefore, in most cases, combination therapy is indicated using several drugs at once. It should be borne in mind that high blood pressure should be reduced gradually. A sharp drop in pressure can be no less dangerous than its increase. Often, an overdose of antihypertensive drugs can cause a very sharp decrease in pressure, which is dangerous in itself, especially for older people with altered blood vessels. Therefore, with stably elevated values of blood pressure, reaching its target values should be gradual, not faster than after a few weeks. In addition, in most cases, you should not stop antihypertensive therapy without consulting a doctor, even if you have reached your target “normal” pressure values for you. Hypertension, as a rule, does not go away so easily: at any moment it can return and remind itself of its usual symptoms: headaches and heartaches, nausea, dizziness, after which, at best, everything will have to start over.

Cardiology Cheat Sheet: Antihypertensive Therapy

Antihypertensive therapy in patients with impaired liver function:

first choice drugs: Verapamil, diltiazem; Nifedipine group;
second choice drugs: Diuretics.

First choice drugs in patients with arterial hypertension:

and rhythm disturbances (sinus tachycardia, supraventricular, ventricular arrhythmias):
- Cardioselective beta-blockers;
- Central antagonists;
- Verapamil;
- Diltiazem.
and rhythm disturbances (sinus bradycardia, sick sinus syndrome, AV blockade):
- Nifedipine-retard and other drugs of this group;
- ACE inhibitors.
- Diltiazem-retard;
- Verapamil-retard;
- Long-acting ACE inhibitors (enalapril).
- ACE inhibitors;
- Moderate diuretics (hypothiazid, indapamide, oxodoline).

Second choice drugs in patients with arterial hypertension:

therapy, which should be carried out for a long time, in patients with a pronounced form of dyslipidemia:
- Cardioselective beta-blockers.
and systolic form of chronic heart failure (CHF):
- Loop diuretics (furosemide, uregit);
- Dihydroperidine calcium antagonists (nifedipine retard, amlodipine);
- Metoprolol.
- Drugs that have the most pronounced antihypertensive effect:
  - calcium antagonists;
- Drugs that do not impair the quality of life and most effectively reduce blood pressure:
  - calcium antagonists;
  - ACE inhibitors;
  - Alpha1-adrenergic blockers
- Drugs that do not adversely affect other risk factors for the development of cardiovascular complications and most effectively reduce blood pressure:
  - calcium antagonists;
  - ACE inhibitors;
  - Alpha1 - blockers;
  - Central agonists;
  - Arteriolar vasodilators (apressin, minoxidin).
  ATTENTION! There may be an inaccurate or incorrect answer. Please check information against other sources, such as lecture notes.
  Hypotensive action: what is it
  Hypotensive effect - what is it? This question is asked by women and men who first encountered the problem of high blood pressure or hypertension and have no idea what the hypotensive effect of drugs prescribed by their doctor means. Hypotensive action is a decrease in blood pressure under the influence of a certain drug.
  Experienced professional therapists of the highest category of the therapy clinic of the Yusupov Hospital, who own advanced methods of treatment and diagnostics, will provide qualified assistance to patients with arterial hypertension, select an effective treatment regimen that excludes the development of negative consequences.
  Antihypertensive therapy: general rules
  Both symptomatic hypertension and hypertension require correction with antihypertensive drugs. Antihypertensive therapy can be carried out with drugs that differ in the mechanism of action: antiadrenergics, vasodilators, calcium antagonists, angiotensin antagonists, and diuretics.
  You can get information about what the hypotensive effect of the drug is, what medications to take with high blood pressure not only from your doctor, but also from a pharmacist.
  Arterial hypertension is a chronic disease that requires constant drug support, daily monitoring and regular intake of prescribed medications. Not only the state of health, but also the life of a person depends on compliance with these rules.
  Despite the general availability of the rules of therapy for reducing pressure, many patients have to be reminded of how the treatment regimen for hypertension should look like:
  - taking antihypertensive drugs should be regular, regardless of the patient's well-being and the level of blood pressure. This allows you to increase the effectiveness of blood pressure control, as well as prevent cardiovascular complications and damage to target organs;
  - it is necessary to strictly observe the dosage and apply the form of release of the drug, which was prescribed by the attending physician. Self-change of the recommended dose or replacement of the drug may distort the hypotensive effect;
  - even under the condition of constant intake of antihypertensive drugs, it is necessary to systematically measure blood pressure, which will allow to evaluate the effectiveness of therapy, timely identify certain changes and adjust treatment;
  - in the case of an increase in blood pressure against the background of constant antihypertensive treatment - the development of an uncomplicated hypertensive crisis, an additional dose of the previously taken long-acting drug is not recommended. It is possible to quickly lower blood pressure with the help of short-acting antihypertensive drugs.
  Antihypertensive therapy: drugs to reduce pressure
  In the course of antihypertensive therapy, several main groups of drugs that help lower blood pressure are currently used:
  - beta-blockers;
  - ACE inhibitors;
  - calcium antagonists;
  - diuretics;
  - angiotensin II receptor blockers.
  All of the above groups have comparable effectiveness and their own characteristics that determine their use in a given situation.
  Beta blockers
  The drugs of this group reduce the likelihood of developing coronary complications in patients suffering from angina pectoris, prevent cardiovascular accidents in patients with myocardial infarction, tachyarrhythmia, and are used in patients with chronic heart failure. Beta-blockers are not recommended for patients with diabetes mellitus, lipid metabolism disorders and metabolic syndrome.
  ACE inhibitors
  Angiotensin-converting enzyme inhibitors have pronounced hypotensive properties, they have organoprotective effects: their use reduces the risk of complications of atherosclerosis, reduces left ventricular hypertrophy, and slows down the decline in kidney function. ACE inhibitors are well tolerated, with no negative effects on lipid metabolism and glucose levels.
  calcium antagonists
  In addition to antihypertensive properties, drugs in this group have antianginal and organ-protective effects, help reduce the risk of stroke, atherosclerotic lesions of the carotid arteries and left ventricular hypertrophy. Calcium antagonists may be used alone or in combination with other antihypertensive drugs.
  Diuretics
  Diuretic drugs are usually used while taking other antihypertensive drugs in order to enhance the therapeutic effect.
  Diuretics are also prescribed for people suffering from pathologies such as refractory hypertension and chronic heart failure. In order to avoid the development of side effects, with the constant intake of these drugs, minimal dosages are prescribed.
  Angiotensin II receptor blockers
  Drugs in this group, which have a neuro- and cardioprotective effect, are used to improve the control of blood glucose. They allow to increase the life expectancy of patients suffering from chronic heart failure. Antihypertensive therapy using angiotensin II receptor blockers can be prescribed to patients who have had a myocardial infarction, suffering from renal failure, gout, metabolic syndrome and diabetes mellitus.
  Antihypertensive therapy in hypertensive crisis
  Even despite constant antihypertensive therapy, a sudden increase in blood pressure to sufficiently high levels may periodically occur (there are no signs of target organ damage). The development of an uncomplicated hypertensive crisis may be due to unusual physical activity, emotional stress, drinking alcohol or salty, fatty foods. Such a condition is not life-threatening, but it threatens the development of negative consequences, therefore, it requires timely treatment.
  Too rapid a decrease in blood pressure is undesirable. Optimally, if in the first two hours after taking the drug, the pressure drops by no more than 25% of the initial values. Normal blood pressure values are usually restored within a day.
  Quick-acting drugs help to restore blood pressure control, due to which an almost instantaneous hypotensive effect is provided. Each of the drugs for quickly lowering blood pressure has its own contraindications, so a doctor should select them.
  30 minutes after taking an antihypertensive drug, it is necessary to measure the level of blood pressure to assess the effectiveness of therapy. If necessary, in order to restore the normal level of blood pressure, after half an hour or an hour, you can take an additional tablet (orally or sublingually). If there is no improvement (less than a 25% decrease in pressure or its previous excessively high rates), you should immediately seek the help of a doctor.
  In order for arterial hypertension not to turn into a chronic form, accompanied by quite serious complications, it is necessary to pay attention to the first signs of arterial hypertension in time. Do not self-medicate and randomly select drugs that reduce pressure. Despite their hypotensive effect, they can have a lot of contraindications and be accompanied by side effects that aggravate the patient's condition. The selection of drugs for antihypertensive therapy should be carried out by a qualified specialist familiar with the characteristics of the patient's body, his anamnesis.
  The Therapy Clinic of the Yusupov Hospital offers a comprehensive approach to addressing problems associated with high blood pressure.
  The clinic has the latest modern diagnostic and treatment equipment from the world's leading manufacturers of medical equipment, which makes it possible to identify the first manifestations of hypertension at the earliest diagnostic level and select the most effective methods of treating the disease. When drawing up a treatment regimen, the age, condition of the patient and other individual factors are taken into account.
  Conservative therapy in the Yusupov hospital involves the use of the latest generation of drugs with a minimum number of side effects. Consultations are carried out by highly qualified general practitioners with extensive experience in the treatment of hypertension and its consequences, including stroke.
  You can sign up for a consultation with the leading specialists of the clinic by phone or on the website of the Yusupov hospital through the feedback form.
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  Antihypertensive therapy: what you need to know?
  Arterial hypertension is one of those chronic diseases that require constant drug support, daily monitoring and regular intake of prescribed drugs. Not only well-being, but also the life of a sick person directly depends on how carefully the rules of antihypertensive therapy are observed.
  Not only the attending physician, but the pharmacist who advises the visitor who has applied to the pharmacy can tell about how to properly treat arterial hypertension, what drugs are used and in what cases.
  General rules of therapy
  The rules of antihypertensive therapy are simple and well known, but many patients often neglect them, and therefore it will not be out of place to remind you once again what the treatment of hypertension should be.
  1. Antihypertensive drugs are taken constantly. Regardless of whether the person feels bad or well, the level of blood pressure (BP) is elevated or remains normal, drug therapy should be constant. Only with daily intake of antihypertensive drugs can effectively control the level of blood pressure, avoid damage to target organs and cardiovascular complications.
  2. Antihypertensive drugs are taken in the dosage and form of release in which they are prescribed by the doctor. You should not independently change the recommended dose or try to replace one drug with another, because. this may adversely affect the hypotensive effect.
  3. Even with constant intake of antihypertensive drugs, blood pressure should be measured regularly, at least 2 times a week. This is necessary to control the effectiveness of therapy, allows you to notice the changes taking place in the body in time and adjust the treatment.
  4. If, against the background of constant antihypertensive therapy, blood pressure suddenly rises, i.e. an uncomplicated hypertensive crisis develops, it is not recommended to take an additional dose of the drug familiar to the patient. For continuous use, long-acting drugs are prescribed, the effect of which develops gradually. To quickly reduce blood pressure, a hypertensive home medicine cabinet must have short-acting antihypertensive drugs.
  Features of different groups of drugs
  For the treatment of arterial hypertension, 5 main groups of antihypertensive drugs are currently used: ACE inhibitors, beta-blockers, diuretics, calcium antagonists and angiotensin II receptor blockers. All of them have comparable effectiveness, but each of the groups has its own characteristics that determine the use of these drugs in different situations.
  ACE inhibitors (enalapril, lisinopril, perindopril, captopril, etc.), in addition to a pronounced hypotensive effect, have organoprotective properties - they reduce the risk of atherosclerosis complications, reduce left ventricular hypertrophy, and slow down the decline in kidney function. The drugs of this group are well tolerated, do not have a negative effect on lipid metabolism and blood glucose levels, which allows them to be used in cases where arterial hypertension is combined with metabolic syndrome or diabetes mellitus, as well as in patients who have had myocardial infarction, in the case of chronic heart failure. insufficiency, arrhythmia, atherosclerosis and impaired renal function.
  Beta-blockers (atenolol, bisoprolol, metoprolol, carvedilol, nebivolol) reduce the risk of coronary complications in patients with angina pectoris and cardiovascular accidents in patients who have had myocardial infarction, as well as patients with chronic heart failure, can be used for tachyarrhythmia. The use of beta-blockers is undesirable in patients with metabolic syndrome, lipid metabolism disorders and diabetes mellitus.
  Diuretics (hydrochlorothiazide, chlorthalidone, indapamide, spironolactone) are most often used in combination with other antihypertensive drugs, such as ACE inhibitors, to more effectively control blood pressure. The drugs of this group have proven themselves in refractory hypertension and chronic heart failure. For continuous use, diuretics are prescribed in minimal doses - to reduce the risk of side effects.
  Calcium antagonists (nifedipine, amlodipine, verapamil, diltiazem), in addition to hypotensive, have antianginal and organ-protective effects, reduce the risk of stroke, prevent platelet aggregation, slow down atherosclerotic lesions of the carotid arteries and left ventricular hypertrophy. Calcium antagonists are used both separately and in combination with other antihypertensive drugs (most often ACE inhibitors).
  Angiotensin II receptor blockers
  Angiotensin receptor blockers (losartan, candesartan, telmisartan, valsartan) have a cardio- and neuroprotective effect, improve blood glucose control, and have a positive effect on the life expectancy of patients with chronic heart failure. All drugs in this group can be used in the treatment of hypertension in patients with impaired renal function, myocardial infarction, metabolic syndrome, gout, diabetes mellitus.
  Hypertensive crisis - what to do?
  Even against the background of constant antihypertensive therapy, blood pressure can periodically rise suddenly to individually high numbers (without signs of target organ damage). This condition is called uncomplicated hypertensive crisis, most often it occurs after unusual physical activity, emotional stress, drinking alcoholic beverages or fatty salty foods.
  And although an uncomplicated form of a hypertensive crisis is not considered a life-threatening condition, it is impossible to leave it without treatment, because. even a small increase in blood pressure (by 10 mmHg) increases the risk of cardiovascular complications by 30%.2 And the sooner treatment is started, the less the chance of undesirable consequences.
  Antihypertensive drugs for uncomplicated hypertensive crisis are often recommended to be taken sublingually, because. this method is convenient for the patient and at the same time provides a rapid development of the therapeutic effect. It is undesirable to reduce blood pressure too quickly - in the first 2 hours by no more than 25% of the baseline and to a normal level within 24 hours. To restore blood pressure control, short-acting drugs that provide a rapid hypotensive effect should be used: nifedipine, captopril, moxonidine, clonidine, propranolol. It is better if a doctor chooses a drug to quickly reduce pressure, since each of them has contraindications.
  Half an hour after taking 1 tablet of an antihypertensive drug, you should measure the level of blood pressure and evaluate the effectiveness of treatment. If necessary, to restore the normal level of blood pressure, after 30-60 minutes, you can additionally take 1 more tablet sublingually or orally. If after that the pressure has decreased by less than 25%, it is urgent to call a doctor.
  Therapy of comorbid conditions
  Arterial hypertension rarely develops as a separate disease, in most cases it is accompanied by underlying disorders that exacerbate target organ damage and increase the risk of cardiovascular complications. Therefore, in addition to antihypertensive drugs, patients with hypertension are often prescribed lipid-lowering therapy, agents for preventing thrombosis and correcting blood glucose levels in patients with metabolic syndrome and diabetes mellitus.
  A particularly important role in arterial hypertension is played by the use of statins (simvastatin, atorvastatin, rosuvastatin) - drugs that reduce the level of total cholesterol, low-density lipoproteins and triglycerides. Long-term use of statins can stop atherosclerotic vascular damage, suppress the inflammatory process in the plaque, improve endothelial function and thereby significantly reduce the risk of cardiovascular accidents (myocardial infarction and stroke). First of all, statins are prescribed to patients with coronary artery disease, as well as after myocardial infarction.
  Prophylactic antiplatelet therapy is also prescribed for patients at high cardiovascular risk, people with impaired renal function, as well as all those who have undergone vascular surgery (bypass surgery, stenting). Drugs in this group prevent the formation of blood clots and reduce the risk of arterial thrombosis. The most widely used today are acetylsalicylic acid, clopidogrel and dipyridamole, which are prescribed for long courses in minimal therapeutic doses.
  And, of course, all these drugs, as well as antihypertensive drugs, are prescribed only by the attending physician, because. any self-treatment for hypertension can be dangerous, which must be reminded to a pharmacy visitor.
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For citation: Karpov Yu.A. Combined antihypertensive therapy is a priority in the treatment of arterial hypertension // BC. 2011. No. 26. S. 1568

The results of large randomized trials have led to the conclusion that without effective control of blood pressure levels, a significant reduction in cardiovascular morbidity and mortality cannot be achieved. A recently published large-scale epidemiological study in several central and eastern European countries showed that BP control is still insufficient, and this applies to patients receiving antihypertensive therapy (Fig. 1). It became clear that reliable control of blood pressure with only one antihypertensive drug without the widespread use of combination therapy is possible only in a small contingent of patients with hypertension.

For example, in the SHEP study, the need for combination antihypertensive therapy arose in 45% of patients, in the ALLHAT study - in 62%, in the INVEST study - in 80%. In the LIFE study, only 11% of patients randomized to losartan received only one drug at the end of the study. In the ASCOT study, 9 out of 10 patients who achieved target BP values of 140/90 mm Hg. Art. and below, it took the appointment of two or more antihypertensive drugs. In the HOT study, combination therapy was required in 63% of patients who achieved a target diastolic BP of 90 mmHg. Art., and in 74% of patients who have reached values of 80 mm Hg. Art. and below.
The need for combination therapy has found a very clear confirmation in the results of a large project that studied the possibility of implementing a qualitative control of blood pressure in everyday clinical practice. A study was conducted during which 3153 doctors were interviewed, who provided information on the first five patients with hypertension at one of the outpatient appointments.
Data from 14,066 patients receiving antihypertensive treatment were analyzed. Patients were divided into three groups according to the degree of risk of developing cardiovascular complications (CVE): group 1 - no risk factors (other than the presence of hypertension); group 2 - with one or two risk factors; group 3 - the presence of three or more risk factors, organ damage or associated clinical conditions (DM, IHD, etc.).
The frequency of blood pressure monitoring decreased markedly as the risk of complications increased. Most of the patients in group 1 (42.9%) had blood pressure below 140/90 mm Hg. Art., despite the fact that only 33% of them received combination therapy. In group 3, only 27% of patients had adequate control of blood pressure, although 50% of patients received a combination of two or more drugs. These data indicate that in general clinical practice, in general, the situation with adequate treatment of hypertension is unsatisfactory; BP is worst controlled in patients at high risk of complications. Improvement in blood pressure control requires more frequent use of combination therapy: among patients in group 3 with uncontrolled hypertension, four out of 10 patients were on monotherapy.
In the new recommendations of the Russian Medical Society for Arterial Hypertension / All-Russian Scientific Society of Cardiology (RMOAG / VNOK), the appointment of a combination of two antihypertensive drugs is considered as an alternative to monotherapy already at the beginning of treatment. Combinations of two, three or more antihypertensive drugs are used. Combined therapy has many advantages:
. enhancement of the antihypertensive effect due to the multidirectional action of drugs on the pathogenetic mechanisms of the development of hypertension, which increases the number of patients with a stable decrease in blood pressure;
. reducing the incidence of side effects both through the use of smaller doses of combined agents, and due to the mutual neutralization of these effects;
. ensuring the most effective organ protection and reducing the risk and number of CVEs.
Combination therapy must meet the following conditions: complementary action of drugs; improving the result when they are used together; the presence of similar pharmacodynamic and pharmacokinetic parameters of drugs, which is especially important for fixed combinations.
In accordance with the recommendations of the Russian Medical Society for Arterial Hypertension, combinations are divided into rational (effective), possible and irrational. All the advantages of combination therapy are fully realized only in rational combinations of antihypertensive drugs. These include: angiotensin-converting enzyme (ACE) inhibitors + diuretic; angiotensin receptor blockers (BAR) + diuretic; ACE inhibitors + calcium antagonists (AK); BAR + AK; dihydropyridine AK + β-blockers (BAB); AK + diuretic; BAB + diuretic. For combined therapy of hypertension, both non-fixed and fixed combinations of drugs can be used, the latter being more promising (Table 1).
According to modern concepts, various mechanisms and systems (renin-angiotensin, sympathetic-adrenal, water-salt), which closely interact with each other, take part in the increase in blood pressure. The effect on blood pressure levels of antihypertensive drugs is often impaired due to the activation of counterregulatory mechanisms. The combination of two drugs that actually interact with the compensatory responses of each of them significantly increases the frequency of BP control. In addition, the doses required for these purposes in the case of a combination of two drugs are usually lower than those required when the components are used in monotherapy. All this is of great importance in terms of tolerability: the incidence of side effects for most classes of antihypertensive drugs is clearly dose-dependent.
When to start
combination therapy?
In most cases of treatment of patients with hypertension, it is necessary to achieve a gradual decrease in blood pressure to predetermined target levels, with particular caution in the elderly who have had a recent myocardial infarction and stroke. The number of prescribed drugs depends on the risk of developing CVD, in the stratification of which great importance is attached to the value of blood pressure.
Currently, it is possible to use two strategies for the initial therapy of hypertension: monotherapy and low-dose combination therapy, followed by an increase in the amount and/or doses of the drug, if necessary (Fig. 2).
Monotherapy as initial treatment is used in individuals with a low or moderate risk of developing CVD, with a 1st degree of BP increase. This treatment regimen is based on the search for the optimal drug for the patient. A second drug of a different class should be added when, after the appointment of the first in adequate doses, blood pressure is not controlled. The advantage of monotherapy is that if the drug is successfully selected, the patient will not take another drug. However, such a strategy requires a painstaking search for the optimal antihypertensive agent for the patient with frequent changes in drugs and their dosages, which deprives the doctor and the patient of confidence in success and, ultimately, may lead to a decrease in adherence to treatment.
The combination of two drugs is recommended in patients with a high or very high risk of developing CVD, with 2nd and 3rd degree of increase in blood pressure. For example, if the initial (before treatment) level of blood pressure exceeds 20/10 mm Hg. Art. the target of your choice, you can immediately prescribe two drugs - either as separate prescriptions or as a fixed-dose combination tablet. Combination therapy at the start of treatment involves the selection of an effective combination of drugs with different mechanisms of action.
What drugs
better to combine?
Many antihypertensive drugs can be combined with each other, however, some combinations have advantages over others, not only because of the main mechanism of action, but also because of the practically proven high antihypertensive efficacy (Table 1). An ACE inhibitor in combination with a diuretic is the optimal choice, in which the benefits are enhanced and the disadvantages are leveled.
The recommendations indicate the circumstances that should be considered when choosing a drug or combination of drugs in a particular patient (Fig. 3). However, the most attractive drugs are those that, in addition to the blood pressure-lowering effect, have additional, primarily organoprotective properties, which should ultimately improve the prognosis in patients with hypertension with long-term use. From these positions, the creation of ACE inhibitors is a huge achievement in the treatment of hypertension and other cardiovascular diseases. This class of drugs has a high antihypertensive efficacy, is well tolerated, has a proven cardio-, vasculo-, and renoprotective effect, and, most importantly, helps to reduce the incidence of cardiovascular events and increase the life expectancy of patients with long-term use of this therapy.
With the appointment of this class of drugs, a good quality of life (normal sexual activity, response to physical activity) is maintained, including in the elderly. Improvement of cognitive functions while taking ACE inhibitors in the elderly allows them to be more widely used in this category of patients.
ACE inhibitors are metabolically neutral drugs: against the background of their use, there are no changes in the lipid profile, uric acid levels, blood glucose levels and insulin resistance (the latter indicators, according to some reports, may even improve). One of the new provisions of the European recommendations on hypertension (2009) is the assessment of the risk of developing diabetes in the presence of antihypertensive drugs. Clinical studies have shown that BP-lowering drugs can both increase and decrease the likelihood of carbohydrate metabolism disorders. According to the ASCOT study, when using a combination of BB / diuretic compared with a combination of calcium antagonist / ACE inhibitor, the development of new cases of DM was significantly more frequent by 23% (p<0,007) . В исследовании INVEST у больных АГ в сочетании с ИБС на фоне лечения верапамилом в комбинации с трандолаприлом риск развития СД был достоверно ниже по сравнению с больными, получавшими терапию атенололом в комбинации с диуретиком .
The combination ACE inhibitor/diuretic is the most popular in the treatment of hypertension due to high antihypertensive efficacy, protection of target organs, good safety and tolerability, as well as attractive pharmacoeconomic indicators. The drugs potentiate each other's action due to the complementary effect on the main links in the regulation of blood pressure and blocking counter-regulatory mechanisms. The decrease in circulating fluid volume due to the saluretic action of diuretics leads to stimulation of the RAS, which is counteracted by an ACE inhibitor. In patients with low plasma renin activity, ACE inhibitors are usually not effective enough, and the addition of a diuretic, leading to an increase in RAS activity, allows the ACE inhibitor to realize its effect. This expands the range of patients responding to therapy, and target blood pressure levels are achieved in more than 80% of patients. ACE inhibitors prevent the development of hypokalemia and reduce the negative effect of diuretics on carbohydrate, lipid and purine metabolism.
A recent large Russian study PIFAGOR showed that when prescribing a combination of antihypertensive drugs, in most cases, doctors prefer an ACE inhibitor with a diuretic, with fixed combinations of these drugs being the most popular (Fig. 4).
ACE inhibitor/
diuretic - effect on prognosis
in patients with hypertension
The effect of this combination on prognosis in patients at high risk of complications has been evaluated in several clinical trials - PROGRESS, ADVANCE, HYVET. The combination of an ACE inhibitor and the diuretic indapamide was shown in the PROGRESS study to result in greater BP reduction than ACE inhibitor alone, and in parallel to greater prevention of recurrent stroke. In the ADVANCE study, the combination of an ACE inhibitor with a diuretic was used in patients with type 2 diabetes to reduce the risk of complications, which was accompanied by a significantly greater blood pressure-lowering effect than placebo (difference in systolic and diastolic blood pressure - 5.6 and 2.2 mm Hg. Art between groups, respectively). During long-term follow-up (mean 4.3 years), this was associated with a 9% reduction in DM-related complications (cumulative point of macro- and microvascular complications). The ACE inhibitor/diuretic combination was very well tolerated, with slightly higher rates of adverse events than placebo, and high adherence (>80%) throughout the study. Similarly, in the HYVET study, a greater reduction in elevated BP compared with placebo in people over 80 years of age, using the combination of indapamide with perindopril in most cases, led to a significant reduction in overall mortality, fatal stroke and heart failure.
Of great interest are studies that have studied the effect of a fixed combination of the ACE inhibitor lisinopril and the thiazide diuretic hydrochlorothiazide. Studies have shown that lisinopril and hydrochlorothiazide do not enter into drug interactions with each other and do not change the pharmacokinetic characteristics of each other. Gerc V. et al. found that tablet preparations containing lisinopril and hydrochlorothiazide normalize blood pressure in 81.5% of patients with mild to moderate hypertension. In addition, it has been shown that a fixed combination of lisinopril and hydrochlorothiazide in more than half of the cases allows you to steadily reduce blood pressure to normal levels in patients with high blood pressure, poorly controlled by other drugs (Co-Diroton, Gedeon Richter).
ACE inhibitor/
diuretic - organoprotective
properties
Along with the control of blood pressure levels, protection of target organs is one of the most important goals of antihypertensive therapy. In this regard, combination therapy also has an advantage over monotherapy due to more effective BP control and organ-protective properties of each of the drugs.
Left ventricular myocardial hypertrophy (LVH) is an independent factor that significantly increases the risk of disease complications (IHD, chronic heart failure, ventricular arrhythmias). The regression (regression) of LVH against the background of antihypertensive therapy is associated with an additional reduction in cardiovascular risk, which should be taken into account when choosing an antihypertensive drug. Studies have shown that the combination of an ACE inhibitor with a diuretic is more effective in reducing LVH. These data are reflected in the recommendations of the Russian Medical Society for Arterial Hypertension, where the combination of an ACE inhibitor with a diuretic is a priority (Fig. 3). So, in particular, after 12 weeks of taking a fixed combination of lisinopril and hydrochlorothiazide, LVH decreases. In addition, against the background of this therapy, normalization of lipid and carbohydrate metabolism is noted.
Microalbuminuria is not only one of the first manifestations of damage to the vascular wall and kidneys in hypertension, but also a marker of poor prognosis. Treatment based on ACE inhibitors and diuretics prevents the progression of diabetic nephropathy and reduces albuminuria. In this category of patients, the use of combined drugs may also be effective.
The main indications for the appointment of rational combinations of antihypertensive drugs, in particular ACE inhibitors and diuretics, are presented in Table 1.
Conclusion
The value of blood pressure is considered as one of the elements of the system of stratification of the total (total) cardiovascular risk in patients with hypertension, and reliable control over it can have a beneficial effect on the prognosis.
The use of a fixed combination of ACE inhibitors and thiazide diuretics (for example, Co-Diroton) in patients significantly improves blood pressure control, has an organoprotective effect and significantly reduces the risk of major cardiovascular events, including death. These data indicate the great potential of this combination and the expediency of its wider introduction into everyday clinical practice.

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Antihypertensive drugs: principles of therapy, groups, list of representatives

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Angiotensin-converting enzyme inhibitors (ACE inhibitors)

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Diuretics

calcium antagonists

Beta blockers

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Treatment of hypertension

Cardiology Cheat Sheet: Antihypertensive Therapy

Hypotensive action: what is it

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Antihypertensive therapy: drugs to reduce pressure

Beta blockers

ACE inhibitors

calcium antagonists

Diuretics

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Antihypertensive therapy in hypertensive crisis

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