Drugs to lower blood pressure: a review of antihypertensive (hypotensive) drugs. Antihypertensive therapy

Since the beginning of the 20th century, the combination of arterial hypertension (AH) with obesity and diabetes mellitus(SD) has been the subject of active attention from theoretical and practical medicine. A long-term search for the causes that unite these diseases allowed G. Reaven in 1988 to suggest that in the development of such a pathophysiological condition combining hypertension, disorders of carbohydrate and lipid metabolism and obesity, important role play insulin resistance (IR) and hyperinsulinemia (HI). Subsequently, many studies have confirmed the connection between known risk factors for cardiovascular diseases and IR. Currently " metabolic syndrome"(MS) is still the object of close attention of doctors of various specialties. The criteria for diagnosing MS are constantly undergoing changes, periodically supplemented with new characteristics, but invariably since the time of G. Reaven, it has included increased blood pressure (BP), impaired carbohydrate metabolism, dyslipidemia and obesity.

In 2007, the All-Russian Scientific Society of Cardiologists developed following criteria MS: abdominal obesity(waist circumference more than 80 cm in women and 94 cm in men), hypertension, increased triglyceride levels (≥ 1.7 mmol/l), decreased lipoprotein cholesterol levels high density(HDL-C) (< 1,0 ммоль/л у мужчин; < 1,2 ммоль/л у женщин), повышение уровня ХС липопротеидов низкой плотности (ЛПНП) (>3.0 mmol/l), fasting hyperglycemia (fasting plasma glucose ≥ 6.1 mmol/l), impaired glucose tolerance (IGT) (plasma glucose 2 hours after a glucose load between ≥ 7.8 and ≤ 11.1 mmol/l).

Pathogenesis of hypertension in MS. Impaired glucose utilization and an increase in its content in the blood as a result of insulin resistance have a stimulating effect on the beta cells of the islets of Langerhans in the pancreas and are the main cause of the development of adaptive hyperthyroidism. The pathogenetic role of GI in the occurrence of hypertension in MS is currently beyond doubt and is well documented. There is convincing evidence of the direct involvement of chronic excess insulin in the manifestation of hypertension, both in the form of a direct effect on the tone of vascular smooth muscles and the activity of beta-adrenergic receptors vascular wall, and in enhancing the reabsorption of water and sodium in the kidneys, increasing the activity of the sympathoadrenal and renin-angiotensin systems. Along with this, the stimulating effect of insulin on the processes of proliferation of smooth muscle cells and fibroblasts of the vascular wall has been proven. However, not only changes in metabolism and architectonics of the vascular wall determine the effect of GI on the development of hypertension, but also the effect on the vascular endothelium and platelets in the form of increased production of endothelin, thromboxane A2, prostaglandin F2 and a decrease in the secretion of prostacyclin and nitric oxide.

Therapy of hypertension in MS. According to the third revision of Russian recommendations on hypertension, the main goal of treatment for patients with hypertension remains the maximum reduction in the risk of developing cardiovascular complications (CVD) and death from them. Since patients with MS belong to the category of people with high level risk, the effectiveness of antihypertensive therapy should be determined not only by the ability of the drug to reduce blood pressure, but also by the ability to have a maximum effect on the total cardiovascular risk. In addition, when selecting antihypertensive therapy, possible negative effects should also be taken into account. metabolic effects a number of drugs. As the well-known TROPHY study showed, the effectiveness of low doses of thiazide diuretics in obese patients is insufficient in most cases. To achieve an adequate antihypertensive effect, a significant increase in the dose of the drug is required. However, for patients with carbohydrate metabolism disorders, the appointment high doses drugs are undesirable due to worsening insulin resistance and negative action to other types of metabolism. Diuretics tend to cause hyperglycemia, hyperlipidemia, hyperuricemia, hypokalemia, hypercalcemia.

Beta-adrenergic blockers also tend to worsen lipid profile and worsening insulin resistance, so they can hardly be considered drugs of choice in patients with MS. Such pro-atherogenic and pro-diabetogenic effects of antihypertensive therapy are undesirable, since in the long term they can increase the risk of developing diabetes and reduce the effectiveness of therapy in terms of preventing cardiovascular complications. In addition, as studies show, in their ability to cause regression of left ventricular myocardial hypertrophy and slow down the decrease in glomerular filtration rate, beta blockers are significantly inferior to angiotensin-converting enzyme inhibitors (ACEIs), calcium antagonists (CA) and angiotensin II receptor antagonists (ATII), which In general, they are metabolically neutral and do not have a negative effect on tissue sensitivity to insulin.

ACE inhibitors are a very promising group in the treatment of patients with hypertension and MS, since the pathogenetic rationale for their use is associated with activation of the renin-angiotensin-aldosterone system (RAAS) in IR. In addition, their mechanism of action predisposes to many beneficial effects, proven in large-scale randomized trials. Thus, a decrease in IR and an improvement in glycemic control are known; no negative effect on lipid and purine metabolism (CAPPP, FASET, ABCD, HOPE, UKPDS studies). Vasoprotective, anti-atherosclerotic (SECURE-HOPE-substudy), as well as nephroprotective effects of ACE inhibitors in diabetic and non-diabetic nephropathy (FACET, MICRO-HOPE, REIN, EUCLID, AIPRI, BRILLIANT) were obtained. Correction of endothelial dysfunction, beneficial effects on platelet hemostasis and fibrinolysis (TREND) are substantiated.

No less promising drugs for the treatment of patients with hypertension and MS are long-acting AKs, the main advantage of which is their metabolically neutral effect on carbohydrate, lipid, and purine metabolism with high antihypertensive activity. The antihypertensive effect of AA is based on the ability to cause peripheral vasodilation through inactivation of voltage-dependent calcium channels vessel walls.

The undoubted effectiveness of the use of AKs of various groups has been very convincingly demonstrated in numerous international multicenter studies. Along with high antihypertensive activity, a beneficial effect on the incidence of fatal and non-fatal strokes, myocardial infarction, sudden death, death from cardiovascular causes (SHE, SHC, NORDIL, VHAT, ALLHAT, HOT, NICS-EH, ASCT, STOP-Hypertension 2, VALUE, SYST-EUR). A decrease in IR, a decrease in basal and glucose-stimulated insulin levels, and a normalization of the insulin response to the glycemic load were found. A slowdown in the progression of the atherosclerotic process has been shown, regardless of the hypotensive effect (INSIGHT, ELSA, CAMELOT). The antispastic effect of AK and the effect on myocardial ischemia (CAPE) have also been registered. Nephroprotective and vasoprotective effects were noted (PREVENT, INSIGHT, ELSA MIDAS). In addition, regression of left ventricular hypertrophy (TOMH) is substantiated. The use of AKs currently seems extremely promising III generation- amlodipine, whose cardio- and nephroprotective effects are comparable to ACE inhibitors.

Thus, modern requirements requirements for antihypertensive therapy, the primary goal of which is undoubtedly an adequate reduction in blood pressure, are based, at a minimum, on its metabolic neutrality, as well as on the ability to provide additional beneficial effects in relation to a cluster of concomitant metabolic changes.

Since patients with MS are included in the group high risk, then the main strategy for the treatment of hypertension is combination therapy with drugs different groups. Important advantages combination therapy are: the possibility of potentiating the antihypertensive effect both due to the multidirectional action of drugs on the totality of individual pressor mechanisms for the development of hypertension in a particular patient, and due to the mutual suppression of counter-regulatory mechanisms that reduce their effectiveness; reducing the incidence of side effects due to lower doses of combined drugs; ensuring the most effective organ protection and reducing the risk and number of cardiovascular events.

Recently, there has been genuine interest in using clinical practice combinations of ACE inhibitors with dihydropyridine AKs. Fundamental in this aspect was the ASCOT-BPLA study, which ended in 2004, which convincingly demonstrated a significant and significantly greater effect of the combination of “dihydropyridine AK (amlodipine 5-10 mg/day) plus ACE inhibitor (perindopril 4-8 mg/day)” compared with combination of “beta blocker (atenolol 50-100 mg/day) plus diuretic (bendroflumethiazide 1.25-2.5 mg/day)” not only on blood pressure levels, but also on the development of cardiovascular complications. Thus, there was a decrease of 11% in deaths from all causes, by 13% in non-fatal myocardial infarction and in all deaths from coronary disease heart disease (CHD), 24% of all deaths due to cardiovascular causes, by 23% - fatal and non-fatal strokes, by 13% - non-fatal myocardial infarction, fatal ischemic heart disease, fatal and non-fatal heart failure, stable and unstable angina ("common coronary point"), by 16% - all cardiovascular events and revascularization procedures. Moreover, the likelihood of developing new cases of diabetes in the group of patients receiving amlodipine and perindopril was 30% lower, which proved the safety of the combination of dihydropyridine AK plus ACE inhibitors.

The complementary effect of ACE inhibitors and AKIs is the possible effective influence on the pathogenesis of hypertension in MS. The renin-angiotensin system (RAS) and the sympathetic nervous system (SNS) are interactive systems that provide fine regulation of the activity of the heart and blood vessels at different levels: central, baroreceptor, adrenal, postsynaptic ATI receptors. ATII, by binding to presynaptic receptors of noradrenergic neurons of the SNS, increases the level of presynaptic release of norepinephrine, thereby causing vasoconstriction and an increase in peripheral vascular resistance. Along with this, acting postsynaptically, it enhances the contractile response to stimulation of vascular alpha-adrenergic receptors. Next is formed vicious circle: ATII activates efferent sympathetic activity, which leads to stimulation of beta-adrenergic receptors of the juxtaglomerular apparatus of the kidneys and promotes the formation of renin by the kidneys. As a result, there is an increase in the amount of ATII, which facilitates the release of norepinephrine at the adrenergic synapses of the adrenal glands. It is the increase in sympathetic tone that is pathophysiologically associated with the formation of GI, which is one of the key mechanisms of changes that develop in MS.

At a certain stage of quite successful antihypertensive therapy, a decrease in blood pressure often contributes to reflex activation of the SNS and RAS. As a result, the effectiveness of antihypertensive therapy is reduced. In addition, the most important hemodynamic consequence of autonomic imbalance may be an increase in myocardial oxygen demand, which is an important predisposing factor in the formation of complications, which is especially important in patients with left ventricular hypertrophy, coronary atherosclerosis, and endothelial dysfunction.

Dihydropyridine AKs (especially the short-acting form of nifedipine), reducing blood pressure, cause quite pronounced vasodilation, which causes reflex activation of the SNS. The presence of an intrinsic natriuretic effect in dihydropyridine AAs may contribute to a compensatory increase in RAS activity. The addition of ACE inhibitors to therapy allows one to overcome the activation of the SAS and RAS, thereby enhancing the hypotensive effect of AK. In the low-renin form of hypertension, when the activity of ACE inhibitors is insufficient, the addition of dihydropyridine AK to therapy provides a slight increase in the activity of the RAS and, thus, enhances the effect of ACE inhibitors.

Control cardiovascular risk suggests, in addition to lowering blood pressure, an effect on possible mechanisms target organ damage at the stages of the cardiovascular and renal continuum. In this regard, the combination of “dihydropyridine AK plus ACEI” is quite justified, since there is convincing evidence of the significant nephroprotective effect of the combination of AK and ACEI. Thus, the effectiveness of the combination of verapamil with the ACE inhibitor trandolapril in patients with diabetic nephropathy(EDICTA, TRAVEND, BENEDICT). There is evidence of a decrease in the severity of microalbuminuria in patients with diabetes when using nitrendipine (SYST-EUR), a slower decline in renal function when using nifedipine in the form of a gastrointestinal therapeutic system (INSIGHT). Also interesting are the results of a double-blind randomized trial. clinical trial(RCT), in which in patients with type 1 diabetes and nephropathy, who were on constant therapy with maximum doses of lisinopril, there was a significant decrease in the albumin/creatinine ratio in urine by 54% when amlodipine (10 mg/day) was added to the main treatment and 56% - when candesartan (16 mg/day) was added to treatment. At the same time, the decrease in albuminuria in both groups did not correlate with the degree of decrease in blood pressure, which proves the actual nephroprotective effect of the drugs.

The possibility of a significant anti-atherosclerotic effect when using a combination of dihydropyridine AK and ACE inhibitors is also promising. Today, the antiatherogenic properties of AKs are their most significant clinical advantage and have been registered in absolutely all representatives of this class. Therefore, the fixed combination of “dihydropyridine AK plus ACEI” is quite capable of providing organ protection in patients with hypertension and MS.

The combination of a dihydropyridine AK and an ACE inhibitor also makes it possible to prevent the occurrence of some adverse effects inherent in their components. Thus, the undoubted advantage of this combination is the ability of ACE inhibitors to prevent swelling of the legs, which develops while taking AA and is a consequence of arteriolar vasodilation, leading to intracapillary hypertension and increased exudation of fluid from the capillaries into the interstitial space. Since there is no increase in circulating plasma volume and sodium retention during the use of AKs due to their own natriuretic effect, edema does not decrease with the use of diuretics, but develops less frequently when prescribing drugs with venodilating properties, in particular, ACE inhibitors.

Dose-dependent effects of AA, such as reflex tachycardia, headaches, hot flashes and facial flushing, also resulting from arteriolar vasodilation, occur less frequently with joint use AK and ACE inhibitors, since fixed combinations allow the use of AK in lower doses without loss of overall antihypertensive effectiveness.

Thus, as F. Messerli predicted back in 1992, obtaining a highly effective fixed combination of metabolically neutral dihydropyridine AK and ACE inhibitors can truly become the “Rolls Royce” of modern antihypertensive therapy in patients with MS.

Among the currently existing combinations of dihydropyridine AK and ACE inhibitors, the fixed combination of amlodipine (Normodipine) 5 mg and lisinopril (Diroton) 10 mg, recently registered in Russia under the name Equator®, is of particular interest.

The most interesting data on the use of the combination of amlodipine and lisinopril in the drug Equator® were obtained during the multicenter, double-blind, placebo-controlled study HAMLET, which studied the effectiveness and safety of the new fixed-dose combination. The study included 195 patients (109 men and 86 women) with untreated or poorly controlled hypertension of I-II degree (BP 140-179/90-99 mm Hg) aged 18-65 years ( average age 48.6 ± 10 years), body mass index 27.7 ± 3.7 kg/m2. Exclusion criteria: symptomatic hypertension; a history of heart attack or stroke within the three months preceding the study. In addition, patients were not included in the study if they had chronic renal failure, malignant neoplasms, severe liver or lung disease, hyperkalemia, obesity (body mass index > 35 kg/m2).

During a run-in period of 14 days, patients took placebo. Subsequently, patients were assigned to a group receiving lisinopril 10 mg/day, or a group receiving amlodipine (5 mg/day), or a group receiving lisinopril in combination with amlodipine in the same doses. The duration of observation was 8 weeks. Blood pressure levels were measured on the day of inclusion (day -14), at the beginning of the study (day 0), and at the end of the 2nd and 8th weeks of drug intake. The criteria for a positive response to treatment was a decrease in blood pressure by at least 20/10 mmHg. Art.

Three patients stopped taking medications early due to adverse events (one due to headache, the second due to increased blood pressure during the placebo period, and the third due to the need for intracardiac examination and upcoming heart surgery). In the lisinopril group, treatment-related complaints were identified in 8 patients, and unrelated to treatment complaints in 5 cases. In the amlodipine group unwanted effects 9 patients noted that they were related to therapy, and 7 patients who were not related to therapy. In the combination therapy group, 7 patients experienced events that were probably related to therapy, and 7 patients that were not related to the drug. Although the complaints present in all groups did not prevent the continuation of treatment.

By the end of observation in the amlodipine group, blood pressure decreased from 155.4 ± 10.2/97.7 ± 4.9 to 140.8 ± 13.7/86.3 ± 7.1 mm Hg. Art.; in the lisinopril group - from 156.4 ± 10.4/97.3 ± 5.7 to 139.8 ± 12.9/87.2 ± 7.7 mm Hg. Art.; in the combination therapy group - from 156.4 ± 9.6/97.5 ± 5.0 to 136.3 ± 11.9/86.0 ± 6.6 mm Hg. Art.

Moreover, in the combination therapy group, systolic blood pressure (SBP) decreased significantly more than in the amlodipine group (-20.1 ± 13.6 and -14.7 ± 13.0 mm Hg, respectively). The reduction in SBP in the combination therapy group also exceeded the changes in pressure in the lisinopril group (-16.8 ± 10.2), but the differences were not statistically significant. There were statistically significant differences between the combination therapy group and the general group receiving any type of monotherapy (p< 0,0236). Максимальный эффект препаратов в отношении диастолического АД (ДАД) не показал статистически достоверных различий между тремя группами.

At the end of the study, the proportion of people who reached the target blood pressure level, according to established criteria, was significantly greater in the combination therapy group compared with the amlodipine group (90.1% versus 79.3%; p = 0.0333) or lisinopril (75.8%; p = 0.0080), as well as compared with generalized data from patients receiving any type of monotherapy (p = 0.0098). There were no statistically significant differences between the two groups of patients receiving monotherapy.

The HAMLET trial is the only RCT to evaluate the antihypertensive efficacy of a fixed combination of two well-studied drugs, lisinopril and amlodipine (Equator®). Of course, the additive organoprotective effect of the drug cannot be based on a simple summation of the effects obtained in independent studies involving amlodipine and lisinopril. Obviously, there is still work to be done in this area. additional research. However, today the high antihypertensive effect and good tolerability profile make it possible to recommend the drug Equator® for use in clinical practice in patients with hypertension and MS. What awaits us along the way? Having experience, we hope that the use of a fixed combination will provide multiple potentiation of the organoprotective properties of its components and will minimize the frequency of adverse reactions, which is very important for increasing the adherence of patients with hypertension to treatment and reducing the risk of cardiovascular complications.

For questions regarding literature, please contact the editor.

M. I. Shchupina, Candidate of Medical Sciences, Associate Professor
Omsk State Medical Academy, Omsk

For quotation: Karpov Yu.A., Starostin I.V. Combined antihypertensive therapy: current state // Breast cancer. 2012. No. 25. S. 1283

Increased blood pressure (BP) levels are the result of a complex interaction of genetic and environment, leading to activation and/or suppression of blood pressure regulation systems. The complexity of the mechanisms that provide blood pressure control, which was first discussed by Irvine Page, significantly influences differences in individual sensitivity to antihypertensive therapy. The huge number of variants of arterial hypertension (AH) makes it almost impossible, with few exceptions, to determine a specific variant of increased blood pressure in the daily practice of a doctor who decides on the choice of treatment.

Hypertension is a hemodynamic disorder by definition, and increased peripheral vascular resistance is a distinctive hemodynamic feature higher level HELL. Understanding of this fact led to the discovery and development of a special class of vasodilators with a targeted mechanism of action, although many of the previously used antihypertensive drugs also had a vasodilating effect, for example, by blocking the activity of the sympathetic nervous system. The first nonspecific vasodilator was hydralazine, followed by vasodilators blocking calcium channels of vascular smooth muscle cells (calcium antagonists - AK), postsynaptic α-adrenergic receptors of peripheral neurons of the sympathetic nervous system (α-blockers) and blockers of the renin-angiotensin-aldosterone system (RAAS) ( angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs); finally, the latest to appear are direct renin inhibitors (DRIs).
The vasodilating effect is also inherent in thiazide diuretics (TD), which, by reducing the sodium content in vascular smooth muscle cells, reduce their sensitivity to vasopressors - catecholamines, etc. When using antihypertensive drugs in a heterogeneous population of patients with hypertension, selectivity active ingredients and their other features lead to an unpredictable decrease in blood pressure in each individual patient. For example, prescribing an ACE inhibitor to a patient with hyperactivation of the RAAS due to stenosis renal artery will lead to a significant decrease in blood pressure and impaired renal function. In turn, the prescription of ACE inhibitors to older people and people of the Negroid race (who in most cases have reduced level RAAS activity) will lead to only a slight decrease in blood pressure. Most often, the “phenotype” of hypertension in a particular patient remains unspecified.
A recent meta-analysis of 354 placebo-controlled studies different modes Antihypertensive monotherapy in unselected hypertensive patients (n=56,000) showed a mean reduction (placebo-adjusted) in systolic blood pressure of 9.1 mmHg. and diastolic blood pressure - by 5.5 mm Hg. . These average values ​​hide a wide range of individual responses to antihypertensive therapy - from a decrease in SBP by 20-30 mmHg. and until there is a complete lack of effect, and sometimes even a slight increase in blood pressure.
The second factor determining individual reaction to antihypertensive monotherapy, - individual differences in blood pressure counter-regulation systems activated in response to a decrease in its level. In some cases, such a reaction can completely compensate for the decrease in blood pressure. Thus, the use of antihypertensive monotherapy does not always give a satisfactory result. What should be the next step in similar situation? Should the dose be increased, the drug changed, or a combination of antihypertensive agents used?
Rationale for use
combination antihypertensive therapy
The rationale for using combination therapy for hypertension is quite obvious. First, in contrast to blindly assigned monotherapy, a combination of drugs acting on different systems regulation of blood pressure, significantly increases the likelihood of it effective reduction. Secondly, prescribing a combination of drugs can be regarded as an attempt to block the activation of counter-regulatory systems that counteract the decrease in blood pressure during the use of monotherapy (Fig. 1).
Thirdly, a significant part of the population of patients with hypertension suffers from so-called moderate or severe hypertension (stage 2), this group includes patients with systolic blood pressure more than 160 mm Hg. and/or diastolic blood pressure more than 100 mm Hg, which is about 15-20% of all patients with hypertension. These patients are at the highest risk of cardiovascular events. Increase in blood pressure for every 20 mm Hg. doubles the risk of such events.
The risk of hypertension increases with age, and the proportion of patients with stage 2 hypertension also increases. Age is also associated with an increase in the proportion of patients with isolated systolic hypertension, which causes loss of vascular elasticity and an increase in vascular resistance.
Despite some differences in recommendations, in some of them combination treatment refers to first-line therapy, however, only when certain conditions. Such a place for combination therapy is logical due to the risks of severe hypertension, recognition of the inevitability of using double (and sometimes triple) therapy to achieve target blood pressure values ​​​​less than 140/90 mm Hg. and the need to quickly reduce blood pressure to a more acceptable level to reduce existing risks.
For systolic blood pressure 20 mmHg above target and/or diastolic blood pressure 10 mmHg above target, the US Joint National Committee on the Prevention, Diagnosis, and Treatment of High Blood Pressure (JNC-7) recommends start antihypertensive therapy with a combination of two drugs. Similar recommendations are contained in the latest Russian guidelines, and the recommendation for the use of first-line combination antihypertensive therapy also applies to patients with more low levels AD with multiple risk factors, target organ damage, diabetes mellitus, kidney disease or associated cardiovascular disease.
There are concerns that the use of more than one antihypertensive drug at the beginning of treatment may in some cases provoke clinically significant hypotension and increase the risk of coronary events. Analysis of studies on the treatment of hypertension has provided some evidence for the existence of a J-shaped relationship between blood pressure reduction and cardiovascular risk, however, this appears to apply to patients at high risk, including those with known coronary artery disease, where a pronounced decrease in blood pressure may lead to deterioration of myocardial perfusion. Patients with uncomplicated hypertension tolerate low blood pressure values ​​satisfactorily, as, for example, in the Systolic hypertension in Elderly study, where in the group active treatment managed to reduce systolic blood pressure to 60 mm Hg. . Ongoing studies designed to compare initiation of antihypertensive therapy with dual and sequential monotherapy will evaluate the safety of the new approach.
Fourthly, compared with monotherapy, combination therapy can achieve a reduction in blood pressure variability. Additional analysis of several randomized trials showed that visit-to-visit variability in systolic blood pressure is a strong predictor of myocardial infarction and stroke, independent of mean blood pressure. It is noteworthy that the greatest efficiency AK and diuretics were shown to reduce such blood pressure variability and the risk of stroke. β-blockers, on the contrary, increased systolic blood pressure variability in a dose-dependent manner and showed the least effectiveness in preventing stroke. The addition of a calcium inhibitor or, to a lesser extent, a diuretic to a RAAS inhibitor reduces systolic blood pressure variability, which is an additional argument in support of combination therapy.
Combinations of drugs
There are 7 classes of antihypertensive drugs, each of which includes several representatives, so there is a large number of combinations (Table 1). Combinations will be presented below according to their division into rational (preferred), possible (acceptable) and unacceptable or ineffective. Assignment of a combination to a particular group depends on outcome data, antihypertensive efficacy, safety and tolerability.
Rational (preferred) combinations
RAAS inhibitors and diuretics. Currently, this combination is most often used in clinical practice. A significant number of studies with a factorial design have shown additional reductions in BP when using a combination of TD and ACEI, ARB or PIR. Diuretics reduce the volume of intravascular fluid, activate the RAAS, which inhibits the excretion of salt and water, and also counteracts vasodilation. Adding a RAAS inhibitor to a diuretic weakens the effect of this counterregulatory mechanism. In addition, the use of a diuretic can cause hypokalemia and impaired glucose tolerance, and RAAS blockers can reduce this undesirable effect. It has been shown that chlorthalidone is more effective in lowering blood pressure than hydrochlorothiazide, because has a longer duration of action, so chlorthalidone should be preferred as the second component in combination with a RAAS inhibitor. Most RAAS inhibitors are available in fixed combination with hydrochlorothiazide.
A study of hypertension in patients was recently completed old age(over 80 years) (HYVET, Hypertension in the Very Elderly), which assessed the effectiveness of the thiazide-like diuretic indapamide. The ACE inhibitor perindopril was added to this diuretic to enhance the antihypertensive effect in 75% of patients. A 30% reduction in stroke and a 64% reduction in heart failure was shown with this combination compared with placebo.

Using a combination of an ACE inhibitor and a diuretic, the EPIGRAF project was carried out under the auspices of the All-Russian Scientific Society of Cardiology. This project consisted of two multicenter studies - EPIGRAPH-1 and EPIGRAPH-2. This project is valuable in that it contributed to the creation of a non-fixed combination of Enzix (“Stada”), containing two drugs in one blister - enalapril (ACE inhibitor) and indapamide (diuretic), which allows, if necessary, to change their dosages and correlate the time of administration with the circadian rhythm of blood pressure , have 2 drugs in one package, rather than using two separate ones. The drug is available in three forms: Enzix - 10 mg enalapril and 2.5 mg indapamide; Enzix Duo - 10 mg enalapril and 2.5 mg indapamide + 10 mg enalapril; Enzix Duo forte - 20 mg enalapril and 2.5 mg indapamide + 20 mg enalapril. Different dosages allow you to adjust therapy depending on the severity and risk of hypertension and drug tolerability.
A study conducted in Ukraine examined the effect of long-term therapy with a non-fixed combination of enalapril and indapamide in 1 blister (Enzix, Enzix Duo) on the daily blood pressure profile and parameters of LV remodeling, its systolic and diastolic function, as well as the quality of life of patients with stable hypertension. The results of the study showed that in patients with hypertension, long-term use of a combination of enalapril and indapamide (Enzix, Enzix Duo) significantly improves the magnitude and speed of the morning rise in blood pressure and has a positive effect on blood pressure variability. Also, the data obtained indicated that long-term use of a non-fixed combination of enalapril and indapamide in 1 blister (Enzix, Enzix Duo) has a clear antihypertensive effect, leading to reverse development LV remodeling and improvement of its diastolic function, improving quality of life along with a good safety and tolerability profile.

RAAS inhibitors and calcium antagonists. Combining AK with ACE inhibitor, ARB or PIR allows you to achieve an additional reduction in blood pressure. Peripheral edema is a common dose-dependent adverse event observed with dihydropyridine CB monotherapy. The severity of this adverse effect can be reduced by adding a RAAS inhibitor to the AA. A recent meta-analysis suggests that ACEIs are more effective in this regard than ARBs. According to the results of the ACCOMPLISH study (The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension Trial), a fixed combination of the ACE inhibitor benazepril with the AC inhibitor amlodipine is more effective in reducing morbidity and mortality than the fixed combination of an ACE inhibitor with hydrochlorothiazide. Overall, ACEIs and ARBs showed similar reductions in endpoint rates, although it has been suggested that ACEIs are slightly more cardioprotective and ARBs are better at protecting against stroke.
The international INVEST study compared two antihypertensive regimens: verapamil, with trandolapril added as needed, and atenolol, with hydrochlorothiazide added as needed. The study included 22,576 patients with hypertension established diagnosis IHD, observation was carried out for 2.7 years. The primary composite endpoint of cardiovascular events was achieved at similar rates in both groups. Apparently, this can be explained by the fact that the disadvantages of the treatment regimen, which included a β-blocker for hypertension, were compensated by the advantages of β-blockers for coronary artery disease.
b-blockers and diuretics. Not all experts consider this combination to be rational. At the same time, it has been shown that the addition of diuretics to β-blockers increases the antihypertensive effect in populations with low-renin hypertension. Although both classes of drugs have similar side effects in the form of impaired glucose tolerance, the development of diabetes mellitus and sexual dysfunction, but the real clinical significance"metabolic" side effects greatly exaggerated, and endpoint studies have shown that this combination results in a reduction in cardiovascular morbidity and mortality.
Possible (acceptable) combinations
Calcium channel blockers and diuretics. Most doctors do not always combine AKs with diuretics. However, in the VALUE study (Valsartan Antihypertensive Long-term Use Evaluation Trial), hydrochlorothiazide was added to amlodipine, when it was insufficiently effective, and this combination was well tolerated by patients, although in comparison with the valsartan group, the risk of diabetes mellitus and hyperkalemia increased. However, the reduction in morbidity and mortality in the amlodipine group was no less than in the valsartan group.
Calcium channel blockers and β-blockers. The combination of a β-blocker with a dihydropyridine AK has additional effect to lower blood pressure and is generally well tolerated. Conversely, β-blockers should not be combined with non-dihydropyridine CBs such as verapamil and diltiazem. The combination of the negative chronotropic effect of both classes of drugs can lead to the development of bradycardia or heart block, up to complete transverse, and to the death of the patient.
Double blockade of calcium channels. A recent meta-analysis showed that the combination of a dihydropyridine CB with verapamil or diltiazem leads to an additional reduction in blood pressure without a significant increase in the incidence of adverse events. Such combination therapy can be used in patients with documented angioedema while taking RAAS inhibitors, as well as in patients with severe renal failure accompanied by a risk of hyperkalemia. However, there are currently no data on long-term safety and outcomes with such therapy.
Double blockade of the RAAS. The use of this combination is based on enhancing the blood pressure-lowering effect, which has been proven in a number of studies. However, the significance of this combination has diminished due to unconfirmed safety in long-term studies. In the ONTARGET study, patients receiving combination therapy with telmisartan and ramipril experienced more adverse events, and the number of cardiovascular events, despite some additional reduction in blood pressure, did not decrease compared to monotherapy. Thus, such a combination in patients at high risk of adverse events does not make much sense. However, because blockade of the RAAS by ACE inhibitors or ARBs increases plasma renin activity, the addition of a direct renin inhibitor has been suggested to be effective. In a double-blind study of the combination of aliskiren and ARBs, conducted in 1797 patients, a small but statistically significant significant decrease HELL. It is noteworthy that in an open-label, prospective, crossover study of patients with resistant hypertension, the aldosterone antagonist spironolactone was more effective in lowering blood pressure than dual blockade of the RAAS. The use of a combination of PIR with an ACE inhibitor or ARB in the ALTITUDE (Aliskiren Trialin Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) study, based on the results of an interim analysis in 2012 . turned out to be inappropriate due to an increased risk of adverse events, and the study was stopped early. Apparently, it is advisable to transfer combinations of ACE inhibitors with ARBs to the group of non-recommended combinations.
Unacceptable and ineffective combinations
RAAS blockers and β-blockers. A combination of these classes of drugs is often used in patients who have had a myocardial infarction, as well as in patients with heart failure, because they have been shown to reduce the incidence of reinfarction and improve survival. However, this combination does not provide any additional reduction in blood pressure compared to monotherapy with these drugs. Thus, using a combination of a RAAS inhibitor and a beta-blocker for the treatment of hypertension per se is inappropriate.
β-blockers and drugs with central antiadrenergic action. Combining beta-blockers with centrally acting antiadrenergic drugs such as clonidine provides little or no additional blood pressure reduction. Moreover, when using such a combination, reactions with an excessive increase in blood pressure were even observed.
Other drug classes in combination therapy: α-blockers and spironolactone
α-Adrenergic receptor antagonists are widely used as complementary therapy to achieve target blood pressure values. The emergence of extended-release dosage forms medicinal substance improved the tolerability profile of these drugs. Data from an observational analysis of the ASCOT study (the Anglo-Scandinavian Cardiac Outcomes Trial) showed that doxazosin dosage form gastrointestinal therapeutic system, used as third line therapy, lowers blood pressure and causes a moderate decrease in serum lipids. In contrast to earlier data from the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), doxazosin use in the ASCOT trial did not show an association with an increased incidence of heart failure.
Therapy consisting of 4 antihypertensive drugs is often required in patients with drug-resistant maximum doses or triple antihypertensive therapy, including a RAAS blocker, a calcium antagonist and a thiazide diuretic, hypertension (inability to achieve target values<140/90 мм рт.ст.). Недавние сообщения свидетельствуют об эффективности добавления спиронолактона к тройной терапии, заключающейся в снижении АД в среднем на 22/9,5 мм рт.ст. Таким образом, спиронолактон может быть рекомендован в качестве компонента антигипертензивной терапии у больных с резистентной АГ.
Adverse events. There is evidence that the severity of edema associated with the use of dihydropyridine OCs may be reduced by the addition of RAAS blockers, which may also reduce the incidence of hypokalemia caused by TDs. On the other hand, the use of β-blockers is associated with an increase in the incidence of diabetes mellitus (DM), and when using a combination of TD with β-blockers, a more significant increase in the incidence of newly diagnosed DM is likely, but paradoxically this does not increase the incidence of diabetes-related heart disease. -vascular endpoints, as shown in the ALLHAT study. The NICE guidelines cite meta-analysis data that found an increase in the incidence of newly diagnosed diabetes with the use of β-blockers and TDs compared with newer drugs.
The findings are based on the assumption that there are no differences in long-term morbidity and mortality between drugs within the same class. Among AKs, amlodipine has the largest evidence base. In studies examining ACEIs and ARBs in combination therapy in patients with hypertension and other cardiovascular diseases, various representatives of these classes were studied, and no differences were found between them. It is believed that among thiazide and thiazide-like diuretics, chlorthalidone in moderate doses has the greatest evidence base for long-term benefits (compared to other TDs in lower doses). Unfortunately, further studies comparing drugs in this class seem unlikely.
The most frequently used β-blocker drug in trials was atenolol, and it was repeatedly stated that if other members of this class had been used in trials, the results would have been different. This seems unlikely, because The adverse events identified in the ASCOT trial of effects on BP variability and increased central intra-aortic pressure compared with amlodipine (both associated with increased cardiovascular risk) are likely to occur with most β-blockers. There have been no studies examining the effects of β-blocker therapy with additional pharmacological properties (eg, β-1, β-2, and α-blocker carvedilol) on long-term outcomes in patients with hypertension.
Fixed combinations
and their advantages in influencing the prognosis
A recent review of the potential benefits of fixed-dose combinations (FDCs) over corresponding drugs taken alone found that the use of FDCs is associated with significant improvements in adherence and a small increase in duration of dosing. The degree of adherence to treatment using FDCs, according to a meta-analysis of 9 studies, is 26% higher compared to taking the same medications separately.
According to studies containing information on blood pressure values, the use of FDC is associated with a slight additional decrease in systolic and diastolic blood pressure (4.1 and 3.1 mm Hg, respectively). If maintained over the long term, such differences in blood pressure may translate into real benefits in cardiovascular outcomes.
Conclusion
The majority of patients with hypertension require treatment with two or more drugs from different classes of antihypertensive drugs to achieve target blood pressure values. Combination antihypertensive therapy should be prescribed to patients with blood pressure above target values ​​by more than 20/10 mmHg. Rational (preferred) and possible (acceptable) combinations of drugs should be used. Fixed combinations increase adherence to therapy, which increases the frequency of achieving target blood pressure values.

Literature
1. Page I.H. The MOSAIC theory // Hypertension Mechanisms. - New York: Grune and Stratton, 1987. P. 910-923.
2. Mimran A., Ribstein J., Du Cailar G. Converting enzyme inhibitors and renal function in essential and renovascular hypertension // Am. J. Hypertens. 1991. Vol. 4 (Suppl. 1). 7S-14S.
3. Dickerson J.E., Hingorani A.D., Ashby M.J. et al. Optimization of antihypertensive treatment by cross-over rotation of four major classes // Lancet. 1999. Vol. 353. P. 2008-2013.
4. Law M.R., Wald N.J., Morris J.K., Jordan R.E. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomized trials // BMJ. 2003. Vol. 326. P. 1427-1435.
5. Attwood S., Bird R., Burch K. et al. Within-patient correlation between the antihypertensive effects of atenolol, lisinoprill and nifedepin // Hypertens. 1994. Vol. 12. P. 1053-1060.
6. Chobanian A.V., Bakris G.L., Black H.R. et al. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh Report of the joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure // Hypertens. 2003. Vol. 42. P. 1206-1252.
7. Russian Medical Society for Arterial Hypertension (RMAS), All-Russian Scientific Society of Cardiologists (VNOK). Diagnosis and treatment of arterial hypertension. Russian recommendations (fourth revision) // Systemic hypertension. - 2010. - No. 3. - P. 5-26.
8. Messerli F.H., Mancia G., Conti C.R. et al. Dogma disputed: can aggressively lower blood pressure in hypertensive patients with artery disease be dangerous? //Ann. Intern. Med. 2006. Vol. 144. P. 884-894.
9. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP) // JAMA. 1991. Vol. 265. P. 3255-3264.
10. Rothwell P.M., Howard S.C., Dolan E. et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension // Lancet. 2010. Vol. 375. P. 895-905.
11. Nice guidelines. Management of hypertension in adults in primary care. 2007. www.nice.org.uk.
12. Jamerson K., Weber M.A., Bakris G.L. et al. ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients /// NEJM. 2008.Vol. 359. P. 2417-2428.
13. Julius S., Kjeldsen S.E., Brunner H. et al. VALUE Trial. VALUE trial: Long-term blood pressure trends in 13,449 patients with hypertension and high cardiovascular risk // Am. J. Hypertens. 2003. Vol. 7. P. 544-548.
14. Williams B., Lacy P.S., Thom S.M. et al. CAFE Investigators; Anglo-Scandinavian Cardiac Outcomes Trial Investigators; CAFE Steering Committee and Writing Committee. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study // Circulation. 2006. Vol. 113. P. 1213-1225.
15. Makani H., Bangalore S., Romero J. et al. Effect of rennin-angiotensin-system blockade on calcium channel blockers associated peripheral edema // Am. J. Med. 2011. Vol. 124. P. 128-135.
16. Pepine C.J., Handberg E.M., Cooper-DeHoff R.M. et al. INVEST Investigators. A calcium antagonist vs. a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial // JAMA. 2003. Vol. 290. P. 2805-2819.
17. Alviar C.L., Devarapally S., Romero J. et al. Efficacy and Safety of Dual Calcium Channel Blocker Therapy for the Treatment of Hypertension: A Meta-analysis // ASH. 2010.
18. Alvares-Alvares B. Management of resistant arterial hypertension: role of spironolactone versus double blockade of the rennin-angiotensin-aldosterone system // J. Hypertens. 2010. Jul 21. .
19. Bailey R.R., Neale T.J. Rapid clonidine withdrawal with blood pressure overshoot exaggerated by beta-blockade // BMJ. 1976. Vol. 6015. P. 942-943.
20. Chapman N., Chang C. L., Dahlof B. et al. For the ASCOT Investigators. Effect of doxazosin gastrointestinal therapeutic system as third-line antihypertensive therapy on blood pressure and lipids in the Anglo-Scandinavian Cardiac Outcomes Trial // Circulation. 2008. Vol. 118. P. 42-48.
21. Chapman N., Dobson J., Wilson S. et al. On behalf of the ASCOT Trial Investigators. Effect of spironolactone on blood pressure in subjects with resistant hypertension // Hypertens. 2007. Vol. 49. P. 839-845.
22. Gupta A.K., Arshad S., Poulter N.R. Compliance, safety and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis // Hypertens. 2010. Vol. 55. P. 399-407.
23. Bangalore S., Kamalakkannan G., Parkar S., Messerli F.H. Fixed-dose combinations improve medication compliance: a meta-analysis // Am. J. Med. 2007. Vol. 120. P. 713-719.

1. Antiadrenergic drugs of predominantly central action:

Dopegit(aldomet, alpha-methyl-dopa), tab. by O.25 * 4 times a day. Increases the activity of alpha-adrenergic receptors in the brain stem, and as a result, reduces sympathetic activity in the periphery. It acts predominantly on total peripheral resistance, and to a lesser extent reduces cardiac output. The mechanism of action is associated with a violation of the synthesis of sympathetic mediators - a complex methylated mediator is formed: alpha-methylnorepinephrine. With long-term use, side effects are possible: sodium and water retention in the body, an increase in blood volume, volume overload of the heart, which can lead to or worsen heart failure. Therefore, it is necessary to combine with saluretics: allergic reactions resembling SLE, dermatitis. It is advisable to start treatment with small doses (3 tablets per day), gradually increasing the dose to 6 tablets per day. For long-term treatment, the Coombs test is performed every 6 months or the drug is replaced.

Hemiton(clonidine, catapresan) tab. O,O75 mg imidazoline derivative. It acts on alpha-adrenergic receptors of the brain and has an inhibitory effect on the vasomotor center of the medulla oblongata, and also has a sedative effect. Mainly, it reduces general peripheral resistance, possibly also affects the spinal cord, there are almost no side effects, except dry mouth, slower motor response. The hypotensive effect is generally weak. Use O.O75 mg * 3 r.

• 2. Postganglionic adrenergic blockers
• a) Guanethidine group

Octadine(isobarine, ismelin, guanethidine sulfate) O, O25. The mechanism of action of octadin is based on the leaching of catecholamines from the granules of nerve endings and increasing their utilization. It is one of the most potent drugs. Unlike reserpine, it is not able to penetrate the BBB. Reduces arteriolar tone (reduces peripheral resistance and diastolic pressure) and venous tone (increases the amount of blood in the venous reservoir and reduces venous return to the heart, thereby reducing cardiac output). The hypotensive effect of the drug increases when moving to a vertical position, thus hypotension may occur in orthostasis and during physical activity. Orthostatic collapse is very dangerous in the presence of atherosclerosis. In the first days of treatment, it is advisable to prescribe small doses (25 mg/day) to avoid orthostatic complications. Then the dose is gradually increased. When monitoring treatment with Octadine, blood pressure must be measured not only while lying down, but also while standing. Due to the significant number of complications, it is not the drug of choice for hypertension. The indication for its use is persistent arterial hypertension + lack of effect from other antihypertensive drugs. Absolutely contraindicated in pheochromocytoma.

b) Rauwolfia group (central acting neuroleptics)

Reserpine (raucedil), ampoules of 1.0 and 2.5 mg, tablets of O.1 and O.25 mg. Penetrates the BBB and has an effect at the level of the brain stem and peripheral nerve endings. The hypotensive effect is average, the mechanism of action is based on the depletion of catecholamine depots (causes degranulation of catecholamines and their subsequent destruction in the axoplasm of neurons). Due to the suppression of the sympathetic nervous system, the parasympathetic begins to predominate, which is manifested by symptoms of vagotonia: bradycardia, increased acidity of gastric juice + increased gastric motility, which can contribute to the formation of peptic ulcers. Reserpine can also provoke bronchial asthma and miosis. Hence the contraindications: peptic ulcer, bronchial asthma, pregnancy. Begin treatment with O.1-O.25 mg/day, gradually increasing the dose to O.3-O.5 mg/day. The decrease in pressure occurs gradually over several weeks, but with parenteral administration of rausedil (usually during crises), the effect occurs very quickly.

Raunatin (rauvazan) tab. O,OO2, has a weaker effect on the central nervous system than reserpine + has antiarrhythmic activity, since it contains the alkaloid ajmaline.

3. Beta-blockers. Blockade of beta-adrenergic receptors is accompanied by a decrease in heart rate, stroke volume and renin secretion. This eliminates the excessive influence of sympathetic nerves on these processes, which are regulated through beta-adrenoreactive systems. They are especially widely used in the treatment of the initial stages of hypertension. A feature of this group of drugs is their good tolerability and the absence of serious complications. Beta receptors in different tissues are specific - they secrete beta-1 and -2 adrenergic receptors. Activation of beta-1 receptors leads to an increase in the strength and frequency of heart contractions and to increased lipolysis in fat depots. Activation of beta-2 receptors causes glycogenolysis in the liver, skeletal muscles, leads to dilation of the bronchi, relaxation of the ureters, and vascular smooth muscles. The mechanism of action is based on competitive blockade of receptors and membrane stabilization similar to local anesthetics.

Anaprilin (propanol, inderal, obzidan) O, O1 and O, O4. It is used most often due to the lack of sympathomimetic activity. Inhibits both beta-1 and beta-2 adrenergic receptors. Causes bradycardia, reduces cardiac output. It also blocks the synthesis of renin, since the juxtaglomerular apparatus contains beta-2 receptors. The initial dose is 60-80 mg/day, then increased to 200 mg/day. When the effect is achieved, maintenance doses are given.

Oxprenolol (Tranzicor) tab. O, O2. It has a number of features: it has antiarrhythmic activity. It has a predominant effect on beta-2 receptors, but the selectivity is incomplete. The hypotensive effect is less pronounced than anaprilin. The drugs are prescribed enterally, the effect appears after 30 minutes, maximum after 2-3 hours. The hypotensive effect develops slowly and depends on the stage of the disease: for example, with labile hypertension, a decrease in blood pressure occurs already on days 1-3, normalization on days 7-10. The effect is most clearly manifested in patients with initial tachycardia and a hyperkinetic type of hemodynamic disturbance. A less clearly hypotensive effect is observed with persistent hypertension at high levels and in old age. Complications are rare, but severe bradycardia with sinoaurical block and other rhythm and conduction disturbances are possible.

Beta-blockers are contraindicated in bronchial asthma, bronchitis, concomitant heart failure, peptic ulcer disease and a number of chronic intestinal diseases. Prescribe with caution in case of initial bradycardia and rhythm disturbances. The combination with saluretics and motor antispasmodics is optimal.

Diuretics: the most justified for hypertension is the use of natriuretic drugs (saluretics).

Hypothiazide (dichlorothiazide) tab. O,O25 and O,1. Has a significant hypotensive effect in hypertension. A decrease in blood pressure is associated with a diuretic effect, a decrease in blood volume, as a result of which cardiac output decreases. Sometimes, when taking hypothiazide, tachycardia occurs as a reflex reaction to a decrease in blood volume and the peripheral blood pressure increases. As treatment progresses, the electrolytic gradient of the vascular wall normalizes, its swelling decreases, and sensitivity to catecholamines and angiotensinogen decreases. The loss of K+ in urine increases. The dose is selected individually.

Furosemide (Lasix) tab. O.O4 ampoules 1% - 2.0 ml. A potent diuretic. The effect after administration begins on average after 30 minutes. The drug acts especially quickly when administered intravenously - after 3-4 minutes. The mechanism of action is based on inhibition of the reabsorption of sodium and water, sodium begins to leave the vascular wall, because Predominantly intracellular sodium is excreted. K+ ions are always lost in the urine, so it is necessary to prescribe potassium supplements or a combination with potassium-sparing diuretics. Lasix causes a short-term hypotensive effect, so the drug is not very suitable for long-term use; it is used more often during crises. With prolonged use of saluretic, gout can be provoked and latent hyperglycemia can be turned into overt hyperglycemia. Blood clotting also increases, and a tendency to thrombosis appears.

Clopamide (brinaldix) tab. O, O2, the mechanism of action is the same; but unlike furosemide, it has a longer effect - up to 20 hours.

Triamterene (pterophen) capsules of O, O5. It is an active diuretic, causes active excretion of sodium without increasing the excretion of potassium (since it inhibits the secretion of potassium in the distal tubules). Combined with drugs that cause potassium loss. The effect is quick, after 15-20 minutes, lasts 2-6 hours.

Spironolactone (veroshpiron, aldactone) tab. Oh, O25. Blocks the action of aldosterone through a specific interaction, because close to it in structure. Reduces the phenomena of secondary hyperaldosteronism that develops in the late stages of hypertension and with symptomatic hypertension, as well as during treatment with thiazide-type saluretics (hypothiazide). Use only in combination with saluretics, 75-13O mg/day, in courses of 4-8 weeks. It also potentiates the effect of sympatholytics. Particularly effective for increased secretion of aldosterone and low plasma renin activity.

Myotropic drugs

Apressin (hydralysine) tab. O, O1 and O, O25. It has a direct effect on the smooth muscles of arterioles. Suppresses the activity of a number of enzymes in the vascular wall, which leads to a drop in its tone. Mainly lowers diastolic pressure. Start with doses of 1O-2O mg * 3 times a day, then increase the single dose to 2O-5O mg. Used only in combination with other drugs, especially indicated for bradycardia and low cardiac output (hypokinetic type). A rational combination of reserpine + apressin (adelfan) + hypothiazide. It combines well with beta-blockers - this is one of the best combinations for patients with persistent hypertension. Side effects of apressin: tachycardia, increased angina, throbbing headaches, redness of the face.

Dibazol tab. O, O4 and O, O2; amp. 1% - 1 ml. Similar in action to papaverine, reduces OPS, improves renal blood flow, few side effects.

Papaverine O, O4 and O, O2; amp. 2% - 2.O. See dibazol. Side effects include ventricular extrasystole and atrioventricular block.

Potent vasodilators synthesized in recent years: Minoxidil (prazosin) O,OO1. Diazoxide (hyperstad) 5O mg. Sodium Nitroprusside amp. 5O mg. Depressin: hypothiazide 1O mg + reserpine O.1 mg + dibazole O, O2 + nembutal Oh, 25.

Treatment of hypertensive crises:

Hospitalization is required. Dibazol 1% to 1O,O IV, effect after 15-2O min. Rausedil 1 mg IM or slowly IV in an isotonic solution. Lasix 1% to 4.0 IV, effect after 3-4 minutes.

Many patients benefit from neuroleptics: Aminazine 2.5% 1.0 i.m. Droperidol O.25% up to 4 ml IM or IV slowly: 2 ml in 20 ml 40% glucose.

If there is no effect, ganglion blockers are prescribed: Pentamin 5% 1.O IM or IV drip! have on hand Benzohexonium 2.5% 1.O i/m! mezaton.

It is necessary to ensure that the decrease in blood pressure is not very sharp, which can lead to coronary or cerebrovascular insufficiency. Hemiton O.O1% O.1 IM or slowly IV per 2O ml of isotonic solution (max after 2O-3O min). Dopegit(for prolonged crises!) orally up to 2.0 g per day. Tropaphen 1% 1.O per 2O ml of isotonic solution slowly intravenously or intramuscularly during symatoadrenal crises. Sodium Nitroprusside O.1 on glucose intravenously.

For symptoms of encephalopathy associated with cerebral edema: Magnesium Sulfate 25% 1O,O w/m.

Osmodiuretics: 20% solution Mannitol in an isotonic solution. Calcium chloride 1O% 5.O IV - when breathing stops from the administration of magnesium.

For cardiac form: Papaverine; beta-blockers (anaprilin O, 1% 1, O); Rausedil 1 mg IM or IV slowly: ganglion blockers - as a last resort! Arfonad - to create controlled hypotension, “at the tip of the needle” effect. Use only in a hospital setting.

For pulmonary edema with apoplexy: Bloodletting is the best method - up to 500 ml. Be sure to puncture the vein with a thick needle, since this sharply increases the coagulation capacity of the blood.

*******************************************************

Doses of antihypertensive drugs:

Dibasoli 1% 4 ml; Lasix 4,O ml, Benzogexonii 2.5% 1,O;

Pentamini 5% 1.O; Clophelini О,ОО1 1,О i.v. slowly; pheno-

An antihypertensive effect is a decrease in blood pressure under the influence of a particular drug.

Experienced professional therapists of the highest category at the Yusupov Hospital Therapy Clinic, who are proficient in advanced treatment and diagnostic methods, will provide qualified assistance to patients with arterial hypertension and select an effective treatment regimen that eliminates the development of negative consequences.

Antihypertensive therapy: general rules

Both symptomatic hypertension and hypertension require correction with drugs that have a hypotensive effect. Antihypertensive therapy can be carried out with drugs that differ in their mechanism of action: antiadrenergic agents, vasodilators, calcium antagonists, angiotensin antagonists, and diuretics.

You can obtain information about the hypotensive effect of the drug and what medications to take for high blood pressure not only from your doctor, but also from your pharmacist.

Arterial hypertension is a chronic disease that requires constant drug support, daily monitoring and regular use 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 treatment rules for reducing blood pressure, many patients have to be reminded what a treatment regimen for hypertension should look like:

• Antihypertensive medications should be taken regularly, regardless of the patient’s well-being and blood pressure level. This allows you to increase the effectiveness of blood pressure control, as well as prevent cardiovascular complications and target organ damage;
• It is necessary to strictly adhere to the dosage and use the form of the drug prescribed by the attending physician. Independently changing the recommended dose or replacing the drug may distort the hypotensive effect;
• even if you are constantly taking antihypertensive drugs, it is necessary to systematically measure blood pressure, which will allow you 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 a previously taken long-acting drug is not recommended. Blood pressure can be quickly reduced using short-acting antihypertensive drugs.

Antihypertensive therapy: drugs to lower blood pressure

During 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

Drugs in 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 the decline in renal function. ACE inhibitors are well tolerated and have no negative effects on lipid metabolism and glucose levels.

Calcium antagonists

In addition to antihypertensive properties, drugs in this group have antianginal and organoprotective effects, help reduce the risk of strokes, atherosclerotic lesions of the carotid arteries and left ventricular hypertrophy. Calcium antagonists may be used alone or in combination with other drugs that have antihypertensive properties.

Diuretics

Diuretic drugs are usually used in combination with other antihypertensive drugs in order to enhance the therapeutic effect.

Diuretics are also prescribed to persons suffering from pathologies such as refractory hypertension and chronic heart failure. To avoid the development of side effects, when taking these drugs continuously, minimal dosages are prescribed.

Angiotensin II receptor blockers

Drugs in this group, which have neuro- and cardioprotective effects, are used to improve control of blood glucose levels. They can 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, suffer from renal failure, gout, metabolic syndrome and diabetes mellitus.

Antihypertensive therapy for hypertensive crisis

Even despite constant antihypertensive therapy, a sudden increase in blood pressure to fairly high levels may periodically occur (there are no signs of target organ damage). The development of an uncomplicated hypertensive crisis can be caused by unusual physical activity, emotional stress, consumption of alcohol or salty, fatty foods. This condition is not life-threatening, but it threatens the development of negative consequences, and therefore requires timely treatment.

A too rapid decrease in blood pressure is undesirable. It is optimal if in the first two hours after taking the drug the pressure decreases by no more than 25% of the initial values. Normal blood pressure values ​​are usually restored within 24 hours.

Rapid-acting medications help restore blood pressure control, providing an almost immediate hypotensive effect. 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 blood pressure to assess the effectiveness of therapy. If necessary, in order to restore normal blood pressure levels, after half an hour or an hour you can take an additional tablet (orally or sublingually). If there is no improvement (pressure decrease by less than 25% or its previous excessively high levels), you should immediately seek the help of a doctor.

In order to prevent arterial hypertension from becoming chronic, accompanied by quite serious complications, it is necessary to pay attention to the first signs of arterial hypertension in time. You should not self-medicate and randomly select drugs that reduce blood 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 medications for antihypertensive therapy should be carried out by a qualified specialist familiar with the characteristics of the patient’s body and his medical history.

The Therapy Clinic of the Yusupov Hospital offers a comprehensive approach to eliminating problems associated with high blood pressure.

The clinic has the latest modern diagnostic and treatment equipment from world leaders - manufacturers of medical equipment, which allows us to identify the first manifestations of hypertension at the earliest diagnostic level and select the most effective methods for treating the disease. When drawing up a treatment regimen, the patient’s age, condition and other individual factors are taken into account.

Conservative therapy at the Yusupov Hospital involves the use of the latest generation drugs that have minimal side effects. Consultations are carried out by highly qualified therapists who have extensive experience in treating hypertension and its consequences, including stroke.

You can make an appointment with the clinic’s leading specialists by phone or on the Yusupov Hospital website using the feedback form.

Our specialists

Prices for services *

(comprehensive diagnostics of cardiovascular diseases)

(advanced screening and treatment of cardiovascular diseases

for overweight and obese patients

*The information on the site is for informational purposes only. All materials and prices posted on the site are not a public offer, defined by the provisions of Art. 437 Civil Code of the Russian Federation. For accurate information, please contact the clinic staff or visit our clinic.

Thank you for your request!

Our administrators will contact you as soon as possible

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

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

Arterial hypertension (AH) is the most commonly diagnosed disease of the cardiovascular system. According to statistics, approximately every second elderly person on the planet has signs of high blood pressure, which requires timely and correct correction.

To prescribe drugs that lower blood pressure (BP), it is necessary to establish the very presence of hypertension, assess the possible risks for the patient, contraindications to specific medications and the feasibility of treatment in principle. The priority of antihypertensive therapy is to effectively reduce blood 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 that should be achieved with the help of treatment is considered to be a figure not exceeding 140/90 mmHg. Art. Of course, in each case, the need for therapy is decided individually, but in case of prolonged high blood pressure, the presence of damage to the heart, kidneys, or retina, it should be started immediately.

According to the recommendations of the World Health Organization, diastolic pressure of 90 mmHg or higher is considered an absolute indication for antihypertensive therapy. Art., especially if such a figure lasts for several months or six months. Usually medications 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 experience symptoms of hypertension again.

Many patients are afraid of long-term or even lifelong use of medications, and often the latter are prescribed in combinations that include several items. Of course, concerns are understandable, because any medicine has side effects. Numerous studies have proven that there is no health risk with long-term use of antihypertensive drugs, side effects are minimal, provided the dose and dosage regimen are correctly selected. In each case, the doctor individually determines the specifics of treatment, taking into account the form and course of hypertension, contraindications, and concomitant pathology 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 basic principles of drug treatment of arterial hypertension were formulated:

• Treatment begins with the smallest doses of the drug, using a medicine with a minimum of side effects, that is, choosing the safest remedy.
• If the minimum dose is well tolerated, but the blood pressure level is still high, then the amount of medication is gradually increased to what is 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 combination treatment regimens for hypertension have been developed.
• If the second prescribed drug does not give the desired result or its use is accompanied by side effects, then it is worth trying a drug from another group, without changing the dosage and regimen of the first drug.
• Long-acting drugs are preferable, allowing you to maintain normal blood pressure throughout the day, without allowing fluctuations, which increase the risk of complications.

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. There are five main groups of antihypertensive drugs used today:

1. Angiotensin-converting enzyme inhibitors (ACEIs).
2. Angiotensin II receptor blockers.
3. Diuretics.
4. Calcium antagonists.
5. Beta blockers.

Medicines from these groups are effective for arterial hypertension and can be prescribed as initial treatment or maintenance therapy, alone or in various combinations. When choosing specific antihypertensive drugs, the specialist is based on the patient’s blood pressure, the characteristics of the course of the disease, the presence of target organ damage, and concomitant pathology, especially from the cardiovascular system. The overall probable side effect, the possibility of combining drugs from different groups, as well as existing experience in treating hypertension in a particular patient are always assessed.

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 (ACEIs)

Drugs from the ACE inhibitor group are quite popular and are widely prescribed to a wide variety of patients with high blood pressure. The list of ACE inhibitors includes such drugs as: captopril, enalapril, lisinopril, Prestarium, etc.

As is known, blood pressure levels are regulated by the kidneys, in particular, by the renin-angiotensin-aldosterone system, the proper functioning of which determines the tone of the vascular walls and the final level of pressure. With an excess of angiotensin II, spasm of arterial type vessels in the systemic circulation occurs, which leads to an increase in total peripheral vascular resistance. To ensure adequate blood flow in the internal organs, the heart begins to work with excess load, pumping blood into the vessels under increased pressure.

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

mechanism of action of ACE inhibitors in CHF

Prescribing an ACEI 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 improves when taking drugs from the ACEI group.

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 for diabetes mellitus, and in some cases can even be used by pregnant women.

The disadvantage of ACE inhibitors is that the most common adverse reactions are dry cough associated with changes in bradykinin metabolism. 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 requires the choice of another drug.

The following are considered absolute contraindications to the use of ACE inhibitors:

• Pregnancy;
• Significant increase in potassium levels in the blood;
• Severe stenosis of both renal arteries;
• Quincke's edema with previous use of ACE inhibitors.

Angiotensin II receptor blockers (ARBs)

Drugs from the ARB group are the most modern and effective. Like ACEIs, they reduce the effect of angiotensin II, but, unlike the latter, their point of application is not limited to a single enzyme. ARBs act more broadly, providing a powerful antihypertensive effect by disrupting the binding of angiotensin to receptors on cells in 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 enhanced.

The most popular ARBs are losartan, valsartan, irbesartan, etc.

Like ACE inhibitors, drugs from the group of angiotensin II receptor antagonists show high effectiveness in kidney and heart pathologies. In addition, they are practically free of adverse reactions and are well tolerated with 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 longest used group of drugs. They help remove excess fluid and salt from the body, thereby reducing the volume of circulating blood, the load on the heart and blood vessels, which ultimately relax. The classification involves the separation of groups of potassium-sparing, thiazide and loop diuretics.

Thiazide diuretics, including hypothiazide, indapamide, chlorthalidone, are not inferior in effectiveness to ACE inhibitors, beta blockers and other groups of antihypertensive drugs. High concentrations 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 as part of combination therapy along with ACE inhibitors and angiotensin II receptor antagonists. They can be prescribed to elderly patients, people suffering from diabetes mellitus, and various metabolic disorders. Gout is considered an absolute contraindication to taking these drugs.

Potassium-sparing diuretics have a milder effect compared to other diuretics. The mechanism of action is based on blocking the effects of aldosterone (an antidiuretic hormone that retains fluid). A decrease in pressure is achieved by removing fluid and salt, but potassium, magnesium, and calcium ions are not lost.

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

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

Loop diuretics (Lasix, Edecrine) act the most aggressively, but at the same time they can reduce blood pressure faster than others. They are not recommended for long-term use, since the risk of metabolic disorders is high due to the excretion of electrolytes along with fluid, 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. Drugs from the group of calcium antagonists exert their effect by reducing the penetration of calcium ions into the smooth muscle cells of blood vessels. The sensitivity of blood vessels to vasopressor substances that cause vascular spasm (adrenaline, for example) also decreases.

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

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

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

When prescribing non-dihydropyridine diuretics, possible bradycardia and other types of bradyarrhythmias must be taken into account. These medications are contraindicated in severe heart failure, atrioventricular blockade, and simultaneously with intravenous beta-blockers.

Calcium antagonists do not affect metabolic processes, reduce the degree of hypertrophy of the left ventricle of the heart 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 heart rhythm and have an antianginal effect, beta blockers are preferred for reducing blood pressure in patients suffering from coronary heart disease (angina pectoris, cardiosclerosis), as well as in chronic heart failure.

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

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

Other drugs with antihypertensive effects

In addition to the described groups of pharmacological agents for the treatment of arterial hypertension, additional drugs are 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 stimulation of blood vessels. 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 reduce the concentration of renin, angiotensin, angiotensin-converting enzyme in the blood serum, providing a hypotensive, as well as cardioprotective and nephroprotective effect. Aliskiren can be combined with calcium antagonists, diuretics, beta-blockers, but simultaneous use with ACE inhibitors and angiotensin receptor antagonists is fraught with impaired renal function due to the similarity of pharmacological action.

Alpha-blockers are not considered drugs of choice; they are prescribed as part of combination treatment as a third or fourth additional antihypertensive agent. Medicines in 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 lower blood pressure. The latest generation of drugs can be considered aliskiren (Rasilez), olmesartan from the group of angiotensin II receptor antagonists. Among diuretics, torasemide has proven itself well, which is suitable for long-term use and is safe for elderly patients and patients with diabetes mellitus.

Combination drugs are also widely used, including representatives of different groups “in one tablet,” for example, Equator, which combines amlodipine and lisinopril.

Traditional antihypertensive drugs?

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

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

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

Of course, herbal infusions 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 cardiac pathology, diabetes, atherosclerosis, then the effectiveness of traditional medicine alone is questionable. In such cases, drug therapy is required.

In order for drug treatment to be more effective and drug dosages to be minimal, the doctor will first advise patients with arterial hypertension to change their lifestyle. Recommendations include quitting smoking, normalizing weight, and a diet with limited consumption of table salt, liquids, and alcohol. Adequate physical activity and the fight against physical inactivity are important. Non-drug measures to lower blood pressure can reduce the need for medications and increase their effectiveness.

Antihypertensive therapy

What medications should be prescribed first when selecting antihypertensive therapy? Science is still developing different methods and approaches, and new groups of drugs are being tested. 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. Large-scale studies involving patients have shown that the use of diuretics and beta-blockers reduces the risks of cerebrovascular accidents, sudden death, and myocardial infarction.

An alternative option is the use of captopril. According to new data, the incidence of heart attacks, strokes, and deaths when using conventional treatment or using captopril is almost the same. Moreover, in a special group of patients who had not previously been treated with antihypertensive drugs, captopril showed 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, and exacerbation of angina.

Therapy for left ventricular hypertrophy

Many doctors use angiotensin-converting enzyme (ACE) inhibitors as antihypertensive therapy. These drugs have cardioprotective properties and lead to a decrease in the mass of the LV myocardium (left ventricle). When studying the degree of impact 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 nephroprotective effects. This is important, because despite all the successes of antihypertensive therapy, the number of patients who develop end-stage renal failure is growing (4 times compared to the “eighties”).

Calcium antagonist therapy

Calcium antagonists are increasingly used as first-line drugs. For example, long-acting dihydropyridine calcium channel blockers are effective for isolated systemic arterial hypertension (AH). A four-year study of 5,000 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 observed for four years. As BP (blood pressure) decreased, the beneficial effects increased, the risk of cardiovascular complications decreased significantly, and the incidence of sudden death did not increase. The SystEur study, which involved 10 Russian centers, also showed a 42% reduction in the incidence of strokes with the use of nisoldipine.

Calcium antagonists are also effective for pulmonary arterial hypertension (this is systemic hypertension that occurs in patients with obstructive pulmonary diseases). 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 increases in pressure. The advantage of calcium antagonists in pulmonary hypertension is that they reduce calcium ion-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 patients with hypertension. By normalizing or reducing blood pressure, these drugs can prevent the development of dyslipidemia, glucose and insulin tolerance.

For calcium antagonists, a clear relationship has been identified between dose, plasma concentration and pharmacological hypotensive effect. By increasing the dose of the drug, you can, as it were, control the hypotensive effect, increasing or decreasing it. For long-term treatment of hypertension, long-acting drugs with a low absorption rate are preferred (amlodipine, a long-acting gastrointestinal form of nifedipine, or osmoadolate, a long-acting form of felodipine). 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 therapy: what you need to know?

Arterial hypertension is one of those chronic diseases that require constant drug support, daily monitoring and regular use of prescribed medications. Not only the well-being, but also the life of the sick person directly depends on how carefully the rules of antihypertensive therapy are followed.

Not only the attending physician, but also the pharmacist advising a visitor to the pharmacy can tell you how to properly treat arterial hypertension, what medications 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 would not be amiss to once again remind what treatment of hypertension should be.

1. Antihypertensive drugs are taken constantly. Regardless of whether a person feels bad or good, whether blood pressure (BP) is elevated or remains normal, drug therapy should be constant. Only with daily intake of antihypertensive drugs can blood pressure levels be effectively controlled and target organ damage and cardiovascular complications avoided.
2. Antihypertensive drugs are taken in the dosage and release form in which they are prescribed by the doctor. You should not change the recommended dose yourself or try to replace one drug with another, because this may negatively affect the hypotensive effect.
3. Even with constant use of antihypertensive drugs, blood pressure should be measured regularly, at least 2 times a week. This is necessary to monitor the effectiveness of therapy, allows you to timely notice changes occurring in the body and adjust treatment.
4. If, against the background of constant antihypertensive therapy, blood pressure suddenly increases, i.e. An uncomplicated hypertensive crisis develops; it is not recommended to take an additional dose of the patient’s usual drug. For continuous use, long-acting drugs are prescribed, the effect of which develops gradually. To quickly reduce blood pressure, a hypertensive patient's home medicine cabinet must contain short-acting antihypertensive drugs.

Features of different groups of drugs

For the treatment of arterial hypertension, 5 main groups of antihypertensive drugs are used today: ACE inhibitors, beta-blockers, diuretics, calcium antagonists and angiotensin II receptor blockers. All of them have comparable effectiveness, but each group 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 developing complications of atherosclerosis, reduce left ventricular hypertrophy, and slow down the decline in kidney function. Drugs in this group are well tolerated and do not have a negative effect on lipid metabolism and blood glucose levels, which allows their use in cases where arterial hypertension is combined with metabolic syndrome or diabetes mellitus, as well as in patients who have suffered a myocardial infarction, in the case of chronic cardiac failure, arrhythmia, atherosclerosis and renal dysfunction.

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, and 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. Drugs in this group have proven themselves to be effective 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 organoprotective 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 either alone or in combination with other antihypertensive drugs (most often ACE inhibitors).

Angiotensin II receptor blockers

Angiotensin receptor blockers (losartan, candesartan, telmisartan, valsartan) have cardio- and neuroprotective effects, 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, previous myocardial infarction, metabolic syndrome, gout, and diabetes mellitus.

Hypertensive crisis - what to do?

Even with constant antihypertensive therapy, blood pressure may periodically suddenly rise to individually high numbers (without signs of target organ damage). This condition is called an uncomplicated hypertensive crisis; most often it occurs after unusual physical activity, emotional stress, consumption of alcoholic beverages or fatty salty foods.

And although the uncomplicated form of hypertensive crisis is not considered a life-threatening condition, it cannot be left without treatment, because even a small increase in blood pressure (by 10 mm Hg) increases the risk of cardiovascular complications by 30%.2 And the earlier treatment is started, the less likely there are adverse 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 ensures 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 initial values ​​and to normal levels 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 selects a drug to quickly reduce blood pressure, since each of them has contraindications.

Half an hour after taking 1 tablet of an antihypertensive drug, blood pressure levels should be measured and the effectiveness of treatment assessed. If necessary, to restore normal blood pressure levels, after 30–60 minutes you can additionally take 1 more tablet sublingually or orally. If after this the pressure decreases by less than 25%, you should urgently call a doctor.

Treatment of associated conditions

Arterial hypertension rarely develops as a separate disease; in most cases it is accompanied by background disorders that aggravate target organ damage and increase the risk of developing cardiovascular complications. Therefore, in addition to antihypertensive drugs, patients with hypertension are often prescribed lipid-lowering therapy, drugs for the prevention of thrombosis and correction of blood glucose levels in patients with metabolic syndrome and diabetes mellitus.

A particularly important role in arterial hypertension is played by taking statins (simvastatin, atorvastatin, rosuvastatin) - drugs that reduce the level of total cholesterol, low-density lipoproteins and triglycerides. Long-term use of statins makes it possible to 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.

Preventive antiplatelet therapy is also prescribed to patients at high cardiovascular risk, people with impaired renal function, and anyone who has 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 drugs today are acetylsalicylic acid, clopidogrel and dipyridamole, which are prescribed in long courses in minimal therapeutic doses.

And, of course, all these drugs, like antihypertensive therapy, are prescribed only by the attending physician, because any self-medication for hypertension can be dangerous, which is something that the pharmacy visitor must be reminded of.

Reproduction of materials is permitted only subject to the restrictions established by the Copyright Holder, indicating the author of the materials used and a link to the “Pharmaceutical Vestnik” as the source of borrowing, with a mandatory hyperlink to the website www.pharmvestnik.ru.

Restrictions and prohibitions on reproducing materials from the Site:

1. Materials posted on the website www.pharmvestnik.ru (hereinafter referred to as the “Site”), in respect of which the Copyright Holder has established restrictions on free reproduction:

1. access to which is provided on the Site only to subscribers;
2. any materials published in the printed version of the newspaper and containing the mark “Published in the newspaper issue”;
3. all materials from the Site reproduced in any way other than distribution on the Internet.

The use of materials subject to these restrictions requires the written consent of the Copyright Holder - Bionica Media LLC.

1. reproduction of materials of other copyright holders (the user must resolve issues of lawful distribution of such materials without the involvement of Bionica Media LLC);
2. the use of excerpts from materials in which the context changes, the excerpts acquire an ambiguous character or dissonant connotation, as well as any processing of the material;
3. commercial use of materials, i.e. use of certain material (a fragment thereof) selected on the Site for the purpose of commercial implementation of the right to access such material or granting rights to it to third parties.

Drug antihypertensive therapy

Angiotensin II receptor antagonists.

Centrally acting α2-agonists.

Potassium channel activators.

Vasoactive prostaglandins and stimulators of prostacyclin synthesis.

The main groups of antihypertensive drugs are currently considered to be the first 4 groups: beta-blockers, diuretics, calcium antagonists, ACE inhibitors. When choosing antihypertensive drugs, the ability of the drugs to influence left ventricular hypertrophy, quality of life, as well as the ability of the drugs to affect the level of atherogenic lipoproteins in the blood are taken into account. The age of the patients and the severity of concomitant ischemic heart disease should also be taken into account.

Propranolol (anaprilin, inderal, obzidan) - non-cardioselective beta-blocker without intrinsic sympathomimetic activity. It is prescribed to patients with arterial hypertension initially at 40 mg 2 times a day; a decrease in blood pressure is possible on the 5-7th day of treatment. In the absence of a hypotensive effect, every 5 days you can increase the daily dose by 20 mg and bring it to the individual effective one. It can range from 80 to 320 mg (i.e. 80 mg 4 times a day). After achieving the effect, the dose is gradually reduced and switched to a maintenance dose, which is usually 120 mg per day (in 2 divided doses). Propranolol extended-release capsules are prescribed once a day.

Nadolol (korgard) - non-cardioselective beta-blocker of extended action without internal sympathomimetic activity and membrane stabilizing effect. The duration of action of the drug is about one hour, so it can be taken once a day. Treatment begins with taking 40 mg of the drug once a day, then you can increase the daily dose by 40 mg every week and bring it up to 240 mg (less often - 320 mg).

Trazicore (oxprenolol) - a non-cardioselective beta-blocker with intrinsic sympathomimetic activity, prescribed 2 times a day. Available in tablets with a regular duration of action of 20 mg and extended action of 80 mg. Treatment begins with a daily dose of mg (in 2 doses), followed by an increase in mg

Cardioselective beta blockers

Cardioselective beta-blockers selectively block beta1-adrenergic receptors of the myocardium and have almost no effect on beta2-adrenergic receptors of the bronchi, do not cause vasoconstriction of skeletal muscles, do not impair blood flow in the extremities, have little effect on carbohydrate metabolism and have a less pronounced negative effect on lipid metabolism.

Atenolol - a cardioselective beta-blocker without internal sympathomimetic activity, devoid of membrane stabilizing effect. At the beginning of treatment, a daily dose of 50 mg is prescribed (in 1 or 2 doses). In the absence of a hypotensive effect, the daily dose can be increased after 2 weeks to 200 mg. The drug has a prolonged effect and can be taken 1-2 times a day.

Tenoric - a combination drug containing 0.1 g of atenolol and 0.025 g of the diuretic chlorthalidone. Tenorik is prescribed 1-2 tablets 1-2 times a day.

Metoprolol (Spesicor, betaxolol) is a cardioselective beta-blocker without intrinsic sympathomimetic activity. The drug acts for about 12 hours, is prescribed 100 mg once a day or 50 mg 2 times a day. After 1 week, the dose can be increased to 100 mg 2 times a day. The maximum daily dose with a gradual increase is 450 mg.

Betalok Durules - metoprolol extended release. Available in tablets of 0.2 g. Treatment begins with a dose of 50 mg once a day and gradually increases the dose to 100 mg. In the absence of a hypotensive effect, the daily dose is increased to 200 mg.

Cordanum (talinolol) - a cardioselective beta-blocker with intrinsic sympathomimetic activity. Treatment begins with taking 50 mg of the drug 3 times a day, then, if necessary, the daily dose is increased (in 3 doses).

Betaxolol (locrene) - long-acting beta-blocker with high cardioselectivity. The hypotensive effect of the drug lasts for 24 hours, so it can be prescribed once a day. The effect of betaxolol begins to appear after 2 weeks, and reaches its maximum after 4 weeks. Treatment begins with a dose of 10 mg per day. If the hypotensive effect is insufficient, after 2 weeks from the start of treatment, the dose is increased to 20 mg per day (average therapeutic dose), and, if necessary, gradually to 30 and even 40 mg per day.

Bisoprolol - long-acting cardioselective beta-blocker. The drug is prescribed 1 tablet 1 time per day, in the morning.

For the treatment of patients with arterial hypertension, it is advisable to use beta-blockers that have vasodilating properties.

Beta blockers with vasodilating properties include:

non-cardioselective (pindolol, dilevalol, labetolol, niprandilol, proxodolol, carteolol);

cardioselective (carvedilol, prisidilol, celiprolol, bevantolol).

Carvedilol (dilatrend) - a vasodilating cardioselective beta-blocker, prescribed as a daily dose (in 1-2 doses).

Labetolol (Trandat, Albetol, Normodin) - non-cardioselective vasodilating beta-blocker, used daily (in 2-4 doses). It has intrinsic sympathomimetic activity and has almost no effect on lipid levels.

Bevantolol - long-acting cardioselective vasodilating beta-blocker without intrinsic sympathomimetic activity. Prescribed 100 mg 1 time per day. If the hypotensive effect is insufficient, the daily dose can be increased to 600 mg (in 1-2 doses).

Side effects of beta blockers

negative inotropic effect, which may contribute to or worsen the development of heart failure;

negative chronotropic effect (development of bradycardia);

slowing of atrioventricular conduction;

suppression of mechanisms that counteract the development of hypoglycemia in diabetes mellitus;

the ability to provoke the development of Raynaud's syndrome, intermittent claudication and gangrene;

increased angina pectoris with sudden cessation of beta-blockers in patients suffering from coronary artery disease;

increased triglyceride levels and decreased high-density lipoprotein cholesterol; this negative effect is much less pronounced with beta-blockers with intrinsic sympathomimetic activity and vasodilating properties;

withdrawal syndrome with rapid cessation of beta-blockers, which is manifested by tachycardia, tremors, sweating, and increased blood pressure.

Indications for long-term monotherapy of hypertension with beta-blockers and factors influencing the choice of drug

Arterial hypertension with the presence of left ventricular myocardial hypertrophy; Beta blockers reverse the development of left ventricular hypertrophy and thereby reduce the risk of sudden death.

Arterial hypertension in young patients who, as a rule, lead an active lifestyle. In such patients, an increase in the tone of the sympathetic nervous system and plasma renin activity is usually detected. The volume of circulating blood is not changed or even reduced. Beta-blockers reduce sympathetic activity, tachycardia, and normalize blood pressure. However, it should be borne in mind that beta-blockers adversely affect high-density lipoproteins, can cause sexual dysfunction and interfere with sports activities, as they reduce cardiac output.

Combination of arterial hypertension with angina pectoris. Beta-blockers have an antianginal effect. In this case, non-selective adrenergic blockers are preferable to prescribe to non-smoking patients with arterial hypertension, while in smokers, selective adrenergic blockers (metoprolol or atenolol) should apparently be given preference.

Long-term treatment of patients with arterial hypertension who have suffered transmural myocardial infarction. According to the results of controlled studies, in this situation, adrenergic blockers without intrinsic sympathomimetic activity (propranolol, nadolol, sotalol, timolol, atenolol) should be used for at least 1-3 years, regardless of the presence or absence of angina.

Arterial hypertension in combination with cardiac arrhythmias, primarily supraventricular, as well as sinus tachycardia.

In patients with arterial hypertension in combination with dyslipidemia, especially in young people, preference should be given to cardioselective adrenergic blockers, as well as drugs with internal sympathomimetic activity or vasodilating effects.

When arterial hypertension is combined with diabetes mellitus, non-cardioselective adrenergic blockers, which can disrupt carbohydrate metabolism, should not be prescribed. Selective adrenergic blockers (atenolol, acebutalol, metoprolol, talindol) or adrenergic blockers with pronounced internal sympathomimetic activity (pindolol) have the least effect on carbohydrate metabolism and insulin secretion.

In patients with arterial hypertension and liver dysfunction, lower doses of lipophilic adrenergic blockers (propranolol, metoprolol) should be used than under normal conditions, or hydrophilic drugs (nadolol, atenolol, etc.) that are not metabolized in the liver should be prescribed.

When arterial hypertension is combined with impaired renal function, the most suitable drug is the non-cardioselective adrenergic blocker nadolol, which does not change renal blood flow and glomerular filtration rate or even increases them, despite a decrease in cardiac output and mean blood pressure. Other non-cardioselective adrenergic blockers reduce renal blood flow due to the fact that they reduce cardiac output. Cardioselective adrenergic blockers and drugs with intrinsic sympathomimetic activity worsen renal function.

Diuretics have been used for many years not only as diuretics, but also to lower blood pressure.

The following groups of diuretic drugs are used to treat arterial hypertension:

thiazide and thiazide-like;

with vasodilating properties.

Thiazide and thiazide-like diuretics

Thiazide diuretics are most often used in patients with mild and moderate arterial hypertension. When treated with these drugs, in the first 2-3 days, a large natriuresis develops, which promotes the removal of large amounts of water from the body, which leads to a decrease in blood volume, a decrease in blood flow to the heart and, consequently, cardiac output. Thiazide diuretics are ineffective if the glomerular filtration rate is less than 25 ml/min. In these cases, stronger loop diuretics should be used.

Hydrochlorothiazide (hypothiazide, dihydrochlorothiazide, esidrex) - for high arterial hypertension, treatment with hydrochlorothiazide begins with a dose of 1 mg once a day in the morning or 50 mg in 2 doses in the first half of the day, for mild and moderate hypertension - with a dose of 25 mg 1 time in the morning. The maintenance dose for long-term use is mg in 1 dose (sometimes the daily dose is 50 mg in 2 doses).

While taking hypothiazide and other thiazide diuretics, it is necessary to adhere to a hyposodium and potassium-enriched diet. Following such a diet requires the use of smaller doses of drugs, therefore, the likelihood of side effects and their severity are reduced.

Korzid - a combination drug containing in 1 tablet 5 mg of bendroflumetazide and 40 or 80 mg of the non-selective adrenergic blocker nadolol.

Chlorothiazide (diuril) - the hypotensive effect develops several days after administration, the diuretic effect - after 2 hours. Treatment begins with a dose of 250 mg per day (in 1 dose), in the absence of a hypotensive effect, the dose is increased to 500 mg per day in 1 dose or 1000 mg per day in 2 doses.

When treated with thiazide diuretics, the following may develop: side effects:

hypokalemia (manifested by muscle weakness, paresthesia, sometimes muscle cramps, nausea, vomiting, extrasystole, decreased potassium levels in the blood;

hyponatremia and hypochloremia (main manifestations: nausea, vomiting, severe weakness, decreased levels of sodium and chlorides in the blood);

hypomagnesemia (the main clinical signs are muscle weakness, sometimes muscle twitching, vomiting);

hypercalcemia (rarely develops);

hyperglycemia (its development is directly dependent on the dose of hypothiazide and the duration of its administration; cessation of treatment with hypothiazide can restore glucose tolerance, but not completely in some patients; adding potassium salts to treatment with hypothiazide can reduce the severity of hyperglycemia or even eliminate it. It has been established that the combination of hypothiazide with ACE inhibitors has a beneficial effect, preventing a decrease in carbohydrate tolerance);

increased levels of cholesterol and beta lipoproteins in the blood. In recent years, it has been found that hydrochlorothiazide violates carbohydrate tolerance and increases blood cholesterol and triglycerides only during the first two months of regular use of these drugs. In the future, with continued treatment, normalization of these indicators is possible;

Due to the relatively high frequency of side effects, many experts believe that monotherapy with hypothiazide and other thiazide compounds is not always advisable.

From thiazide-like diuretics The most commonly used drugs are the following.

Chlorthalidone (hygroton, oxodoline) - after oral administration, the diuretic effect begins after 3 hours and lasts up to 2-3 days. In contrast to hypothiazide, hypokalemia is observed less frequently during treatment with chlorthalidone. The drug is used in a daily dosage.

Klopamide (brinaldix) - in a daily dose, it helps to reduce systolic blood pressure by 30 mm Hg. Art., diastolic blood pressure - by 10 mm Hg. Art., the most pronounced hypotensive effect occurs after 1 month.

Loop diuretics act primarily at the level of the ascending limb of the loop of Henle. By inhibiting sodium reabsorption, they cause the most powerful diuretic effect, depending on the dose. At the same time, the reabsorption of potassium, calcium and magnesium is inhibited.

The following loop diuretics are known: furosemide (Lasix), ethacrynic acid (edecrin, uregit), bumetanide (Bumex).

Typically, loop diuretics are used in patients with arterial hypertension who are resistant to thiazide diuretics, to relieve hypertensive crises, and in severe renal failure.

The most commonly used loop diuretics are furosemide and ethacrynic acid.

When taken orally, the initial dose of furosemide is 40 mg 2 times a day, but in many patients the initial dose may be 20 mg. If necessary, the daily dose is gradually increased, but the maximum daily dose should be no more than 360 mg (in 2 doses). For hypertensive crises accompanied by pulmonary edema, as well as for acute renal failure, the initial dose is mg intravenously. In case of stable hypertension, dosumg is used for intravenous administration.

Furosemide is the drug of choice in the treatment of patients with impaired renal function (glomerular filtration rate less than 25 ml/min).

Ethacrynic acid (uregit) - Currently, ethacrynic acid is rarely used for the treatment of arterial hypertension.

The most common side effects of loop diuretics are: hypovolemia, hypokalemia, hyperuricemia; high doses may have ototoxic effects, especially in patients with renal failure. Loop diuretics may also have an adverse effect on carbohydrate and lipid metabolism.

Potassium-sparing diuretics have a weak diuretic effect, but they reduce the excretion of potassium in the urine due to a decrease in its secretion into the lumen of the tubules. These drugs also have a hypotensive effect. The most commonly used potassium-sparing agents are:

spironolactone (veroshpiron, aldactone);

Spironolactone (veroshpiron, aldactone) - Available in tablets of 25, 50 and 100 mg.

The use of spironolactone in hypertension is justified by the fact that it has a hypotensive effect, reduces fibrosis in the myocardium and retains potassium in the body, preventing hypokalemia during treatment with diuretics.

When using spironolactone, it is recommended to start treatment with a daily dose of mg (in 1 or 2 doses) for at least 2 weeks, then gradually increase the daily dose to 200 mg at 2-week intervals. The maximum daily dose is 400 mg.

Spironolactone does not cause hyperglycemia, hyperuricemia and does not have a negative effect on lipid metabolism (does not increase cholesterol and triglycerides in the blood), therefore it can be prescribed to those patients in whom thiazide diuretics cause these side effects.

TO side effects spironolactone include:

Contraindications to prescribe spironolactone:

increased levels of creatinine or urea nitrogen in the blood;

taking potassium supplements or potassium-sparing agents;

Triamterene - available in capsules of 50 and 100 mg, as well as in the form of fixed combination drugs of the following composition:

pills triampur compositum(25 mg triamterene and 12.5 mg hydrochlorothiazide);

capsules diazide(50 mg triamterene and 25 mg hydrochlorothiazide);

tablets m akszid(75 mg triamterene and 50 mg hydrochlorothiazide).

The hypotensive effect of triamterene is weak, but its potassium-retaining effect is significant. As a rule, the drug is prescribed in combination with hydrochlorothiazide or furosemide. For antihypertensive purposes, triampur compositum is most often used, 1-2 tablets per dose 1-2 times a day.

Contraindications to the use of triamterene :

severe liver failure;

simultaneous use of potassium supplements or potassium-sparing agents.

Diuretics with vasodilating properties

Indapamide hemihydrate (ariphon) - available in tablets of 1.25 and 2.5 mg, is a sulfonamide diuretic, specially created for the treatment of arterial hypertension.

Indapamide does not have a negative effect on lipid and carbohydrate metabolism, it can cause the development of hypokalemia and slightly increase the level of uric acid in the blood.

It is recommended to use the drug in a dose of 2.5 mg 1 time per day for any severity of hypertension; after 1-2 months the dose can be increased to 5 mg per day. Contraindicated in case of liver and kidney failure.

The hypotensive effect of indapamide is enhanced when combined with beta-blockers, ACE inhibitors, and methyldopa.

Indications for the predominant use of diuretics V as antihypertensive drugs

As stated above, diuretics do not reduce the severity of myocardial hypertrophy, do not significantly improve quality of life, and have an adverse effect on lipid and carbohydrate metabolism. In this regard, diuretics are most often used as a second drug in combination with other antihypertensive drugs.

The main indications for prescribing diuretics for arterial hypertension are:

volume-dependent hyporenin variant of hypertension, which is often found in women in the pre- and menopausal periods. It is characterized by clinical symptoms of fluid retention (tendency to edema, increased blood pressure after taking excess water and salt, periodic oliguria, headaches in the occipital region), low renin levels in the blood;

high stable arterial hypertension, since it is accompanied by sodium and water retention that is not caused by cardiac failure; long-term use of diuretics leads to a vasodilating effect;

a combination of arterial hypertension with congestive heart failure, obstructive bronchial diseases (in this situation, beta-blockers are contraindicated), diseases of peripheral arteries;

combination of arterial hypertension with renal failure (except for potassium-sparing diuretics).

Treatment with calcium antagonists

Calcium antagonists have the following mechanisms of action:

block slow calcium channels and the flow of calcium into smooth muscle cells, due to which arteries and arterioles relax, total peripheral resistance decreases and a hypotensive effect is manifested;

increase renal blood flow without changing or increasing glomerular filtration;

reduce sodium reabsorption in the renal tubules, which leads to increased sodium excretion (natriuretic effect) without significant loss of potassium and hypokalemia;

reduce platelet aggregation by reducing the production of thromboxane and increasing the production of prostacyclin, which reduces platelet aggregation and dilates blood vessels;

reduce the degree of left ventricular myocardial hypertrophy, which reduces the risk of developing fatal cardiac arrhythmias;

verapamil and diltiazem have an antiarrhythmic effect and are the drugs of choice for stopping paroxysmal supraventricular tachycardia, as well as for the treatment of supraventricular extrasystoles that occur in patients with arterial hypertension;

have angioprotective, antiatherogenic effects, prevent the deposition of cholesterol and calcium into the vessel wall.

Calcium antagonists do not change the plasma lipid profile, tolerance to carbohydrates, do not increase the level of uric acid in the blood, do not impair sexual function in men, do not impair bronchial conduction, do not reduce physical performance, as they do not aggravate muscle weakness.

First generation calcium antagonists

The main first generation calcium antagonists are:

dihydropyridine derivative nifedipine;

phenylalkylamine derivative verapamil;

benzothiazepine derivative diltiazem.

Nifedipine is available in the following dosage forms:

conventional dosage forms: adalat, corinfar, cordafen, procardia, nifedipine in 10 mg tablets; the duration of action of these forms is 4-7 hours;

prolonged dosage forms - adalat retard, nifedipine SS in tablets and capsules of 20, 30, 60 and 90 mg. The duration of the hypotensive effect of these forms is 24 hours.

Nifedipine is the most powerful short-acting calcium antagonist and has a pronounced antianginal and hypotensive effect.

To relieve a hypertensive crisis, short-acting capsules or tablets, pre-chewed, are taken under the tongue. The hypotensive effect occurs within 1-5 minutes.

For the regular treatment of arterial hypertension, extended-release nifedipine is used - slow-release tablets and capsules and very prolonged-release tablets, they are prescribed pomg 1 time per day; with an interval of 7-14 days, the dose can be gradually increased once a day; extended-release dosage forms must be swallowed whole, without chewing; the maximum permissible daily dose is 120 mg.

The most significant side effects nifedipine are:

pastiness on the ankles and legs;

increased frequency of angina attacks or silent myocardial ischemia (“steal syndrome”);

decreased myocardial contractility.

Basic contraindications to treatment with nifedipine: aortic stenosis, hypertrophic cardiomyopathy, decreased myocardial contractility, unstable angina and myocardial infarction.

Verapamil is available in the following dosage forms:

conventional dosage forms: verapamil, isoptin, finoptin in tablets, dragees and capsules of 40 and 80 mg;

extended forms: tablets of 120 and 240 mg, capsules of 180 mg;

ampoules of 2 ml of 0.25% solution (5 mg of substance per ampoule).

For the treatment of arterial hypertension, the drug is used as follows:

a) in conventional dosage forms - the initial dose is 80 mg 3 times a day; in elderly patients, as well as in people with low body weight, with bradycardia - 40 mg 3 times a day. During the first 3 months, the effect of verapamil may increase. The maximum daily dose for arterial hypertension is mg;

b) extended forms of verapamil - the initial dose is mg 1 time per day, then after a week you can increase the dose to 240 mg 1 time per day; then, if necessary, you can increase the dose to 180 mg 2 times a day (morning and evening) or 240 mg in the morning and 120 mg in the evening every 12 hours.

Main side effects verapamil are:

development of bradycardia and slowing of atrioventricular conduction;

decreased myocardial contractility;

Verapamil promotes the development of glycoside intoxication, as it reduces the clearance of cardiac glycosides. Therefore, when treating with verapamil, the dose of cardiac glycosides is reduced by.

Basic contraindications to treatment with verapamil:

sick sinus syndrome;

Atrial fibrillation in patients with additional conduction pathways;

Diltiazem is available in the following dosage forms:

conventional dosage forms: diltiazem, dilzem, cardizem, cardil in tablets of 30, 60, 90 and 120 mg;

prolonged dosage forms in capsules of 60, 90 and 120 mg with slow release of the drug;

ampoules for intravenous administration.

Diltiazem is used to treat hypertension as follows:

a) conventional dosage forms (capsule tablets) - start with a dose of 30 mg 3 times a day, then the daily dose is gradually increased to 360 mg (in 3 doses);

b) long-acting dosage forms (slow release) - start with a daily dose of 120 mg (in 2 divided doses), then the daily dose can be increased to 360 mg (in 2 divided doses);

c) very prolonged forms - start with a dose of 180 mg 1 time per day, then the daily dose can be gradually increased to 360 mg (with a single dose).

Diltiazem has the same side effects as verapamil, but its negative chrono- and inotropic effects are less pronounced.

Second generation calcium antagonists

Nicardipine (cardin) - compared to nifedipine, it has a more selective effect on the coronary and peripheral arteries.

The drug has a very weak negative inotropic and chronotropic effect and slightly slows down intraventricular conduction. The hypotensive effect of nicardipine is similar to the hypotensive effect of other calcium antagonists.

Nicardipine is available in extended-release capsules and is prescribed initially at 30 mg 2 times a day, then the dose is gradually increased to 60 mg 2 times a day.

Darodipine - prescribed 50 mg 2 times a day, steadily reduces systolic and diastolic blood pressure without increasing heart rate.

Amlodipine (norvasc) - Available in tablets of 2.5, 5 and 10 mg. The drug has a long-term hypotensive and antianginal effect; it is prescribed once a day initially at a dose of 5 mg; if necessary, after 7-14 days the dose can be increased to 10 mg.

Logimax - a combination drug consisting of the extended-release dihydropyridine drug felodipine and the beta blocker metoprolol. The drug is used once a day.

Thus, calcium antagonists are effective hypotensive and antianginal agents, which lead to the reverse development of left ventricular hypertrophy, improve the quality of life, have a nephroprotective effect, and do not cause significant metabolic disorders and sexual dysfunction.

Indications for the primary use of calcium antagonists in arterial hypertension

combination of hypertension with exertional angina and vasospastic angina;

combination of hypertension and cerebrovascular disease;

combination of arterial hypertension with severe dyslipidemia;

Arterial hypertension in patients with diabetic nephropathy;

The presence of chronic renal failure in patients with arterial hypertension;

Combination of arterial hypertension with heart rhythm disturbances.

Treatment with ACE inhibitors

In addition to the hypotensive effect, ACE inhibitors also have the following positive effects:

reduce left ventricular myocardial hypertrophy;

significantly improve quality of life;

have a cardioprotective effect (reduce the likelihood of developing a recurrent infarction and the risk of sudden death, increase coronary blood flow, eliminate the imbalance between myocardial oxygen needs and its delivery);

Reduce myocardial excitability, tachycardia and the frequency of extrasystole, which is due to an increase in the content of potassium and magnesium in the blood, a decrease in myocardial hypertrophy and hypoxia;

have a beneficial effect on carbohydrate metabolism, increase the uptake of glucose by cells due to the fact that an increase in bradykinin content under the influence of ACE inhibitors increases the permeability of cell membranes to glucose;

exhibit a potassium-sparing effect;

The following ACE inhibitors are most often used to treat arterial hypertension.

Captopril (capoten, tensiomin) - available in tablets of 12.5, 25, 50 and 100 mg, as well as in the form of fixed complex preparations capozide-25(captopril and hydrochlorothiazide 25 MG each) and capozide-50(captopril and hydrochlorothiazide 50 mg).

Treatment of arterial hypertension with capoten begins with a dose of 12.5-25 mg 2-3 times a day, then, in the absence of a hypotensive effect, the dose is gradually increased to 50 mg 2-3 times a day. If necessary, the daily dose of captopril can be increased.

Enalapril (enap, renitek, vasotec, xanef) - available in tablets of 2.5, 5, 10 and 20 mg and ampoules for intravenous administration (1.25 mg per 1 ml). The initial dose is 5 mg orally 1 time per day. If necessary, you can gradually increase the dose of Domg/day in 1-2 doses. Maintenance dose - 10 mg per day. The drug has a renoprotective effect even in cases of significant renal failure.

Cilazapril (inhibase) - prolonged ACE inhibitor. It is superior to captopril and enalapril in strength and duration of action. Usually the drug is prescribed in a dose of 2.5-5 mg 1 time per day, with 2.5 mg in the first 2 days. Next, the dose is selected individually depending on changes in blood pressure.

Ramipril (tritatse) - is a long-acting drug. Treatment begins with taking 2.5 mg of ramipril once a day. If the hypotensive effect is insufficient, the daily dose of the drug can be increased to 20 mg.

Perindopril (prestarium, coversil) - long-acting ACE inhibitor. Perindopril is available in tablets of 2 and 4 mg, prescribed 2-4 mg once a day, in the absence of a hypotensive effect - 8 mg per day.

Quinapril (accupril, accupro) - duration of action - hours. For patients with mild and moderate hypertension, the drug is initially prescribed 10 mg 1 time per day, then the daily dose can be increased every 2 weeks to 80 mg (in 2 divided doses).

ACE inhibitors have the following side effects :

with long-term treatment, inhibition of hematopoiesis is possible (leukopenia, anemia, thrombocytopenia);

cause allergic reactions - itching, redness of the skin, urticaria, photosensitivity;

from the digestive system, sometimes there is a perversion of taste, nausea, vomiting, discomfort in the epigastric region, diarrhea or constipation;

Some patients may experience heavy wheezing breathing, dysphonia, and dry cough;

Contraindications to treatment with ACE inhibitors :

Individual hypersensitivity, including if there is a history of indications of angioedema;

severe aortic stenosis (danger of decreased perfusion of the coronary arteries with the development of myocardial ischemia);

pregnancy (toxicity, development of hypotension in the fetus), lactation (drugs pass into breast milk and cause arterial hypotension in newborns);

renal artery stenosis.

Indications for preferential use of inhibitors ACE for arterial hypertension

ACE inhibitors can be used at any stage of arterial hypertension, both as monotherapy and in combination with calcium antagonists or diuretics (if monotherapy is ineffective), as they significantly improve quality of life, reduce left ventricular myocardial hypertrophy, improve life prognosis, and have a cardioprotective effect .

Indications for the primary use of ACE inhibitors for arterial hypertension:

combination of arterial hypertension with congestive circulatory failure;

combination of arterial hypertension with coronary artery disease, including after myocardial infarction (cardioprotective effect);

arterial hypertension in diabetic nephropathy (nephroprotective effect);

combination of arterial hypertension with chronic obstructive bronchial diseases;

a combination of arterial hypertension with impaired glucose tolerance or diabetes mellitus (ACE inhibitors improve carbohydrate metabolism);

development of unfavorable changes in lipid metabolism and increased levels of uric acid in the blood during the treatment of arterial hypertension with diuretics and beta-blockers;

severe hyperlipidemia in patients with arterial hypertension;

combination of arterial hypertension with obliterating diseases of peripheral arteries.

Angiotensin receptor antagonists II

A drug losartan (kozaar) is a non-peptide antagonist of AT II receptors and blocks the following effects of AT II related to the pathogenesis of arterial hypertension:

renin release (negative feedback);

development of left ventricular myocardial hypertrophy.

The advantages of losartan are its good tolerability and the absence of side effects characteristic of ACE inhibitors. Indications for use of the drug are the same as for ACE inhibitors. Available in capsules of 50 and 100 mg, used once a day.

Direct vasodilators cause immediate relaxation of blood vessels, primarily arterial ones.

Hydralazine (apressin) - Available in tablets of 10, 25, 50 and 100 mg, as well as in ampoules of 20 mg/ml for intravenous and intramuscular administration. The drug is a peripheral vasodilator, reduces arteriolar resistance, causes a decrease in blood pressure, myocardial load, and increases cardiac output.

The drug is not capable of causing regression of left ventricular myocardial hypertrophy; with prolonged use, tolerance to its hypotensive effect develops.

Hydralazine is initially prescribed at 10 mg 2-4 times a day, then if the hypotensive effect is insufficient, the daily dose is gradually increased to 300 mg in 3-4 doses.

When treated with hydralazine, the following are possible: side effects:

Headache; nausea;

tachycardia (due to activation of the sympathetic nervous system); when combined with beta-blockers, tachycardia is less pronounced;

sodium and water retention;

Adelfan-esidrex - a combination drug consisting of adelfan 10 mg hydrochlorothiazide, prescribed 1-4 tablets per day.

Adrenergic blockers block adrenergic receptors at the level of peripheral arterioles, which reduces peripheral resistance and causes a hypotensive effect.

For the treatment of arterial hypertension, highly selective postsynaptic adrenergic blockers are used - prazosin and second generation drugs - doxazosin, terazosin, ebrantil (urapidil).

Postsynaptic adrenergic blockers do not cause reversal of left ventricular myocardial hypertrophy and have an antiatherogenic effect (they reduce the blood levels of cholesterol, triglycerides, atherogenic lipoproteins and increase the level of high-density lipoproteins). They do not cause reflex tachycardia. These drugs almost do not retain sodium and water in the body, do not increase the level of uric acid in the blood, and do not have a negative effect on carbohydrate metabolism.

Prazosin . Treatment with prazosin begins with a dose of 0.5-1 mg at bedtime, after stopping diuretics several days before. After the first dose of the drug, the patient must be in a horizontal position due to the risk of developing orthostatic hypotension (“first dose effect”). In the future, prazosin is prescribed 1 mg 2-3 times a day. The maximum daily dose of the drug is 20 mg.

Prazosin may cause the following: side effects :

sodium and water retention during long-term treatment;

orthostatic hypotension up to fainting when taking the first dose;

Second-generation postsynaptic adrenergic blockers have a prolonged effect, are better tolerated, the phenomenon of the first dose (orthostatic syncope) is less typical for them, and they have more pronounced positive properties such as an antiatherogenic effect and improved glucose metabolism.

Terazosin (hitrin)- The initial dose is 1 mg per day. Subsequently, if there is no effect, you can increase the dose to 5-20 mg 1 time per day.

Doxazosin (kardura) - used in a daily dose of 1 to 16 mg (in 1 dose).

Ebranil(urapidil) - Treatment begins with a dose of 30 mg 2 times a day. In the future, you can gradually increase the daily dose to 180 mg in 2 doses.

α2-Central acting agonists

Centrally acting a2-agonists stimulate adrenergic receptors in the vasomotor center of the medulla oblongata, which leads to inhibition of sympathetic impulses from the brain and a decrease in blood pressure. Centrally acting adrenergic receptor stimulants reverse the development of left ventricular hypertrophy.

Clonidine (clonidine) - for oral treatment of arterial hypertension with clonidine, the initial dose is 0.075-0.1 mg 2 times a day, then every 2-4 days the daily dose is increased by 0.075-1 mg and adjusted to 0.3-0.45 mg (in 2-3 doses). After achieving the hypotensive effect, the dose can be gradually reduced to maintenance, which is usually 0.15-0.2 mg per day.

When using clonidine, it is possible side effects :

severe dry mouth due to inhibition of the secretion of the salivary glands;

drowsiness, lethargy, sometimes depression;

sodium and water retention due to increased reabsorption in the kidneys;

constipation with prolonged use;

impaired carbohydrate tolerance, development of morning hyperglycemia with long-term treatment with clonidine;

a significant increase in blood pressure (up to a hypertensive crisis) with abrupt withdrawal of clonidine;

inhibition of gastric juice secretion;

a sharp drop in blood pressure, loss of consciousness and subsequent amnesia;

glomerular filtration may be reduced.

Contraindications to treatment with clonidine:

treatment with antidepressants (an antagonistic relationship is possible, which interferes with the hypotensive effect of clonidine);

professions that require quick physical and mental reactions;

inhibited state of patients.

Methyldopa (dopegyt, aldomet) -At the beginning of treatment, the dose is 0.25 g 2-3 times a day. Subsequently, the daily dose can be increased to 1 g (in 2-3 doses), the maximum daily dose is 2 g. Methyldopa does not impair renal blood flow or reduce the glomerular filtration rate.

Sodium and water retention with long-term use of the drug, an increase in circulating blood volume, a decrease in the hypotensive effect; Taking this into account, it is advisable to combine methyldopa with saluretics;

Lethargy, drowsiness, but to a lesser extent than during treatment with clonidine;

Significant doses of methiddopa can cause depression, night terrors, and nightmares;

possible development of parkinsonism;

menstrual irregularities;

increased secretion of prolactin, the appearance of galactorrhea;

If treatment with methyldopa is abruptly stopped, withdrawal syndrome may develop with a sharp increase in blood pressure.

Contraindications to treatment with methiddopa:

hepatitis and cirrhosis of the liver;

tendency to depression;

suspicion of pheochromocytoma;

significant circulatory impairment;

Reserpine - has a direct blocking effect on the sympathetic nervous system, reducing the content of norepinephrine in the central nervous system and peripheral nerve endings.

Reserpine is available in tablets of 0.1 and 0.25 mg, as well as in the form of 0.1% and 0.25% solutions for parenteral administration in ampoules of 1 ml (1 and 2.5 mg, respectively).

The drug is prescribed orally, starting with a daily dose of 0.1-0.25 mg, after meals, then, after 5-7 days, the daily dose is gradually increased to 0.3-0.5 mg.

Side effects reserpine:

nasal congestion and difficulty in nasal breathing due to swelling of the mucous membrane;

development of parkinsonism with long-term use;

frequent, loose stools;

weakened libido in men;

increased production of prolactin by the adenohypophysis, persistent galactorrhea;

sodium and water retention;

increased gastric secretion, development of a hyperacid state (heartburn, abdominal pain, exacerbation of gastric and duodenal ulcers).

Contraindications to treatment with reserpine:

bronchial asthma, obstructive bronchitis;

peptic ulcer of the stomach and duodenum;

severe sinus bradycardia;

atrioventricular conduction disorders;

Currently, sympatholytics are not considered as first-line drugs in the treatment of arterial hypertension and are used as more accessible (cheaper) drugs and, moreover, in the absence of effect from other drugs, as well as due to tradition.

The effect of antihypertensive drugs on myocardial hypertrophyleft ventricle

Left ventricular myocardial hypertrophy in hypertension is a risk factor for fatal cardiac arrhythmias, heart failure, and sudden death. In this regard, the effect of some antihypertensive drugs on the reverse development of myocardial hypertrophy is extremely important.

The following antihypertensive drugs can cause regression of myocardial hypertrophy:

beta-blockers: propranolol, acebutalol, nadolol, celi-prolol, devalol, betaxolol, bisoprolol and possibly some others (there are conflicting data regarding atenolol and metoprolol);

calcium antagonists: nifedipine, verapamil, nitrendipine, amlodipine, isradipine; nisoldipine not only does not affect hypertrophy, but can also cause a deterioration in the functional ability of the heart with a sudden increase in blood pressure;

centrally acting antiadrenergic drugs moxonidine and methyldopa;

The main new provisions of the drug strategy treatment of arterial hypertension

individualized, differentiated therapy of patients, taking into account the clinical and pathogenetic features of arterial hypertension;

refusal of rigid treatment regimens, including mandatory step-down therapy; the possibility of monotherapy not only in patients with “mild”, mild forms of arterial hypertension, but also in patients who require more intensive treatment;

Increasing the role of ACE inhibitors and calcium antagonists in the treatment of arterial hypertension and changing the “hierarchy” of antihypertensive drugs: if previously treatment began with a diuretic or beta-blocker and only in the later stages of hypertension they resorted to α1-blockers, calcium antagonists, ACE inhibitors, then in Currently, these drugs can be “starter”, i.e. treatment can begin with them;

displacement of clonidine, reserpine, ismelin (isobarine) from the list of widely used drugs;

the use of diuretics only in a potassium-sparing regimen and in the second (auxiliary) line in most patients;

clarifying the indications for the use of beta-blockers and increasing the role of selective beta-blockers, as well as beta-blockers with vasodilating properties, in antihypertensive therapy;

mandatory assessment of the possible negative effects of antihypertensive drugs on risk factors for coronary artery disease (atherogenic dyslipoproteinemia), glucose tolerance, and uric acid levels in the blood;

mandatory assessment of the effect of an antihypertensive drug on the reverse development of left ventricular myocardial hypertrophy and quality of life;

development and testing of new promising antihypertensive drugs, in particular true angiotensin II receptor blockers (losartan);

transition during maintenance, indefinitely long-term therapy to long-acting drugs (the “one day - one tablet” principle;

Improved cerebral blood flow (treatment with cerebroangiocorrectors)

Cerebral hemodynamics in hypertension is disturbed ambiguously. Rheoencephalography can be used to identify these disorders.

With a “spastic” type of cerebral hemodynamic disorder It is advisable to include antispasmodics in antihypertensive therapy: papaverine, no-shpa. Calcium antagonists can be recommended as antihypertensive drugs.

In case of venous outflow disturbance from the brain, drugs are recommended that increase the tone of the cerebral veins: small doses of caffeine (0.02-0.03 g per dose for intense headaches), magnesium sulfate, diuretics, beta-blockers.

For mixed types of cerebral hemodynamic disorders Cavinton, cinnarizine are indicated, and among antihypertensive drugs - clonidine (hemiton, clonidine), rauwolfia preparations.

Treatment of hypertensive crisis

Hypertensive crisis is a clinical syndrome characterized by a sudden and violent exacerbation of hypertension or symptomatic arterial hypertension, a sharp increase in blood pressure to individually high levels, subjective and objective manifestations of cerebral, cardiovascular and general autonomic disorders.

Non-emergency (within a few hours) relief of hypertensive crisis

Non-emergency relief of a hypertensive crisis (within a period) is carried out when the course is not complicated and not threatening. To relieve such variants of a hypertensive crisis, antihypertensive drugs are used in oral forms.

In addition to the drugs described below, for non-emergency relief of a hypertensive crisis, you can use dibazole in in the form of intramuscular injections (1-2 ml of 1% solution) 3-4 times a day. It is also advisable to include tranquilizers in complex therapy (seduxene etc.), sedatives (valerian, motherwort and etc.).

For quotation: Karpov Yu.A. Combined antihypertensive therapy is a priority in the treatment of arterial hypertension // Breast Cancer. 2011. No. 26. S. 1568

The results of large randomized trials have led to the conclusion that without effective control of blood pressure levels, significant reductions 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 remains poor in patients receiving antihypertensive therapy (Fig. 1). It has become clear that reliable control of blood pressure using only one antihypertensive drug without the widespread use of combination therapy is possible only in a small group 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 blood pressure values ​​of 140/90 mm Hg. Art. and below, the prescription of two or more antihypertensive drugs was required. In the HOT study, combination therapy was required in 63% of patients who achieved a target diastolic blood pressure of 90 mmHg. Art., and in 74% of patients who reached values ​​of 80 mm Hg. Art. and below.
The need for combination therapy was very clearly confirmed by the results of a large project that studied the possibilities of high-quality blood pressure control in everyday clinical practice. A study was conducted in which 3,153 doctors were interviewed who provided information about the first five patients with hypertension at one of their outpatient appointments.
Data from 14,066 patients receiving antihypertensive treatment were analyzed. The patients were divided into three groups according to the degree of risk of developing cardiovascular complications (CVC): group 1 - without risk factors (except for 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. The majority of patients in group 1 (42.9%) had blood pressure below 140/90 mmHg. Art., despite the fact that only 33% of them received combination therapy. In group 3, only 27% of patients had adequate blood pressure control, although 50% of patients received a combination of two or more drugs. These data indicate that the adequate treatment of hypertension is generally poor in general clinical practice; Blood pressure is worst controlled in patients with a high risk of complications. Improving 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 on Arterial Hypertension/All-Russian Scientific Society of Cardiologists (RMOAS/VNOK), the prescription of a combination of two antihypertensive drugs is considered as an alternative to monotherapy at the beginning of treatment. Combinations of two, three or more antihypertensive drugs are used. Combination therapy has many advantages:
. enhancing the antihypertensive effect due to the multidirectional effects of drugs on the pathogenetic mechanisms of hypertension development, which increases the number of patients with a stable decrease in blood pressure;
. reducing the incidence of side effects both due to the use of smaller doses of combined drugs and due to the mutual neutralization of these effects;
. ensuring the most effective organ protection and reducing the risk and number of cardiovascular events.
Combination therapy must meet the following conditions: complementary action of drugs; improved results when 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 on 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 (ARBs) + diuretic; ACE inhibitors + calcium antagonists (CA); BAR + AK; dihydropyridine AK + β-blockers (BAB); AA + diuretic; BAB + diuretic. For combination therapy of hypertension, both non-fixed and fixed combinations of drugs can be used, and the latter are more promising (Table 1).
According to modern concepts, various mechanisms and systems (renin-angiotensin, sympatho-adrenal, water-salt) are involved in the increase in blood pressure, closely interacting with each other. The effect of antihypertensive drugs on blood pressure levels is often impaired due to the activation of counterregulatory mechanisms. The combination of two drugs, which actually interact with the compensatory responses of each of them, significantly increases the frequency of blood pressure control. In addition, the doses required for these purposes when using a combination of two drugs are usually lower than those required when the components are used in monotherapy. All this is of great importance from the point of view 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 reduction in blood pressure to predetermined target levels, with particular caution in the elderly who have recently suffered a myocardial infarction and stroke. The number of prescribed drugs depends on the risk of developing cardiovascular complications, in the stratification of which great importance is attached to the value of blood pressure.
Currently, it is possible to use two strategies for initial treatment of hypertension: monotherapy and low-dose combination therapy, followed by increasing the amount and/or doses of the drug if necessary (Fig. 2).
Monotherapy as initial treatment is used in individuals with a low or average risk of developing cardiovascular events, with a 1st degree increase in blood pressure. This treatment regimen is based on finding the optimal drug for the patient. A second drug of a different class should be added when, after prescribing 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 drug for the patient with frequent changes in medications and their dosages, which deprives the doctor and the patient of confidence in success and, ultimately, can lead to decreased adherence to treatment.
A combination of two drugs is recommended in patients with a high or very high risk of developing cardiovascular complications, with 2nd and 3rd degree increases in blood pressure. For example, if initially (before treatment) the blood pressure level exceeds 20/10 mm Hg. Art. target, then you can prescribe two drugs at once - 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
is it better to combine?
Many antihypertensive drugs can be combined with each other, but some combinations have advantages over others not only because of the main mechanism of action, but also because of their practically proven high antihypertensive effectiveness (Table 1). An ACE inhibitor in combination with a diuretic is the optimal choice, which enhances the advantages and eliminates the disadvantages.
The recommendations indicate the circumstances that should be taken into account when choosing a drug or their combination 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 of patients with hypertension with long-term use. From this perspective, the creation of ACE inhibitors is a huge achievement in the treatment of hypertension and other cardiovascular diseases. This class of drugs has high antihypertensive effectiveness, is well tolerated, has proven cardio-, vasculo- and renoprotective effects and, most importantly, helps reduce the incidence of cardiovascular events and increase the life expectancy of patients with long-term use of this therapy.
When prescribing this class of drugs, a good quality of life is maintained (normal sexual activity, response to physical activity), including in older people. Improvement in cognitive function while taking ACE inhibitors in elderly people allows their wider use in this category of patients.
ACE inhibitors are metabolically neutral drugs: with 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 data, may even improve). One of the new provisions of the European recommendations on hypertension (2009) is the assessment of the risk of developing diabetes during the use of antihypertensive drugs. Clinical studies have shown that blood pressure-lowering drugs can both increase and decrease the likelihood of carbohydrate metabolism disorders. According to the ASCOT study, when using a combination of a beta blocker/diuretic compared with a combination of a calcium antagonist/ACE inhibitor, the development of new cases of diabetes was 23% more likely (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 ACE inhibitor/diuretic combination is the most popular in the treatment of hypertension due to its high antihypertensive efficacy, target organ protection, good safety and tolerability, as well as attractive pharmacoeconomic indicators. The drugs potentiate each other's action due to their complementary effect on the main links in blood pressure regulation and blocking counter-regulatory mechanisms. A decrease in circulating fluid volume due to the saluretic effect 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, which leads to increased RAS activity, allows the ACE inhibitor to realize its effect. This expands the range of patients who respond 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, PYTHAGOR, showed that when prescribing a combination of antihypertensive drugs, in most cases, doctors prefer an ACE inhibitor with a diuretic, and fixed combinations of these drugs are the most popular (Fig. 4).
Combination ACE inhibitor/
diuretic - impact on prognosis
in patients with hypertension
The effect of this combination on the prognosis of patients at high risk of complications was assessed in several clinical studies - PROGRESS, ADVANCE, HYVET. The combination of an ACE inhibitor and the diuretic indapamide, as shown in the PROGRESS trial, led to a greater reduction in blood pressure than an ACE inhibitor alone, and in parallel to greater prevention of recurrent stroke. In the ADVANCE study, to reduce the risk of complications, a combination of an ACE inhibitor with a diuretic was used in patients with type 2 diabetes, 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 diabetes-related complications (sum of macro- and microvascular complications). The ACE inhibitor/diuretic combination was very well tolerated, with a slightly higher incidence of adverse events than in the placebo group, and high adherence to treatment (>80%) throughout the study. Similarly, in the HYVET study, greater reductions in elevated blood pressure compared with placebo in people over 80 years of age, using indapamide plus perindopril in most cases, led to significant reductions in all-cause mortality, fatal stroke, and heart failure.
Of great interest are studies that examined 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 interact with each other and do not change the pharmacokinetic characteristics of each other. Gerc V. et al. found that tablets containing lisinopril and hydrochlorothiazide normalize blood pressure in 81.5% of patients with mild to moderate hypertension. In addition, it has been shown that in more than half of the cases, a fixed combination of lisinopril and hydrochlorothiazide can persistently reduce blood pressure to normal levels in patients with high hypertension, poorly controlled by other drugs (Co-Diroton, Gedeon Richter).
Combination ACE inhibitor/
diuretic - organoprotective
properties
Along with blood pressure control, target organ protection 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 blood pressure control and the organoprotective properties of each drug.
Left ventricular myocardial hypertrophy (LVH) is an independent factor that significantly increases the risk of disease complications (coronary artery disease, chronic heart failure, ventricular arrhythmias). Reversal of LVH during 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 use of a combination of an ACE inhibitor and a diuretic is more effective in reducing LVH. These data are reflected in the recommendations of the Russian Medical Society on arterial hypertension, where the combination of an ACE inhibitor with a diuretic is considered 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 indicators 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 combination drugs may also be effective.
The main indications for prescribing 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 for stratifying the general (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, the drug Co-Diroton) in patients significantly improves blood pressure control, has an organoprotective effect and significantly reduces the risk of developing major cardiovascular events, including death. These data indicate the great potential of this combination and the feasibility of its wider implementation in everyday clinical practice.

Literature
1. Russian Medical Society for Arterial Hypertension (RMAS), All-Russian Scientific Society of Cardiologists (VNOK). Diagnosis and treatment of arterial hypertension. Russian recommendations (3rd revision). // Cardiovascular therapy and prevention. - 2008 - No. 6, appendix. 2.
2. The Task Force for the management of arterial hypertension of the European Society of Hypertension and of the European Society of Cardiology. 2007 Guidelines for the management of arterial hypertension. // J Hypertens. 2007; 25: 1105-1187.
3. Eur Heart J 2011; 32: 218-225.
4. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderty Program (SHEP). // JAMA. 1991; 265:3255-64.
5. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: the Antihypertensive and Lipid Lowering treatment to prevent Heart Attack Trial (ALLHAT). // JAMA. 2002; 288:2981-97.
6. Pepine C.J., Handberg E.M., Cooper-DeHoff R.M. et al. INVEST Investigators. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. // JAMA. 2003; 290: 2805-2816.
7. Dahlof B., Devereux R.B., Kjeldsen S.E. et al. Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. // Lancet. 2002; 359:995-1003.
8. Dahlof B., Sever P.S., Poulter N.R. et al. ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendoflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomized controlled trial. // Lancet. 2005; 366:895-906.
9. Hansson L., Zanchetti J.A., Carruthers S.G. 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.
10. Amar J., Vaur L., Perret M. et al. Hypertension in high-risk patients: be aware of the use of effective combination therapy (results of the PRACTIC study). // J Hypertens. 2002; 20: 79-84.
11. Mancia G., Laurent S., Agabiti-Rosei E. et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. // J Hypertension. 2009; 27: 2121-2158.
12. Leonova M.V., Belousov D.Yu., Steinberg L.L. Analytical group of the PYTHAGORUS study. Analysis of medical practice of antihypertensive therapy in Russia (according to the PYTHAGOR III study). // Pharmateka. - 2009. - No. 12. - P. 98-10.
13. PROGRESS Collaborative Group. Randomized trial of perindopril-based blood pressure lowering regimen among 6,105 individuals with previous stroke or transient ischemic attack. // Lancet. 2001; 358: 1033-1041.
14. ADVANCE Collaborative Group. Effects of fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomized controlled trial. // Lancet. 2007; 370:828-840.
15. Beckett N.S., Peters R., Fletcher A.E. et al. The HYVET Study Group. Treatment of Hypertension in Patients 80 Years of Age or Older. // N Engl J Med. 2008; 358: 1887-1898.
16. Swaisland A.J. The pharmacokinetics of co-administered lisinopril and hydrochlorothiazide. // J Hum Hypertens. 1991;5 Suppl 2:69-71.
17. Laher M.S., Mulkerrins E., Hosie J., et al. The effects of age and renal impairment on the pharmacokinetics of co-administered lisinopril and hydrochlorothiazide. // J Hum Hypertens. 1991;5 Suppl 2:77-84.
18. Gerc V., Begovic B., Vehabovic M. et al. Fixed combination lisinopril plus hydrochlorothiazide in the treatment of essential arterial hypertension: an opened, multi-centre, prospective clinical trial. // Bosn J Basic Med Sci. 2007;7(4):377-82.
19. Vegazo Garcia O., Llisterri Caro J.L., Jimenez Jimenez F.J. et al. Effectiveness of combined therapy at set doses in a cohort of hypertense patients not controlled by single therapy. Aten Primaria. 2003; 28;31(3):163-9.