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MODERN SOLUTIONS FOR RATIONAL TREATMENT OF HYPERTENSION
¹Turayev Hikmatillo Negmatovich
²Urinov Tohir Ramizjon oʻgʻli
³Xudoyberdiyev Ilhom Iskandarovich
¹Assistant Professor, Department of Clinical Pharmacology, Samarkand State Medical
University
²'³Students of Samarkand State Medical University
https://doi.org/10.5281/zenodo.14787219
Abstract.
An important task of a modern cardiologist and therapist is to ensure effective
and safe pharmacotherapy of cardiovascular diseases, adhering to modern standards and
recommendations, as well as taking into account the individual characteristics of the patient and
an individualized approach. The presence of several diseases in a patient, the complexity of their
pathogenesis, as well as the insufficient effectiveness and safety of monotherapy force the doctor
to use drug combinations (DR). At the same time, when implementing combination
pharmacotherapy, its effectiveness and safety depend on the possibility of drug interactions.
Keywords:
Pharmacotherapy, LIFE, VALUE, MARVAL, PRIME, IDNT, DETAIL.
INTRODUCTION
According to epidemiological studies, the prevalence of arterial hypertension (AH) among
the adult population in developed countries ranges from 20 to 40% and increases with age [1].
High blood pressure occurs in more than 50% of men and women over 60 years of age [2]. The
urgency of the problem is supported by the intensification of urbanization processes in society, the
emergence of risk factors (RF) such as stress, physical inactivity, obesity, bad habits and poor
ecology. High blood pressure is one of the main risk factors for the development of stroke,
cardiovascular diseases (CHD) and other cardiovascular diseases of atherosclerotic origin, which
are associated with more than 50% of all deaths.
Clinical practice and the results of numerous multicenter studies [4-6] have shown that the
use of monotherapy in the treatment of hypertension rarely leads to the target level of blood
pressure, increases the risk of adverse events and reduces patient compliance with treatment. The
use of drugs in a rational combination regimen requires compliance with a number of mandatory
conditions: safety and efficacy of the components; the contribution of each component to the
expected result; different but complementary mechanisms of action of the components; the best
result compared with each of the components; the balance of the components in terms of
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bioavailability and duration of action; strengthening of organoprotective properties; the effect on
the universal (most common) mechanisms of blood pressure increase; a decrease in the number of
adverse events and improved tolerability [7-9].
According to current national guidelines [10], the European Society of Hypertension (ESH)
and the European Society of Cardiology (ESC) [11], the treatment tactics for essential
hypertension depend on the level of blood pressure and the level of risk. cardiovascular
complications. The main goal of treatment is to minimize the risk of cardiovascular complications
(CVC) and mortality from them. The main goals are to prevent complications, correct all
modifiable risk factors (smoking, dyslipidemia, hyperglycemia, obesity) in the absence or minimal
incidence of adverse reactions (ADRs), prevent, normalize blood pressure levels in order to slow
down the rate. development and/or reduce organ damage, as well as treat associated and
concomitant diseases - cardiovascular diseases, diabetes mellitus (DM), etc. [10, 11].
In the treatment of patients with hypertension, blood pressure should be below 140/90 mm
Hg. st., which is its target level. If the prescribed therapy is well tolerated, it is recommended to
lower blood pressure to lower values. In patients with high and very high risk of CVD, blood
pressure should be reduced to 140/90 mm Hg. Art. and less than 4 weeks. Subsequently, provided
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that it is well tolerated, it is recommended to reduce blood pressure to 130/80 mm Hg. Art. and
less. In patients with coronary artery disease, blood pressure should be reduced to a target value
of 130/85 mm Hg. Art. In patients with diabetes and / or kidney disease, the target blood pressure
should be below 130/85 mm Hg. Art. [10].
Of course, the treatment of hypertension should begin with lifestyle changes: reducing
excess div weight, limiting salt and alcohol consumption, increasing physical activity, etc.
Limiting salt intake is a fairly effective way to lower blood pressure. It is noted that limiting salt
intake enhances the antihypertensive effect of many antihypertensive drugs, including AT1-
angiotensin receptor blockers and β-blockers.
One of the most important conditions for ensuring adequate blood pressure control and
increasing patient adherence to treatment is the optimal choice of antihypertensive agent as part of
mono or combination pharmacotherapy.
Five main classes of antihypertensive drugs are currently recommended for the treatment
of hypertension [10]:
1. angiotensin-converting enzyme inhibitors (ACE inhibitors) (captopril, enalapril,
perindopril, lisinopril, fosinopril, quinapril, trandolapril, etc.);
2. AT1 receptor blockers (ARBs) (valsartan, losartan, telmisartan, candesartan, irbesartan,
etc.);
3. calcium channel blockers (CCB) (nifedipine, amlodipine, etc.);
4. beta-blockers (BB) (carvedilol, bisoprolol, nebivolol, metoprolol tartrate, metoprolol
succinate, atenolol, etc.);
5. thiazide and thiazide-like diuretics (hydrochlorothiazide (HCTZ), indapamide).
Alpha-blockers (prazosin, doxazosin), imidazoline receptor agonists (moxonidine), and
direct renin inhibitors (aliskiren) can be used as additional classes of antihypertensive drugs for
combination therapy.
RESEARCH METHODS AND APPROACHES
According to current national recommendations [10], the choice of an antihypertensive
drug should depend on its properties of action and its belonging to a particular class, since currently
the results of clinical trials are conducted according to evidence-based rules. medicine has made it
possible to establish cases for choosing a preferential class of drugs. When choosing an
antihypertensive drug, it is necessary, first of all, to assess the effectiveness of the drug in a
particular clinical situation, the likelihood of developing side effects and its benefits.
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The choice of drug is influenced by many factors, the most important of which are:
a.
the presence of RF in the patient;
b.
target organ damage;
c.
concomitant clinical conditions, kidney damage, MS, diabetes;
d.
concomitant diseases that require the prescription or restriction of the use of various
classes of antihypertensive drugs;
e.
the patient's previous individual reactions to different classes of drugs;
f.
the possibility of interactions with medications prescribed to the patient for other
reasons;
g.
socioeconomic factors, including treatment costs.
Treatment should be initiated with a single drug at the lowest daily dose (this
recommendation does not apply to patients with severe hypertension or those who have failed
previous therapy). New drugs should be started at low doses, with each subsequent step of
treatment aiming to reduce blood pressure by 10–15% [10]. If blood pressure is not reduced to the
desired level, further treatment should be carried out by gradually increasing the dose or adding
new drugs. Ineffective drugs (those that do not reduce blood pressure by 10–15 mm Hg) and drugs
that have adverse drug reactions should be discontinued [12].
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There is no single recommendation for which specific medications to start treatment with.
The choice of medications depends on age, gender, and the presence of comorbidities.
RESEARCH RESULTS
Currently, drugs that modify the activity of the RAAS are used in the treatment of most
patients with hypertension. These are ACE inhibitors, beta-blockers and angiotensin II receptor
blockers (ARBs). ARBs are one of the modern and most dynamically developing classes of
antihypertensive drugs. ARBs inhibit the action of angiotensin II through AT1 receptors. It has
been established that hypersecretion of angiotensin II leads not only to the development of
hypertension, but also to damage to target organs, which is one of the main factors in the
development of hypertension and its complications, namely, heart and vascular remodeling. It is
no coincidence that AT1-angiotensin receptor blockers are classified as primary antihypertensive
agents. Numerous controlled studies, such as LIFE, VALUE, MARVAL, PRIME, IDNT, DETAIL
[13], have shown that AT1-angiotensin receptor blockers are effective and safe antihypertensive
drugs. AT1-angiotensin receptor blockers have been shown to be particularly effective in
preventing the development of stroke. In patients with hypertension, AT1 blockers can be used
instead of or in combination with diuretics or calcium antagonists to prevent stroke. ARBs, like
ACE inhibitors, are able to prevent the development of type 2 diabetes, reducing the risk of its
occurrence by 20-25% [14]. Therefore, it can be assumed that AT1-angiotensin receptor blockers
should be used primarily for the treatment of hypertension in patients with a high risk of
developing stroke or diabetes. Excellent tolerability is an undoubted advantage of AT1 blockers
in long-term antihypertensive therapy. The use of AT1-angiotensin receptor blockers improves
patient compliance with long-term therapy, since ARBs are less likely to be discontinued due to
the development of side effects than other antihypertensive drugs. Unlike thiazide diuretics, beta-
blockers, and ACE inhibitors, the antihypertensive efficacy of AT1-angiotensin receptor blockers
does not depend on the age, gender, or race of patients [15].
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The renin-angiotensin-aldosterone system (RAAS) plays a central role both in the
development of hypertension and in the implementation of pathophysiological processes leading
to serious cardiovascular complications, such as stroke, myocardial infarction, vascular
remodeling, nephropathy, congestive heart failure. development of atherosclerotic processes. ACE
inhibitors are the first group of drugs that directly affect the RAAS and are widely used in clinical
practice. The long duration of their use, numerous clinical studies and extensive experience of
practicing physicians in their use have led to the fact that these drugs are currently used more often
in Russia than other antihypertensive agents. In moderate doses, ACE inhibitors reduce SBP to a
slightly lesser extent than diuretics and calcium antagonists. The selection of specific ACE
inhibitors for long-term treatment of patients with hypertension is of great clinical importance,
since these drugs are mainly prescribed for life. Of the ACE inhibitors with proven efficacy,
perindopril and ramipril appear to be the most promising [16, 17].
Clinical practice and the results of numerous multicenter studies have shown that the use
of monotherapy in the treatment of hypertension rarely leads to the target level of blood pressure,
increases the risk of developing adverse events and reduces the patient's compliance with
treatment. The most important conditions for increasing patient adherence to treatment are their
understanding of their goals, objectives, modern methods and principles of treatment, as well as
the correct choice of antihypertensive treatment by the doctor. The tactics of using combination
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therapy with the selection of drugs with different mechanisms of action at the beginning of
treatment significantly increases the chances of successful control of blood pressure. Low-dose
combination rational antihypertensive therapy can be the first choice, especially in patients with a
high risk of developing cardiovascular complications, its advantages are: a simple and convenient
regimen for the patient; ease of titration; ease of prescribing the drug; increased patient
compliance; reduction of adverse effects by reducing the doses of the components used; reduction
of the risk of using irrational combinations; confidence in an optimal and safe dosing regimen; and
reduced cost [17–21].
It should be noted that recent American and European recommendations emphasize the
need to avoid the tactic of frequent changes in drugs and their doses in patients, if possible. It has
now become clear that the effectiveness of monotherapy with drugs of all major groups is low and
comparable: after a year of treatment, even with almost ideal adherence to treatment, the effect of
monotherapy is hardly more than 30% to 50% compared to placebo. . The tactic of “sequential
monotherapy” may actually require 4-5 changes of therapy, each of which may be complicated by
the development of side effects. This tactic is very time-consuming, deprives the doctor and the
patient of confidence in success, which ultimately has a negative psychological effect on the
patient and leads to low adherence to hypertension treatment. One of the common reasons for
unsatisfactory blood pressure control is the lack of a clear assessment of the role of combination
therapy [17-21].
Combination antihypertensive therapy has many advantages:
enhancing the antihypertensive effect due to the multidirectional effect of drugs on the
pathogenetic mechanisms of hypertension development, which increases the number of patients
with a stable decrease in blood pressure;
reduced side effects, both due to lower doses of combined antihypertensive drugs and due
to mutual neutralization of these effects;
to ensure the most effective protection of organs and reduce the risk and number of
cardiovascular complications.
Numerous randomized clinical trials and real-world clinical experience have demonstrated
the benefits of combination therapy, which can be summarized as follows [22, 23]:
The simultaneous use of drugs from two different pharmacological groups reduces blood
pressure more actively due to their effects on different pathogenetic mechanisms of hypertension;
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The combined use of low doses of two drugs that affect different regulatory systems allows
for better blood pressure control, taking into account the heterogeneity of the response of
hypertensive patients to antihypertensive drugs;
The use of a second drug may weaken or counteract the activation of mechanisms to
counteract the decrease in blood pressure that occurs with the use of one drug;
A sustained reduction in blood pressure can be achieved with lower doses of two drugs
(compared to monotherapy);
smaller doses help avoid dose-dependent side effects, the likelihood of which is higher with
a higher dose of a particular drug (when monotherapy is administered);
The use of two drugs prevents damage to target organs (heart, kidneys) due to hypertension;
the use of a second drug can to some extent reduce (and even completely eliminate) the
undesirable effects caused by the first (albeit very effective) drug;
The appointment of a second drug (in particular, a diuretic) allows for a rapid
antihypertensive effect of the drug combination, since most antihypertensive drugs (ACE
inhibitors, CCBs, ARBs, and partly beta-blockers) show their full effect only in the 2nd -3rd week.
of admission (and even later).
The combination of two antihypertensive drugs is divided into rational (effective), possible
and irrational. All the advantages of combination therapy are inherent only to a rational
combination of antihypertensive drugs [24].
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These include the following [10]:
Глава 1
ACE inhibitor + diuretic;
Глава 2
ARB + diuretic;
Глава 3
ACE inhibitor + dihydropyridine calcium channel blocker;
Глава 4
ARB + dihydropyridine calcium channel blocker;
Глава 5
dihydropyridine BCCA + beta-blocker;
Глава 6
dihydropyridine calcium channel blocker + diuretic;
Глава 7
BAB + diuretic;
Глава 8
BAB + α-blocker.
The issue of combining three or more drugs has not yet been sufficiently studied, as there
are no results of randomized controlled clinical trials investigating triple combinations of
antihypertensive drugs. Therefore, the antihypertensive drugs in these combinations are
theoretically combined. However, in many patients, including those with refractory hypertension,
the target blood pressure level can only be achieved with three or more component
antihypertensive therapy [25]. Recommended combinations of three antihypertensive drugs
include:
a.
ACE inhibitor + dihydropyridine calcium channel blocker + beta-blocker;
b.
ARB + dihydropyridine BCCB + beta-blocker;
c.
ACE inhibitor + calcium channel blocker + diuretic;
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447
d.
ARB + CCCB + diuretic;
e.
ACE inhibitor + diuretic + beta-blocker;
f.
ARB + diuretic + beta-blocker;
g.
dihydropyridine calcium channel blocker + diuretic + beta-blocker.
CONCLUSION
Since combination therapy has become one of the main directions in the treatment of
patients with hypertension, a fixed combination of antihypertensive drugs, consisting of two drugs
in one tablet, has become widespread, which improves the patient's psychological response to
treatment and allows you to reduce the risk of complications and side effects. The optimal
combination of components implies the absence of undesirable hypotension, which leads to an
increased cardiovascular risk, especially in elderly patients. Rational selection of components
according to the pharmacokinetic profile creates the necessary conditions for a single use of drugs
that require two or three times the use of monotherapy.
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