Резюме
Григор’єва Л.В. Методи раціональної фармакотерапії артеріальної гіпертензії на підставі доказової медицини в практиці сімейного лікаря.
У огляді літератури проведено узагальнення і аналіз підходів до раціональної фармакотерапії артеріальної гіпертензії, визначені перспективні шляхи підвищення економічності і ефективності лікування. За наслідками рандомізованих контрольованих досліджень доведена ефективність антигіпертензивної фармакотерапії при одночасному використанні комбінацій препаратів різних класів. Тривала терапія діуретиками і β-адреноблокаторами може запобігати серцево-судинним ускладненням у хворих з АГ. Якщо неможливо досягти цільового рівня артеріального тиску, необхідно вирішити питання про додавання в схему лікування препаратів інших фармакологічних груп для успішного проведення ефективного лікування.
Ключові слова: артеріальна гіпертензія, фармакотерапія, комбінації препаратів, рівень артеріального тиску, сімейна медицина.
Резюме
Григорьева Л.В. Методы рациональной фармакотерапии артериальной гипертензии на основании доказательной медицины в практике семейного врача.
В обзоре литературы проведено обобщение и анализ подходов к рациональной фармакотерапии артериальной гипертензии, определены перспективные пути повышения экономичности и эффективности лечения. По результатам рандомизированных контролируемых исследований доказана эффективность антигипертензивной фармакотерапии при одновременном использовании комбинаций препаратов разных классов. Длительная терапия диуретиками и β-адреноблокаторами может предотвращать сердечно-сосудистые осложнения у больных с АГ. Если невозможно достичь целевого уровня артериального давления, необходимо решить вопрос о добавлении в схему лечения препаратов других фармакологических групп для успешного проведения эффективного лечения.
Ключевые слова: артериальная гипертензия, фармакотерапия, комбинации препаратов, уровень артериального давления, семейная медицина.
Summary
Grigorieva L.V. Methods of rational pharmacotherapy of hypertension based on evidentiary medicine in practice of family doctor.
In the review of references was performed the generalization and analysis of approaches of rational pharmacotherapy of hypertension, identified perspective ways to improve the efficiency and effectiveness of treatment. During the results of randomized control researches the efficiency of antihypertensive therapy has been proved while using combinations of drugs of different classes. The long-therm therapy with diuretics and β-adrenergic blockers may prevent cardiovascular events in patients with hypertension. If the achievement of the target blood pressure is impossible the adding to the treatment scheme the drugs from other pharmacological groups can provide effective and successful treatment.
Key words: hypertension, pharmacotherapy, combination of drugs, level of blood presser, family medicine.

УДК 616.12-008.331-085.035-053.88/.89:616.1/.4

Харьковский национальный университет им. В.Н. Каразина

V. N. Karazin Kharkiv National University

Sq. 4, 61022, Kharkiv, Ukraine

площадь Свободы 4, 61022, Харьков

doctor-exclusive@mail.ua

At the present day hypertension (HTN) is still one of the most important medical problems and its presence in the different ages in large measure determines cardiovascular incidence and mortality. Particularly it concerns the elderly which at the same time together with HTN have underlying diseases and numerous target affected organs. Pharmacotherapy which uses the evidence based medicine provides a guaranty of effective and economic treatment [1, 10].

One of the most extended diseases in Ukraine is HTN. Up to now it is registered 5 million patients with HTN problems. In accordance with epidemiological survey near 13 millions of people suffer HTN and the half of them has registered a border-line of blood pressure (BP). Among the people suffering HTN 62 % knows about their disease, 23.2 % of them treats and only 12.8 % – effectively [11].

Hypertension is one of the main forms of cardiovascular system diseases. The patient having high BP the ischemic heart disease (IHD) develops in 3-4 times and the cerebrovascular disease develops in 7 times more often [12].

More than 90 % cases HTN are idiopathic (essential, primary) and it is called an essential hypertension. 5-10 % of cases HTN have ascertained the cause of HTN (a secondary hypertension) [13].

Regulating mechanisms of blood are complex and various. There are more then ten interactive systems in human organism. These systems actively intervene in regulation of blood system. Regulating mechanisms of blood circulation are subdivided into pressor or depressor and also into central (determines amount of BP and general circulation) or local (controlling blood circulation in individual organ and tissues) [4, 28].

Etiology of the secondary HTN is not fully studied. It has been established that the secondary HTN depends on age changes of organism. Rising mean BP is not a natural consequence of aging. Hemodynamic factors and neurohormonal dysfunction are important in the genesis of increasing BP [11].

Essential primary hypertension is the disease characterized by the reduction of adaptive cardiovascular capability, the destruction of the governing circulatory dynamics mechanism and progressing sequels [5].

The secondary HTN is the various groups of the cardiovascular and endocrine disorders, kidney diseases. Within those secondary HTN became a leading sign. Primary disorder affects not only organs and local blood circulation, but it destabilizes circulatory dynamics of the system. As result it received effects similar to the result of effects HTN.

Hypertension affects nearly 20 % of population aged 18 years and older. According to the data of epidemiological surveys periodicity of HTN increases with age and more than 50 % of people older than 50 have it. The significance HTN as a risk factor of cardiovascular diseases (CVD) significantly increases with age. In the age group 65-76 years it is more than 30 %. Hypertension nearly in 2/3 cases is observed like isolated systolic hypertension – special form of essential HTN [2].

According to the definition of experts WHO isolated systolic hypertension (ISH) is the arising of systolic blood pressure (SBP)>140 mm Hg with the normal or reduced diastolic blood pressure (DBP) <90 mm Hg. The presence of isolated systolic hypertension is associated with increasing cardiovascular mortality from 2 to 5 times, multiplying cerebral incidence 2.5 times and increasing by 51 % the total mortality. Isolated systolic hypertension is most prevalent in older adults. The close connection SBP with the risk of coronary, cerebral and renal complications was established. The risk of complications depends on the level SBP and allows predicting the cardiovascular risk. According to Framingham Heart Study, the increasing pulse presser more 60 mm Hg is wrong prognostic factor to the cardiovascular complications and mortality. The high pulse presser is the age marker and in accordance to definition is main characteristic of isolated systolic hypertension. Elderly have a high periodicity combining ISH and metabolic disorder (diabetes, gout).

The isolated systolic hypertension characterized by the hypokinetic type of homodynamic with increasing of main periphery resistance. Abnormality of the circadian rhythm is observed with age. Over 50 % of patients have night hypertension or over-dipping is registered at the night’s hours. Expressed morning presser blood-up is commonly observed. The abnormality of circadian rhythm of elderly indicates the high risk of target lesions and cardiovascular complications.

According to diurnal monitoring BP for estimating the risk of isolated systolic hypertension the patients are separated into three subgroups: non-resistant HTN<140 mm Hg, lung- resistant HTN 140-159 HTN and moderately resistant HTN>160 mm Hg.

The treatment of isolated systolic hypertension includes the complex therapy. It provides using medicaments and not-medicaments methods for preventive hard cardiovascular complications. Reducing SBP to <140 mm Hg is the task of the treatment.

The treatment without drugs provides limiting salt consumption. The pathogenetic ground of this is the fact that elderly have high sensitivity to sodium chloride. The elderly patients with isolated systolic hypertension, especially post-menopause women have salt-sensitivity in 30-50 % cases. The ordinary salt limitation makes possible to lower BP for this category of patients. Other methods without medicaments: the smoking cessation, hypocholesteremic diet and dosing increasing physical activity. Physical activity favors to the weight reduction and healthy influences on the SBP-level.

The non-medicaments therapy is started in the first degree of HTN with a low risk. Salt intake reducing from 10 to 4.5 g/day is lower SBP-level to 4-6 mmHg. The overweight reducing to 10 kg goes to reducing BP to 5-20 mm Hg. The limits of drinking, increasing physical activity, smoking cessation, the treatment chronic illness (they are exiting cause of secondary HTN) and ruling out effects of occupational exposures (vibration, noise, ultrasound, mercury, lead) are recommended [2, 3].

Therapeutic decision about drug’s group and a medicine is determined in accordance with particular clinical setting, clinical and pharmacological characteristics of the medicine, and the presence of comorbidities and complications of hypertension. Because of proven effectiveness the choosing drugs for HTN are calcium channel blockers (calcium antagonists). The nature of these drugs is the capacity to reversibly inhibit the flow of calcium through the slow calcium channel. These drugs used in cardiology since the end of 1970s. Now these medicines are very popular and used more often in the majority of developed countries [4, 5]. It is caused by the high clinic efficacy of calcium antagonists (not only for HTN therapy, but also for therapy of stenocardia, circulatory collapse, cerebrovascular insufficiency and peripheral atherosclerosis), on the other hand – the relatively small contraindications number and their comparatively low level of complications.

The modern ideas about pharmacotherapy of isolated systolic hypertension are based on the results of several massive researches, especially STOP-Hypertension, SHEP, Syst-Eur., Syst-China etc. [4, 5, 6].

The common antihypertensive medicinal products are diuretics, β-adrenergic blockers, calcium channel blockers, inhibitors, angiotension-converting enzymes (ACE), angiotensin II (AT₁-receptors) receptor blockers and α₁- adrenergic blockers. The varied categories of antihypertensive medicinal products reduce BP almost equally, but they have different side effects.

The high potency of diuretics is proved by many researches, such as ALLHAT [46], TOMHS [41], SHEP [45], LIVE [27], STOP [21], NESTOR [38] etc.

Several dozen randomized controlled clinical trials have proved the capability to long-term therapy by diuretics and β-adrenergic blockers which prevent cardiovascular complications of hypertensive patients [32].

In case of isolated systolic hypertension the diuretics are primary agents. When urinative drug’s therapy is impossible, calcium dihydropyridine antagonists are recommended. Using calcium dihydropyridine antagonists for older adults has sense if IHD and heart rhythm disorder presents.

This therapy is recommended to start from small dozes of thiazide diuretics (hydrochlorothiazide, chlorthalidone, indapamide) [33].

The positive effect, high potency hydrochlorothiazide and chlorthalidone for isolated systolic hypertension are proved. At the same time efficiency and preventive effects of hydrochlorothiazide and chlorthalidone using are proved for preventive cardiovascular complications (cerebral and coronar). It is established, that hydrochlorothiazide and chlorthalidone may successfully be used use for elderly with diabetes mellitus. These drugs not inferior to new antyhyertensive agents, but also they have advantages in terms of cost and efficiency [34].

There ware another circumstances retarding implantation of active therapy for the elderly persons with isolated systolic hypertension. First of all it depended on the fears of continued depressurization DBP and reduction of coronary circulation and a result of drug’s therapy. Later it was proved that reduction of BP does not increase periodicity of cardiovascular accidents, even if it was lower than 80 mm Hg [35].

At the present day β-adrenergic blockers are not recommended for using like monotherapy primary agent for elderly and for those who had cardiovascular accident. The inhibitors ACE can be exhibited like secondary agents for reducing SBP of older adults. This using was based on some researches (CARE). The ACE inhibitors are possible supplement to diuretic therapy or to calcium channel inhibitors. In recent times new method of low-dose combination therapy takes attention, for instance, the combination of perindopril (2 mg) and indapamide (0.625 mg) [36].

The experts of WHO and International Society of Hypertension developed a number of recommendations for the treatment of HTN [6]. The main task of therapy the patient with HTN is the reduction of risk of cardiovascular complications as much as possible. We need not only to reduce the high BP, but also to attack all reversible risk factors, such as smoking, hypercholesteremia, diabetes mellitus (DM) and other comorbidities.

The lifestyle changing is recommended to the hypertensive patients. The lipotrophy patients need to lose weight at least 10 kg. This body weight loss promotes reducing BP and has a positive effects to other risk factors, such as insulin resistance, DM, hyperlipidemia and left ventricular hypertrophy. The drinking patients have to be explained the high risk of cerebrovascular incident. For reduction the risk of adverse reaction the experts of WHO recommend the next combination of antihypertensive medicinal products: diuretic and β-adrenergic blocker; diuretic and inhibitor ACE; calcium dihydropyridine antagonist and β-adrenergic blocker; calcium channel blocker and inhibitor ACE; β-adrenergic blocker and α₁- adrenergic blockers[37].

Dozen randomized controlled clinical trials proved the ability to long-term therapy by diuretics and β-adrenergic blockers to avert cardiovascular complications of HTN patients.

The stage scheme of antihypertensive medicines had proved by НОТ (Hypertension Optimal Treatment) study. The long-acting form of the calcium antagonist felodipine 5 mg / day was used for first stage of therapy. At the second and third stage of therapy – felodipine-retard increased to 10 mg. At the fourth stage ACE inhibitor or β-adrenergic blockers, which dozes were doubled. And at fifth stage the diuretic was added [38].

Taking into account that hypertension patients have a high risk of cardiovascular complications, connecting with BP increasing and other factors, their therapy should be using not only antihypertensive drugs. Randomized controlled study HOT had shown that adding low-dozes of aspirin (75 mg/day) to the patients who had successfully antihypertensive therapy significantly reduced the risk of cardiovascular complications (15 %) including heart attack (36 %). Several randomized controlled clinical trials had proved the high efficiency of anticholesteremic agents of the statins in primary and secondary prevention of IHD for the peole with different blood cholesterol levels [39]. The efficiency and safety long therapy of statins (lovastatin, pravastatin and simvastatin) was good known. Using the atorvastatin and cerivastatin seems potential. These drugs superior other statins with gipoholesterinemich expression. Recently the interest to application of diuretics therapy of hypertension has been increased. Pathogenetic relevance, substantial evidence base and low cost became the main reasons for the high using periodicity of these pharmacological drugs.

The results of multi-institutional studies demonstrated that torasemide significantly differs from the predecessors in strategic clinic and pharmacologic characteristic of efficiency and safety. One of the main differences of torasemide is its antialdosterone effect proved by several researches [1, 17]. The current wave of interest of using aldosterone antagonists started at the end of the 1990s with patients with congestive heart failure (CHF) because of improving prognosis of that patients (reduction of mortality, hospitalization rates and severity of symptoms). It has shown RALES clinic research [15, 49].

One of the most significant defect in using thiazide and loop diuretics is considered to be the overmuch activation of the renin-angiotensin-aldosterone system (RAAS). Taking furosemide induces high sodium and water excretion which replaces by retention of sodium and water in the rest of the day. As a result the day excretion of sodium and water may insignificantly increase, but only in the case of low doses of sort-range diuretics. Torasemide as opposite to other diuretics has the additional positive effect like blockade of RAAS [1, 14, 33, 40].

General practice doctors, family physician the especially interesting in the fact of reducing diastolic BP to a level below 90 mm Hg in 70-80 % of patients [12, 20] when torasemide is used these doses [48].

Real increasing of aldosterone in blood serum of patient is determined by the action of torasemide, but not furosemide. It can be explained from the position of the negative feedback of the mechanism activating during blockade of aldosterone receptors by torasemide [3, 15].

It’s known that aldosterone potentiates the undesirable consequences of sympathetic nervous system’s excessive activation. It increases the capture of catecholamines by cardiomyocytes and simultaneously inhibits the function of the parasympathetic nervous system [25, 26].

It is important to know for a primary care physician that torasemide has not proarrhythmic effects which typical to indapamid. It is known property of indapamid can long Q-T interval and predisposing ventricular tachycardia [29]. It is explained the indapamid’s capacity to inhibit the activity of potassium channels in the membranes of cardiomyocytes. The function of membrane’s potassium channels is broken of the patients with diabetes mellitus and congestive heart failure [16].

Torasemide (at doses 2.5-5 mg) has mainly antihypertensive and antialdosterone influence with a week natriuretic effect which allows using torasemide for daily continuous therapy of hypertension [21, 47].

Many studies have proved that torasemid is the main medicine of loop diuretic’s of new generation which range of pharmacological effects fundametelly different from the first generation of diuretics. The antialdosterone effects are based on torasemid’s ability to block aldosteron receptors in kidney and heart and inhibit the aldosterone secretion by adrenal. The antyaldosterone effects provide positive results of CHF-therapy and edemas of various origins [2, 22].

Torasemid does not activate sympathetic nervous system (does not effect on the levels of adrenalin and noradrenalin) and doesn’t increase cardiac rate. The clinical data tells about reducing left ventricular hypertrophy during treatment with torasemide[16, 23].

In recent years the clinic practice had widespread introduction of low-dose diuretic therapy for the control of water balance for assessment the patients with urine output. The last one can be explained by increasing the level of night BP which is a necessity for maintain kidney function. Presence of nycturia and elevated blood pressure is a sign of using diuretic therapy for reducing HTN [30].

Special attention is given the problem of morning increase of BP which can be the reason of heart attack, stroke and other dangerous cardiovascular events [40]. Theoretically, protection from rising BP in the morning should be prevented by a single dose of antihypertensive drugs with 24 hours action. There are most modern ACE inhibitors and ARBs II – sartans [20].

Appearance of two fixed combination - lisinopril with amlodipine (Equator) and hydrochlorothiazide (Co-Diroton) makes it possible to use them together with a reduction its dosage level twice [7]. According these treatment options the drug’s combinations increase to three medicines in one pill with total doses: lisinopril - 10 mg, amlodipine - 2.5 mg, hydrochlorothiazide - 6.25 mg. Triple therapy is recommended for using during meteo irregular periods- autumn, winter and spring months [10].

In the summer, especially during hot weather, the control of water exchange and consumption of fluid is executed by measurements of body mass. Taking of diuretics in the heat is limited to full withdrawal, this is for daily use of amlodipine also [20].

Using of fixed combinations of antihypertensive drugs, such as lisinopril with hydrochlorothiazide (Co-Diroton) with amlodipine and lisinopril (Equator), increases efficiency of BP-control and patient’s mood for treatment. The severity of water stress and individual mechanisms increasing patient’s BP should be taken into account in choosing therapy. It connected with violation of the daily water balance of the body [9, 31].

The important objective of HTN-treatment is the maximum reduction the total risk of cardiovascular morbidity and mortality. It includes not only the correction of blood pressure, but also the reduction the risk damaging target-organs. A general practitioner should be aim to the stabilization of BP to range of optimal or normal range (<140/90 mm Hg). BP of young and middle aged patients with diabetes should not exceed 130/85 mm Hg [8, 40].

Amplodipin blocks flow of calcium ions across the cell membrane into cardiac and smooth muscles. The mechanism of antihypertensive action of amlodipine explained by a direct relaxing effect on vascular smooth muscle which leads to a reduction of the total peripheral vascular resistance. This effect is most expressed at the dihydropyridine calcium antagonist (amlodipine, isradipine, nitrendipine) [32].

In contrast from non-dihydropyridine calcium antagonists (verapamil and diltiazem) dihydropyridine calcium channel blockers (amlodipine) minimal influence on myocardial contractility in a less measure and do not affect the function of the sinus node and the atrioventricular conduction. Normodipin (amlodipine) leads to a gradual decrease in blood pressure without changes in heart rate. Normodipin is metabolically neutral, it reduces endothelial dysfunction and it has a balanced normalizing effect on the NO-system which also reduces the risk of cardiovascular complications [41].

Pharmacodynamic interactions of calcium antagonists appear in changing antihypertensive effect and increasing cardiodepressive effects (decreasing myocardial contractility, slowing conduction along pathways, etc.). A favorable effect on blood pressure observed in synchronous administration of amlodipine with β-adrenergic blockers. During taking calcium antagonist and antihypertensive drugs together it should be preferred amlodipine (normodipin) or, in the case with "solt-sencitive" hypertensives, should make combination of calcium antagonist with diuretic drugs for preventing sodium and water retention. Amlodipine is dihydropyridine calcium antagonist medicine which hypotensive effects not directly connected with prostagladins involving. Amlodipine is compatible with diuretics, ACE inhibitors, β- adrenergic blockers, nitrates, and hypoglycemic drugs [41].

The peak of hypertensive effect in the treatment of 5 mg normodipin comes only at the 6^th week of using the drug. It makes impractical earlier increasing of the  dose during incomplete control of blood pressure [17]. The drug has a dose-dependent effect on blood pressure and it is characterized by a linear dependence of the "dose-concentration" in the blood plasma [22].

A shown effect of amlodipine is proved by several important studies, such as TOMHS, ALLHAT, VALUE, PREVENT. TOMHS research compared the efficiency of different types of hypertensive drugs on patients with soft form of HTN. TOMHS had proved the best engagement of patients to amlodipine’s therapy with the same efficiency with β-adrenergic blockers, diuretics, ACE inhibitors and α-adrenergic blockers [46].

According to recommendations of European Society of Hypertension / European Society of Cardiology (ESH / ESC) (2007) calcium channel blockers are particularly indicated in the case of combination HTN with variant angina, of peripheral arteries, diabetes, asthma or chronic obstructive pulmonary disease (COPD) in elderly patients with hypertension and systolic hypertension [42].

A justifiable prescription for the patients with polypathia of HTN and IHD in stage form (stable exortional angina, old myocardial infarction) is β- adrenergic blocker monotherapy or combination therapy including β- adrenergic blockers and dihydropyridine calcium channel blockers. When β-adrenergic blockers have contraindications and the inability to use them for treating of asthma COPD, chronic dust bronchitis, chronic toxic bronchitis, delayed conduction II-III degree, serious disease of peripheral arterials high priority in HTN-therapy is given to dihydropyridine calcium channel blockers which have antianginal effect [43].

It is proved that calcium antagonists (calcium channel blockers) are the drugs of choice for treating patients with hypertension and vasospastic angina (Prinzmetal's angina). When calcium antagonists bloke calcium channel of platelets they reduce aggregation of platelets. Antianginal effect of amlodipine is maximum in patients with significant obstructive coronary spastic component. [21] Amlodipine is effective in the case of stable angina. It significantly reduces the frequency, duration and severity of ischemia [22-26].

The efficiency of amlodipine in cases of CHD had proved by PREVENT study. Amlodipine was added to patients with coronary heart disease during three years and all this time its impact on the course of atherosclerosis of the coronary and carotid arteries was estimated [44]. Using a long-acting amlodipine should be justified in clinical situation involves a combination of hypertension and coronary heart disease (stable angina) for preventing anginal attacks in vasospastic angina and silent myocardial ischemia. Amlodipine may be used as monotherapy (usually with contraindications to the use of β-adrenergic blockers) and in combination with β-adrenergic blockers.

If patients with chronic heart failure (CHF) has HTN the drugs of choice, of course, should be ACE inhibitors (with poor tolerance of treatment - an angiotensin II receptor blockers), in combination with diuretics and β-adrenergic blockers. If the combined therapy with an ACE inhibitor, diuretic and β-adrenergic blockers can not reach target blood pressure, so, in this clinical setting to the treatment scheme should be added dihydropyridine calcium channel blocker (amlodipine) [6].

At the present moment CHF-therapy (PRAISE study) has a positive clinical experience of using amlodipine [34]. Besides, the meta-analysis which was made by Kloner R.A et al. [35] had shown that main cardiovascular mortality, periodicity of developing acute myocardial infarction and progressing IHD had lower index than other similar calcium antagonists.

The combination of diabetes with hypertension is relatively unfavorable clinical situation. Because of the diabetes in patients with HTN have significantly number of cardiovascular complications and mortality. The treating HTN in patients with diabetes has to provide not only attaining the target value of BP but to has distinct properties of organ’s protection and be metabolically neutral. [5] Amlodipine belongs to a group of dihydropyridine calcium antagonists. It is a drug of choice for patients with HTN and DM because of its expressing nephroprotective activity (it reduces microalbuminuria and slows the progression of diabetic nephropathy) and beneficial metabolic effects, while other antihypertensive agents (diuretics, β- adrenergic blockers, especially non-selective) impair the lipid profile, increase insulin resistance, thereby exacerbates existing metabolic disorders in diabetes.

It is proved that the dihydropyridine calcium channel blockers have no adverse effect on lipid , purine and carbohydrate metabolism which is especially important in the treatment of hypertensive patients, many of them have similar violations. Thus, the results of ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) have convincingly shown that the combination of amlodipine + ACE inhibitors was more effective than the combination of β-adrenergic blockers + diuretic. It has shown the effect on both hard and surrogate endpoints and on metabolic parameters in patients with hypertension and high risk of cardiovascular complications [11, 37].

During the INVEST study HTN patients with CHD had therapy with combination of verapamil (calcium channel blocker) and ACE inhibitor. It was established that they had a risk of DM-increasing significantly lower than patients who had therapy with combination of diuretic and atenolol [39]. Amlodipine reduces urinary albumin excretion in of patients with diabetes type 2.

It is recognized that hypertension is a progressing factor of chronic kidney disease (CKD) regardless of its origin. Particular attention should be paid to nephroprotection in diabetic nephropathy. It is necessary to achieve a strict control of target value of BP (BP<130/80 mm Hg) and decrease in proteinuria. ACE inhibitors and angiotensin II receptor antagonists are the drugs of choice for reducing proteinuria. The combination therapy with an addition of a loop diuretic (in violation of nitrogen excretive function of renal) and calcium antagonist is necessary for achievement a target value of BP. Experimental and clinical studies have shown the positive effect of amlodipine on renal hemodynamics: a renal blood flow and glomerular filtration rate increased, renal vascular resistance decreased [41].

A nephroprotective effects of amlodipine of patients with HTN are complicated by chronic renal failure shown the AASK study [42]. This medicine is effective in reducing BP of patients with HTN and kidney disease, it potentiates the antihypertensive effect of ACE inhibitors, increases renal flow of plasma, natriuresis and diuresis [43].

A common clinical situation is a combination of HTN and broncho-obstructive disease (asthma, COPD, chronic dust bronchitis, chronic toxic bronchitis etc.). In this clinical situation calcium antagonists are certainly preferable. The patients with bronchial obstruction disease β- adrenergic blockers are contraindicated because of their ability to induce bronchoconstriction, bronchospasm. ACE inhibitors may become a cause of increasing cough in these patients (cough itself is the one of the most common side effects with ACE inhibitors). This impairs a portability of antihypertensive therapy and can be reason of non-compliance medical recommendation. Using amlodipine for patients with bronchial obstruction syndrome effectively reduces blood pressure and also induces dilatation of vessel of pulmonary circulation reducing the severity of pulmonary hypertension. Amlodipine has mild bronchodilatory effect (due to a direct effect on bronchial smooth muscle) which leads to the normalization of breathing in these patients [14].

Antihypertensive therapy prevents the development and progression of dementia in the patients aged 60. The dementia limits their ability to self-service and increasing medical expenses and the costs of caring for elderly patients [45].

The most common form of hypertension of the elderly is isolated systolic hypertension. High efficiency of dihydropyridine calcium antagonists in the therapy of elderly is proved. It reduces hypertrophy and improving diastolic function of left ventricle [46]. It is also important that the hypotensive effect was not accompanied by reducing blood flow to target organs (heart, brain, kidneys) of elderly patients who treated with amlodipine. The data analysis of day monitoring of BP was shown a mild antihypertensive effect of amlodipine with enough duration for overlap. Analyzing the data of daily monitoring of blood pressure of these patients was shown a mild antihypertensive effect of amlodipine with enough duration for overlap the possible variations in blood pressure in the early morning hours. Amlodipine simplifies treatment of elderly patients minimizing the number of using drugs and the frequency of their taking [27].

It is important to assess the body's response to the drug’s action because treatment failure can depend on incorrectly chosen drug and from errors in the dosage.

Only the knowledge of the pharmacodynamics of different groups of drugs and peculiarities of the HTN-pathogenesis of this patient allows to choose drugs and optimize drug therapy rationally by an effective and harmless way.

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