For quotation: Sidorenko B.A., Preobrazhensky D.V. PHARMACOTHERAPY OF HYPERTENSION // Breast cancer. 1998. No. 8. S. 1

The article is an introduction to a series of publications devoted to the pharmacotherapy of hypertension.

The article discusses general issues related to the classification of arterial hypertension, target organ damage, and discusses the goals and principles of therapy.

The paper is an introduction to a series of publications on the pharmacotherapy for hypertensive disease. It considers the general problems of classification of arterial hypertension, lesions of target organs, discusses the goals and principles of therapy.

B.A. Sidorenko, D.V. Preobrazhensky Medical Center of the Administration of the President of the Russian Federation, Moscow
B.A.Sidorenko, D.V.Preobrazhensky Medical Center, Administration of Affairs of the President of the Russian Federation, Moscow

Part I
Classification, target organs, goals and principles of treatment

Hypertension is the most common disease of the cardiovascular system in many countries of the world. Hypertension accounts for at least 90 - 95% of all cases of arterial hypertension. Therefore, the prevalence of hypertension in a particular population can be judged by the frequency of detection of high blood pressure - BP (i.e. systolic BP - at least 140 mm Hg and/or diastolic BP - at least 90 mm Hg. ) with repeated measurements. In the USA, for example, according to a large-scale epidemiological survey conducted in 1988 - 1991, elevated blood pressure (? 140/90 mm Hg) occurred in approximately 25% of the adult population. The prevalence of hypertension was only 4% among people 18 to 29 years of age, but it increased sharply after age 50. Among persons 50 - 59 years of age, the prevalence of arterial hypertension (i.e., essentially hypertension) was 44%, among persons 60 - 69 years of age - 54%, and among persons 70 years of age and older - 65%.
In the late 1980s, the Joint National Committee on to identify, evaluate and treat high blood pressure, the United States has tightened the criteria for diagnosing arterial hypertension. In his Fourth Report (1988), he recommended classifying as arterial hypertension those cases when the level of systolic blood pressure, according to repeated measurements, is at least 140 mm Hg. Art. The Fifth Report of the United States Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure (1993) recommended taking into account the average values ​​of not only diastolic but also systolic blood pressure when diagnosing arterial hypertension. For the diagnosis of arterial hypertension, it is considered sufficient that at least two blood pressure measurements during at least two visits to the doctor, the average values ​​of systolic blood pressure were at least 140 mmHg. Art. and/or diastolic blood pressure - at least 90 mm Hg. Art.
In the recommendations of experts from the World Health Organization (WHO) and the International Society of Hypertension (1993 and 1996), it is recommended that systolic blood pressure equal to 140 mm Hg be considered criteria for arterial hypertension. Art. and above and (or) diastolic blood pressure - 90 mm Hg. Art. and higher .
Table 1. Classification of arterial hypertension
(WHO and International Society of Hypertension expert recommendations 1993 and 1996)

Stages of arterial hypertension
		Symptoms
I		Absence of objective signs of target organ damage
II		The presence of at least one of the following signs of target organ damage: . left ventricular hypertrophy (according to chest x-ray, electrocardiography or echocardiography) . generalized or focal narrowing of the retinal arteries . microalbuminuria, proteinuria and/or a slight increase in plasma creatinine (1.2 - 2.0 mg/dl) . atherosclerotic lesions of the aorta, carotid, coronary, iliac or femoral arteries (according to ultrasound or angiographic examination)
III		Presence of symptoms and signs of target organ damage Heart: angina, myocardial infarction, heart failure Brain: stroke, transient cerebrovascular accidents, hypertensive encephalopathy, vascular dementia Retina: hemorrhages and exudates with or without papilledema Kidneys: plasma creatinine levels above 2.0 mg/dL, renal failure Vessels: dissecting aortic aneurysm, symptoms of occlusive arterial disease
Forms of arterial hypertension
Form	Systolic blood pressure, mmHg Art.		Diastolic blood pressure, mmHg Art.
Soft
Moderate
Heavy

Blood pressure level is below 140/90 mm Hg. Art. conventionally considered to be “normal”, however, according to epidemiological studies, the risk of developing cardiovascular complications appears to be increased in individuals with blood pressure in the range of 130 - 139/85 - 89 mm Hg. Art. compared to individuals with lower blood pressure levels. Systolic blood pressure levels are from 130 to 139 mmHg. Art. and diastolic blood pressure - from 85 to 89 mm Hg. Art. US experts from the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure define it as “high normal” blood pressure. In their opinion, persons with elevated normal blood pressure should be examined at least once a year and, if possible, change their lifestyle to reduce blood pressure to lower values.
In the general population, the risk of developing cardiovascular disease is lowest in adults with mean systolic blood pressure less than 120 mmHg. Art. and diastolic blood pressure less than 80 mm Hg. Art. Therefore, from the point of view of the risk of developing cardiovascular diseases, systolic blood pressure below 120 mm Hg should be considered optimal. Art. and diastolic blood pressure below 80 mm Hg. Art.
Table 2. Recommendations for lifestyle changes in the treatment of patients with hypertension

Measures whose benefits have been proven 1. Reduction of excess body weight, especially in persons with abdominal obesity (optimal body mass index? 26). 2. Limit sodium intake from food to 2 g/day (88 mmol/day), i.e., up to 5 g of table salt per day. 3. Limit alcohol consumption to 168 ml of 100% alcohol per week for men and to 112 ml per week for women. 4. Regular isotonic physical activity (physical exercise in the open air of moderate intensity and duration of at least 30-60 minutes 3-4 times a week). 5. Increasing potassium intake with food. Measures whose benefit has not been proven 6. Adding calcium to food. 7. Adding magnesium to food. 8. Adding fish oils (for example, eikonol). 9. Relaxation exercises. 10. Limiting caffeine consumption (from tea, coffee, etc.).

There is no generally accepted classification of hypertension. The most widespread classification of arterial hypertension was proposed by WHO experts in 1962. In 1978, 1993 and 1996. Some changes have been made to this classification. The latest edition of the classification of arterial hypertension, recommended by WHO experts together with the International Society of Hypertension, provides for the identification of three stages of the disease and three degrees of its severity (or forms). In table 1 The criteria for diagnosing various stages of arterial hypertension (i.e., essentially hypertension) and blood pressure levels characteristic of mild (mild), moderate and severe forms of the disease are given.
It should be remembered that the criteria for diagnosing mild, moderate and severe forms of arterial hypertension in the classification of experts from WHO and the International Society of Hypertension differ from those in the classification of the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure in the United States. For example, in the Fifth Report, mild hypertension is usually classified as cases of systolic blood pressure from 140 to 159 mm Hg. Art. and (or) diastolic blood pressure from 90 to 99 mm Hg. Art. American experts classify moderate hypertension as systolic blood pressure in the range of 160 - 179 mm Hg. Art. and (or) diastolic blood pressure in the range of 100 - 109 mm Hg. Art. . Apparently to avoid confusion in terminology, the Sixth Report of the US Joint National Committee (1997) does not use terms such as mild, moderate or severe hypertension to describe the severity of hypertension. Instead, the terms 1st, 2nd and 3rd stages of arterial hypertension are used to characterize the degree of increase in blood pressure. The use of the term “stage” to characterize the degree of increase in blood pressure in the classification of the US Joint National Committee cannot be considered successful, given that since 1962, in the classification of WHO experts, this term has been used to describe the degree of involvement of target organs in the pathological process in patients with arterial hypertension .
Thus, there are currently at least two classifications of arterial hypertension developed by reputable researchers and clinicians - the classification of WHO and International Society of Hypertension experts (1996) and the classification of the US Joint National Committee (1997). The use of the WHO expert classification, in our opinion, is preferable, since it allows us to unify approaches to the diagnosis and treatment of hypertension in different countries of the world.
Hypertension is not dangerous in itself. After all, elevated blood pressure does not create an immediate threat to the life and health of patients. But arterial hypertension is one of the main risk factors for the development of cardiovascular diseases of atherosclerotic origin, which are associated with about 1/2 of all deaths in developed countries of the world. Consequently, complications of hypertension pose a danger.
The main vascular complications of hypertension can be conditionally divided into two groups: 1st - hypertensive, i.e. associated directly with overload of the cardiovascular system with pressure and 2nd - atherosclerotic, i.e. associated with the accelerated development of atherosclerotic lesions of the aorta and its large branches in conditions of high blood pressure.
Hypertensive complications include: a rapidly progressive or malignant phase in the development of arterial hypertension, hemorrhagic stroke, congestive heart failure, nephrosclerosis and dissecting aortic aneurysm. Examples of atherosclerotic complications of hypertension are: coronary heart disease (CHD), sudden death, other arrhythmias, atherothrombotic stroke and obliterating atherosclerosis of the lower extremity vessels.
Of the organ lesions that precede the development of congestive heart failure in patients with hypertension, left ventricular hypertrophy is the most well studied.
The frequency of detection of left ventricular hypertrophy among patients with hypertension varies widely, depending on the severity and duration of hypertension and especially on the instrumental methods used for its diagnosis. The most widely used method for diagnosing left ventricular hypertrophy is electrocardiography. Electrocardiographic signs of left ventricular hypertrophy are found in approximately 3 - 8% of patients with mild hypertension. The most sensitive electrocardiographic indicators of left ventricular hypertrophy are the Sokolov-Lyon sign (Sv1 + Rv5-v6) and the Cornell sign (Ravl + Sv3).
Echocardiography is approximately 5 to 10 times more sensitive than electrocardiography, a method for diagnosing left ventricular hypertrophy. Echocardiography reveals myocardial hypertrophy in 20–60% of patients with hypertension, more often in men than in women.
Detection of left ventricular hypertrophy using electro- or echocardiography is important in hypertension. Firstly, the detection of left ventricular hypertrophy in an asymptomatic patient with hypertension serves as the basis for diagnosing stage II of the disease (according to the classification WHO experts). Secondly, in patients with hypertension with electrocardiographic signs of left ventricular hypertrophy, the risk of developing cardiovascular complications is 3 to 6 times higher than in patients of the same age and sex, but without signs of hypertrophy. According to some observations, in patients with left ventricular hypertrophy, according to echocardiography, mortality from cardiovascular causes is 30 times higher than in patients with normal left ventricular myocardial mass. Thirdly, and most importantly, some antihypertensive drugs, when administered for a long time, can reverse the development of left ventricular hypertrophy and thereby improve the long-term prognosis in patients with hypertension.
Thus, the approach to a hypertensive patient with electro- or echocardiographic signs of left ventricular hypertrophy is significantly different from that to patients without hypertrophy. In patients with left ventricular hypertrophy, blood pressure levels need to be closely monitored, and some antihypertensive drugs appear to be preferable for treatment, while others should not be used. In all cases, it is important to ensure that antihypertensive therapy is administered to reverse the development of left ventricular hypertrophy.
The kidneys are the second most studied target organ in patients with hypertension. In typical cases, kidney damage in hypertensive disease, which is based on angionephrosclerosis, is characterized by a decrease in glomerular filtration rate. According to some data, hypertension is the main or one of the main causes of end-stage renal failure in 10 - 30% of patients on program hemodialysis. In the United States over the past two decades, thanks to the widespread use of effective antihypertensive drugs, mortality from cerebral stroke has been reduced by 60% and mortality from coronary artery disease by 53%. At the same time, the number of cases of end-stage renal failure has increased more than 2.5 times, the two main causes of which are considered to be diabetes mellitus and arterial hypertension.
A number of long-term studies have shown that diuretics, b-blockers and direct vasodilators, while effectively lowering blood pressure, do not prevent the progression of renal dysfunction in patients with hypertension. It is believed that not all antihypertensive drugs are equally useful in the treatment of hypertensive patients with kidney damage. According to some observations, angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists and the diuretic with vasodilating properties indapamide are more effective than other antihypertensive drugs in slowing down the rate of decline in glomerular filtration rate in patients with hypertension.
Difficulties in treating hypertensive kidney in the later stages of its development prompted the search for methods for early diagnosis of kidney damage in patients with hypertension. Currently, two indicators are known that indicate an increased risk of developing hypertensive angio-onephrosclerosis - glomerular hyperfiltration and microalbuminuria.
According to the observations of R. Schmieder et al. , in hypertensive patients with a high glomerular filtration rate (more than 130 ml/min), subsequent serum creatinine concentrations increase faster than in patients with a normal glomerular filtration rate.
Microalbuminuria is another prognostically significant indicator for hypertension. Microalbuminuria refers to urinary excretion of albumin ranging from 30 to 300 mg per 24 hours or from 20 to 200 mcg per 1 minute. Albumin in such quantities is not detectable in urine using conventional methods, such as precipitation with sulfasalicylic acid. To determine the content of albumin in urine, radioimmune, immunoenzyme and immunonephelametric methods are used.
Antihypertensive drugs have different effects on microalbuminuria in patients with essential hypertension. ACE inhibitors, for example, reduce microalbuminuria, while diuretics do not have a significant effect on it. Considering that microalbuminuria is an unfavorable prognostic indicator in patients with hypertension, when choosing an antihypertensive drug, its effect on urinary albumin excretion should be taken into account whenever possible.
In the vast majority of cases, hypertension and other forms of arterial hypertension are asymptomatic, and therefore the elimination of symptoms cannot be the goal of antihypertensive therapy. Moreover, when choosing antihypertensive drugs for long-term therapy, if possible, preference should be given to those that do not cause a significant change in the patient’s quality of life and that can be taken once a day. Otherwise, it is very likely that an asymptomatic hypertensive patient will not take a drug that makes him feel worse. When prescribing one or another antihypertensive drug, one should not forget about the degree of its availability (primarily price) to a given patient.
Long-term therapy of patients with hypertension has three main goals:
1) reduce blood pressure below 140/90 mmHg. Art., and in patients under 60 years of age with mild hypertension - up to 120 - 130/80 mm Hg. Art.;
2) prevent the occurrence of target organ damage (primarily the heart and kidneys) or promote their reverse development;
3) reduce the increased risk of developing cardiovascular complications and, if possible, increase the patient’s life expectancy.
To achieve all three of these goals, long-term administration of effective antihypertensive drugs as monotherapy or in combination with each other is necessary. Drug therapy is started in cases where recommendations to the patient to change his lifestyle are not effective enough (Table 2) In patients In case of hypertension in combination with coronary artery disease, diabetes mellitus, atherogenic dyslipidemia, effective drugs should be selected for the treatment of concomitant diseases (nitrovasodilators, hypoglycemic agents, lipid-lowering drugs, acetylsalicylic acid, etc.). It is important to take into account both the effects of antihypertensive drugs on the course of concomitant diseases, and the effects associated with the interaction of antihypertensive drugs and drugs used in the treatment of concomitant diseases.
Currently, several groups of drugs are used to treat patients with hypertension. Antihypertensive drugs suitable for both long-term therapy and combination therapy are:
1) thiazide and thiazide-like diuretics;
2) b - adrenergic blockers;
3) ACE inhibitors;
4) calcium antagonists;
5) a 1 - adrenergic blockers;
6) a-b - adrenergic blockers;
7) AT blockers 1 - angiotensin receptors;
8) central agonists a 2 -adrenergic receptors;
9) agonists I 1 -imidazoline receptors. Loop diuretics are rarely used to treat hypertension, mainly in patients with impaired renal function. Potassium-sparing diuretics, direct vasodilators and sympatholytics of central and peripheral action (reserpine, guanethidine) have been used in recent years only in combination with other antihypertensive drugs.
Drugs occupy a certain place in the treatment of hypertension. drugs that are not formally classified as antihypertensive drugs (for example, nitrates) or have a complex or unknown mechanism of antihypertensive action (for example, magnesium sulfate, dibazole).
The authors intend to consider the clinical pharmacology of the main groups of antihypertensive drugs and their place in the treatment of various forms and stages of hypertension in subsequent articles devoted to the pharmacotherapy of hypertension.

Literature:

1. Memoandum from a WHO/JSH meeting - 1993 Gnidelines for management of mild hypertension. Clin Exp Hypertens 1993;15:1363-95.
2. WHO Expert Committee on Hypertension Control - Hypertension control. WHO techn report series No. 862. Geneva 1996. (Russian translation: Combating arterial hypertension. Report of the WHO Expert Committee. - M. - 1997)
3. The fifth report of the joint National Committee on detection, evaluation, and treatment of high blood pressure. Bethesda, 1993.
4. The sixth report of the Joint National Committee on defection, evaluation,and treatment of high blood pressure. Bethesda, 1997.
5. Kaplan NM. Clinical hypertension - 5th ed. Baltimore, 1990.
6. Koren MJ, Deverenx RB, Casale PN, et al. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991;114:345-52.
7. Schmieder RE, Veelken R, Jatjra CD, et al. Predictors for hypertensive nephropathy: results of a 6-year follow-up study in essential hypertension. J Hypertension 1994;13:357-65.

Yu.A. Bunin
Russian Medical Academy of Postgraduate Education, Moscow

Classification, main reasons for development
and general principles of treatment of hypertensive crises
Despite intensive study of arterial hypertension (AH) and the presence of a number of national and international recommendations for its treatment, it is often difficult for practicing physicians of various specialties to decide when and how to begin treatment of patients with a significant increase in blood pressure, because there is no consensus on the issue about what kind of increase in blood pressure is a condition requiring emergency medical care. In addition, in Russia there is still no number of effective antihypertensive drugs for parenteral and oral use.
In international clinical practice, situations associated with severe hypertension (blood pressure from 180/110 mm Hg and above) are divided into three groups:
1) emergency conditions (hypertensive emergencies);
2) hypertensive urgencies;
3) stable, asymptomatic (little symptomatic) uncontrolled severe hypertension.
Emergency and emergency conditions are usually the result of a hypertensive crisis.
Emergency conditions in most cases include:
rapidly progressing or malignant hypertension;
diseases of the central nervous system:
hypertensive encephalopathy;
hemorrhagic stroke;
subarachnoid hemorrhage;
atherothrombotic cerebral infarction with very high hypertension;
diseases of the cardiovascular system:
acute aortic dissection;
acute left ventricular failure;
acute myocardial infarction or unstable angina;
kidney diseases:
acute glomerulonephritis;
renal crises due to collagenosis;
severe arterial hypertension after kidney transplantation;
increased concentration of catecholamines:
hypertensive crises with pheochromocytoma;
hypertensive crises (“rebound”) after sudden cessation of antihypertensive drugs;
use of sympathomimetic drugs;
food or drug interactions with monoamine oxidase inhibitors*;
neurological disorders (autonomic dysfunction) in Guillain-Barre syndrome or after spinal cord injury;
preeclampsia/eclampsia;
surgical interventions:
severe arterial hypertension in patients requiring urgent surgery;
postoperative arterial hypertension;
postoperative bleeding in the area of ​​the vascular suture;
condition after coronary bypass surgery;
severe body burns;
severe nosebleeds.
A sudden, usually significant, increase in blood pressure (often systolic blood pressure (SBP) more than 220-230 mm Hg and/or diastolic blood pressure (DBP) more than 120-130 mm Hg) is accompanied by acute damage to target organs: cardiac -vascular system, brain, kidneys, eyes. This complicated hypertensive crisis is quite rare and requires a rapid but controlled reduction in blood pressure to a safe level (not necessarily to normal values), which is usually achieved by intravenous administration of drugs. Patients should be immediately hospitalized in specialized emergency departments that have trained personnel and modern equipment for dosed intravenous administration of drugs and dynamic, including invasive, monitoring of hemodynamics and the condition of target organs. The primary goal of treatment for most of them is to reduce mean blood pressure (MAP) by no more than 25% over a period of several minutes to one to two hours, depending on the patient's condition. You can then continue to lower your blood pressure to approximately 160/100 mmHg. Art. over the next two to six hours. An excessive drop in blood pressure should be avoided, as this can cause ischemia or even infarction of the target organ.
The term “urgent condition” (hypertensive urgency) is used for severe hypertension (according to some authors, not always a crisis course), which does not lead to rapid damage to target organs. If a hypertensive crisis is diagnosed in these patients, then it should be classified as an “uncomplicated” form. From a practical point of view, this means that lowering blood pressure can not be carried out as quickly as in a hypertensive emergency, but over several hours or one or two days and often using oral medications. It is likely that sometimes, when the risk of complications is high, treatment of emergency conditions should begin in the hospital (emergency department) and then continue on an outpatient basis.
Shayne P.H. and Pitts S.R. propose to include in the group of emergency conditions patients with a significant increase in blood pressure (diastolic blood pressure (DBP) more than 115-120 mm Hg) and a high risk of rapid progression of target organ damage, but without the development of acute damage. In their opinion, this group should primarily include patients who already have a history of target organ disease: incoming cerebrovascular accident or stroke, acute coronary syndrome, coronary artery disease, congestive heart failure, renal dysfunction, etc. These authors also classify high blood pressure in pregnant women, not accompanied by preeclampsia, as hypertensive urgency. We submit the opinion of Shayne P.H. and Pitts S.R. quite specific and worthy of attention from the point of view of its practical use.
Thus, the first two groups of conditions (hypertensive emergencies and hypertensive urgencies) require rapid intervention, while severe but stable and asymptomatic arterial hypertension requires timely (according to some authors, within a week) routine examination and selection of effective antihypertensive therapy.
Hypertensive crisis, considered as a condition characterized by a sudden, usually significant rise in blood pressure, which is accompanied by damage to vital organs or poses a real threat of damage to them, is the main clinical situation requiring urgent antihypertensive therapy. However, the need for emergency medical care in patients with arterial hypertension arises not only during its crisis, and the blood pressure level is not considered as the main criterion for diagnosing emergency conditions. The main reasons for the development of hypertensive crises are:
sudden increase in blood pressure in patients with chronic arterial hypertension;
sudden withdrawal of certain antihypertensive drugs;
parenchymal kidney diseases (acute glomerulonephritis, collagenosis);
renovascular arterial hypertension (atherosclerosis of the renal arteries, fibromuscular dysplasia, etc.);
pheochromocytoma, renin-secreting tumor, primary hyperaldosteronism (rare);
the use of tricyclic antidepressants (amitriptyline, clomipramine, imipramine, etc.), cocaine, amphetamines, sympathomimetics, cyclosporine, erythropoietins;
consumption of foods containing tyramine while using MAO inhibitors; taking glucocorticoids, non-steroidal anti-inflammatory drugs;
preeclampsia, eclampsia;
traumatic brain injury, ischemic stroke, brain tumor.
Hypertensive crises are more often recorded in elderly patients. Complicated hypertensive crises develop in less than 1-2% of patients. About 500 thousand such cases are registered annually in the USA. In most of them, the cause of hypertensive crises is ineffective treatment of essential hypertension (hypertension). However, according to some data, more than 20% of these patients have symptomatic (secondary) arterial hypertension. Among them, parenchymal kidney diseases, renovascular hypertension (most often (2/3 of all cases) is based on atherosclerosis of the renal arteries) and pheochromocytoma predominate, and primary aldosteronism (Conn's syndrome) is rare. Hypertensive crises may be caused by rapid discontinuation of antihypertensive medications (especially beta-blockers and central a-adrenergic agonists, such as clonidine), use of certain medications, or drug use.
Complaints, anamnesis, physical examination, supported by a number of laboratory and instrumental studies, determine the tactics of managing patients with acute hypertension syndrome (the need for hospitalization, the rate of blood pressure decrease, the choice and method of administration of an antihypertensive drug, etc.). The key to their successful treatment is differentiation between complicated and uncomplicated hypertensive crisis, identifying and, if possible, eliminating the cause of the hypertensive crisis and/or determining adequate treatment for the underlying disease that led to its development.
Physical examination should be aimed directly at looking for signs of target organ damage. Blood pressure should be measured in both arms (a significant difference in it may indicate, in particular, dissection of the aortic aneurysm) while lying and standing (if possible). The cardiovascular examination focuses primarily on identifying symptoms of heart failure (shortness of breath, wheezing in the lungs, galloping rhythm, etc.). A neurological examination determines the presence of disturbances of consciousness, cerebral or focal symptoms. Ophthalmoscopy allows you to detect changes in the fundus (hemorrhage, exudate, swelling of the optic nerve nipple, etc.).
Registration of an ECG, a general blood test, a study of the concentration of creatinine, urea in the blood plasma and a urine test are carried out in all patients with a hypertensive crisis. At the same time, chest radiography, echocardiography, CT, MRI are performed according to indications. In most cases, these studies are carried out simultaneously with the initiation of antihypertensive treatment.

Basic antihypertensive drugs
used to treat hypertensive crises
A fairly large number of drugs (parenteral and oral) (Tables 1 and 2) are used to treat hypertensive crises. The main requirements for them are: rapid onset of action and rapid manifestation of the maximum effect (preference is given to short-acting drugs), the ability to titrate the dose over a wide range, and a low frequency of severe side effects. If the cause of a hypertensive crisis is unknown, then empirical therapy is carried out, and in some cases specific treatment is used (acute coronary syndrome, pheochromocytoma, eclampsia, etc.). In the absence of hypertensive drugs for the treatment of hypertensive crises listed in table. 1, IV forms of other drugs can be used: calcium antagonists (verapamil, diltiazem, etc.), beta-blockers (for example, propranolol: IV bolus 2.5-10 mg over 3-5 minutes; IV infusion 3 mg/h). At the same time, the prescription of diuretics for hypertensive crises should not be routine, but should be carried out only for special indications (for example, pulmonary edema).
Sodium nitroprusside, which is an active arterial and venous nitrovasodilator, remains one of the main drugs for the relief of complicated hypertensive crises. When administered intravenously, it begins to act within a few seconds, and its effect disappears within three to five minutes after stopping the drug, which allows for good control of the decrease in blood pressure and minimizes the risk of hypotension.
The use of nitroglycerin is preferable to sodium nitroprusside in patients with arterial hypertension and coronary artery disease (unstable angina, coronary artery bypass surgery, myocardial infarction) due to the fact that it is known to have, along with antihypertensive, also a pronounced antianginal (anti-ischemic) effect. In patients with coronary artery disease, blood pressure should be carefully monitored because a significant decrease in blood pressure may increase myocardial ischemia. With prolonged continuous infusion (more than 24-48 hours), tolerance to nitroglycerin may develop.
Fenoldopam is a selective agonist of postsynaptic dopaminergic receptors, the use of which does not worsen renal perfusion, despite a decrease in systemic blood pressure. It can be used in most complicated hypertensive crises (a “rival” of sodium nitroprusside) and is an alternative to traditional antihypertensive drugs for the treatment of patients with renal failure.
Drugs that, according to many cardiologists, are an alternative to sodium nitroprusside in the treatment of complicated hypertensive crises (high efficiency and no risk of accumulation of toxic metabolites) include nicardipine (a dihydropyridine calcium antagonist), used as an intravenous infusion, and labetalol (a blocker b-adrenergic and a-adrenergic receptors), administered both IV bolus and IV drip (Table 1).
The use of labetalol leads to a combined blockade of a- and b-adrenergic receptors, a decrease in total peripheral vascular resistance (TPVR), without a negative effect on coronary, cerebral and renal blood flow. Therefore, it is effective and safe in many complicated hypertensive crises, including cases of exacerbation of coronary heart disease (unstable angina, myocardial infarction) and pathology of the central nervous system (hypertensive encephalopathy, acute cerebrovascular accident, etc.).
Similar to the use of sublingual captopril, IV enalaprilat has been used successfully for about 20 years to treat hypertensive crises. A number of studies have noted that its effectiveness (the severity of blood pressure reduction) correlates with the concentration of angiotensin II and renin activity in the blood plasma. Intravenous administration of enalaprilat does not cause serious adverse reactions. However, its use, like other angiotensin-converting enzyme inhibitors, is contraindicated in pregnant women. It should not be used in the acute period of MI.
The pharmacological properties of esmolol make it an “ideal b-blocker” for use in emergency situations because it has a rapid (within 60-120 seconds) and short-lasting (10-20 minutes) action. Esmolol is recommended to reduce high blood pressure in patients with acute myocardial ischemia, dissecting aortic aneurysm and arterial hypertension that occurs during surgery, during recovery from anesthesia and in the postoperative period.
Hydralazine has been used as an antihypertensive drug for over 40 years. The rather long duration (up to 8 hours or more) and the unpredictability of its antihypertensive effect create, according to some authors, significant difficulties in the use of this drug in patients with complicated hypertensive crises, including in the treatment of eclampsia. The use of hydralazine is contraindicated for lowering blood pressure in patients with coronary artery disease and aortic dissection.
Quite narrow indications for the treatment of severe hypertension have been defined for the use of phentolamine and trimethaphan, and diazoxide is falling out of use, although our limited clinical experience indicates its sufficient effectiveness and safety.
For the treatment of uncomplicated hypertensive crises, oral antihypertensive drugs are more often used (Table 2).
Nifedipine is not included in the table. 2, since the use of its usual dosage form (without sustained release), especially sublingual, for the relief of hypertensive crises is not recommended by most clinicians. There is quite convincing data on the possibility of developing severe complications when using nifedipine, which are associated with a rapid and significant decrease in blood pressure, leading to a deterioration in coronary and cerebral blood flow. Thus, it should not be prescribed for the treatment of hypertensive crises or used with great caution orally (5-10 mg). Nifedipine is clearly contraindicated in patients with hypertensive crisis and acute coronary syndrome, stroke, angina pectoris of functional class III-IV.

Features of treatment of certain types
emergency conditions for arterial
hypertension (complicated hypertensive crises)
Brief recommendations for pharmacotherapy of some emergency conditions in arterial hypertension are presented in Table. 3 and in the figure.

Ischemia or myocardial infarction
Since the goal of treatment for these patients is to stop or reduce myocardial ischemia, preference is given to the intravenous administration of nitroglycerin, which, along with a decrease in blood pressure (reduction in peripheral vascular resistance), causes dilatation of the large coronary arteries, reduces venous return to the heart (reduction of preload) and end-diastolic pressure LV. All this helps to improve myocardial perfusion. In patients with exacerbation of coronary artery disease and high arterial hypertension, in the absence of contraindications, it is possible to use labetalol, b-blockers (esmolol, etc.), as well as non-dihydropyridine calcium antagonists (verapamil, diltiazem). Sodium nitroprusside or fenoldopam are recommended only in cases of refractoriness to nitroglycerin, labetalol and b-blockers. It is not advisable to use drugs that cause reflex tachycardia (diazoxide, hydralazine, dihydropyridine calcium antagonists), which can lead to expansion of the zone of myocardial ischemia.

Pulmonary edema
Reduction of high blood pressure in patients with acute LV systolic dysfunction causing pulmonary edema should be carried out with vasodilators that reduce both pre- and afterload (sodium nitroprusside), in combination with loop diuretics. IV administration of nitroglycerin, enalaprilat (contraindicated in MI) and fenoldopam can also be effective.
Drugs that increase myocardial work (diazoxide, hydralazine) or worsen its contractile function (labetalol, b-blockers, calcium antagonists) should not be used in acute systolic heart failure.

Aortic dissection
This is the most dangerous acute disease of the aorta, which poses a significant threat to the patient’s life. In the United States, about 2,000 aortic dissections are reported annually, with a mortality rate of 3-4% of all sudden deaths from cardiovascular disease. The most common risk factor for aortic dissection is hypertension. Both the ascending and descending aorta can be affected.
Intravenous antihypertensive therapy should be started immediately in all patients with suspected aortic dissection (with the exception of patients with hypotension, of course). At the same time, the pain syndrome is relieved by intravenous administration of morphine. As a rule, it is recommended to reduce blood pressure more quickly than in other complicated hypertensive crises. Reducing SBP to 100-120 mmHg. Art. (or blood pressure up to 60-75 mm Hg) is achieved within a few minutes, provided there are no symptoms of organ hypoperfusion. The goal of pharmacotherapy is to reduce blood pressure, myocardial contractility (dp/dt), heart rate and, ultimately, aortic wall tension. Therefore, standard treatment includes a combination of a vasodilator (sodium nitroprusside) and a b-blocker (esmolol, propranolol, metoprolol, etc.).
Fenoldopam can be used instead of sodium nitroprusside. When there are contraindications for the use of b-blockers, it is advisable to prescribe intravenous administration of verapamil or diltiazem, which reduce blood pressure and myocardial contractility. Intravenous administration of the α- and β-adrenergic receptor antagonist labetalol is an alternative to the combination of a vasodilator and a β-blocker. The use of the ganglion blocker trimethaphan, which causes a decrease in both blood pressure and dp/dt, is also probably possible without b-blockers. At the same time, monotherapy with drugs that can increase tachycardia, cardiac output and aortic wall tension (hydralazine, diazoxide, dihydropyridine calcium antagonists) should not be carried out in these cases.
For dissection of the ascending aorta, emergency surgical treatment is indicated (aortic replacement and sometimes aortic valve replacement), and in patients with damage to the descending aorta, long-term medical treatment is possible.

Hypertensive encephalopathy
The stability of cerebral blood flow is maintained by the mechanism of autoregulation with changes in blood pressure in healthy individuals ranging from 60 to 120 mmHg. Art., and in patients with chronic hypertension – from 110 to 160 mm Hg. Art. . If systemic blood pressure exceeds the upper limit of autoregulation, then a significant increase in cerebral blood flow and the development of cerebral edema, which is the main cause of hypertensive encephalopathy, are possible.
The main symptoms of hypertensive encephalopathy are headache, nausea, vomiting, blurred vision, and lethargy. Impaired consciousness, convulsions are possible, and in the absence of adequate treatment, the development of cerebral hemorrhages, coma and death. During the examination, in addition, swelling of the optic nerve nipple is detected, combined or not combined with other manifestations of retinopathy. To confirm the diagnosis of hypertensive encephalopathy, it is necessary to exclude a number of diseases that have similar symptoms (stroke, subarachnoid hemorrhage, brain tumor, etc.). For this purpose, most patients are advised to undergo computed tomography or magnetic resonance imaging.
In case of hypertensive encephalopathy, it is necessary to quickly (approximately within an hour) reduce blood pressure (average blood pressure by 25% or DBP to 100-110 mm Hg) by intravenous administration of labetalol, sodium nitroprusside, nicardipine or fenoldopam.
The use of antihypertensive drugs that have a sedative effect (clonidine, methyldopa, reserpine) is contraindicated. After lowering blood pressure, the symptoms of hypertensive encephalopathy go away within a few hours.

Ischemic, hemorrhagic strokes
and subarachnoid hemorrhage
Current recommendations suggest withholding antihypertensive therapy for at least 10 days after the onset of ischemic stroke. The exception is patients in whom cerebrovascular accident is combined with acute heart failure, acute coronary syndrome, aortic dissection, or when their blood pressure exceeds 220/120 mmHg. Art. .
These recommendations are justified by the fact that in most people with ischemic stroke, high blood pressure, which is probably a protective reaction in these cases, decreases independently within a few days, and a decrease in blood pressure in the first hours and days of the disease can lead to a deterioration in blood flow in the peri-infarction area. zone and expansion of the focus of brain damage.
When it is necessary to lower blood pressure (BPMR by no more than 25% over several hours), it is currently recommended to use labetalol first rather than sodium nitroprusside, which, like other vasodilators (for example, nitroglycerin), should be a second-line drug due to the risk of increased intracranial pressure when using it (Kaplan N.M., 2003).
As with ischemic stroke, it is not recommended to reduce blood pressure in patients with subarachnoid hemorrhage (SAH), except in special cases when it is excessively elevated (more than 220/120 mmHg). As a number of studies have shown, antihypertensive therapy does not improve the course of the disease: reducing blood pressure during SAH, while reducing the risk of repeated hemorrhages, significantly increases the number of cases of cerebral infarction.
If a decision is made about the need to control blood pressure in patients with subarachnoid hemorrhage, one must remember the possibility of increased intracranial pressure when using sodium nitroprusside or nitroglycerin (although this is quite rare in the clinic), so preference is given to labetalol. It is advisable to prescribe nimodipine, which helps reduce the incidence of cerebral vascular spasm (which is characteristic of this disease) and therefore reduces the risk of cerebral ischemia.
Although the optimal tactics for controlling arterial hypertension in patients with hemorrhagic stroke is still unclear, most of them are recommended to gradually and carefully lower blood pressure if it is more than 180/105 mm Hg. Art. (IV labetalol, sodium nitroprusside, etc., see Table 3). The goal of treatment is to maintain SBP between 140 and 160 mmHg. Art., carefully monitoring the patient’s condition to prevent an increase in neurological symptoms associated with a decrease in blood pressure and cerebral hypoperfusion.
In ischemic, hemorrhagic strokes and subarachnoid hemorrhage, as well as in hypertensive encephalopathy, the use of antihypertensive drugs that have a depressant effect on the central nervous system (clonidine, methyldopa, reserpine) is contraindicated.
Preeclampsia and eclampsia
Pregnant women with preeclampsia and eclampsia require hospitalization and bed rest. In case of treatment-resistant preeclampsia or development of eclampsia, immediate delivery is indicated. For a rapid but controlled reduction in blood pressure in these clinical situations, drugs that are safe and effective when administered parenterally are recommended: hydralazine, labetalol, nicardipine. Although hydralazine has traditionally been widely used in the treatment of preeclampsia and eclampsia, some experts prefer labetalol and nicardipine due to fewer adverse reactions and high effectiveness. Thus, a number of studies have shown that intravenous administration of labetalol at a dose of 1 mg/kg to women with hypertension in the last trimester of pregnancy did not affect uteroplacental blood flow and fetal heart rate, despite a significant decrease in blood pressure and heart rate in the mother.
At the same time, there is evidence that sodium nitroprusside may pose a certain danger to the fetus, so it should be a reserve drug and used during pregnancy only as a last resort. Trimethaphan and diuretics are not recommended for the treatment of preeclampsia and eclampsia - due to an increased risk of developing meconium ileus - since with preeclampsia there is almost always a decrease in uteroplacental blood flow. To prevent seizures, use magnesium sulfate: 4-6 g IV for 15-20 minutes, then a continuous IV infusion at a rate of 1-2 g/hour.

Postoperative hypertension
Arterial hypertension quite often, in 25-75% of cases, develops after surgery. It increases the number of complications in the postoperative period (bleeding from the area of ​​vascular sutures, myocardial ischemia, acute heart failure, etc.), and also has a negative effect on the prognosis. Severe postoperative hypertension is more often reported in patients whose blood pressure was poorly controlled before surgery. It is obvious that many patients in the postoperative period cannot take drugs orally for a certain time, and therefore they must use parenteral administration of antihypertensive drugs.
Before performing noncardiac surgery in patients with arterial hypertension, it is necessary to achieve a stable reduction in blood pressure. Most oral antihypertensive medications can be prescribed on the morning of surgery, with the exception of diuretics due to the risk of hypovolemia. Drugs whose use cannot be interrupted (for example, b-blockers) should be administered parenterally. In the days immediately after surgery, antihypertensive therapy selected before surgery continues.
After coronary artery bypass surgery, blood pressure increases in more than 33% of cases. Arterial hypertension, in the pathogenesis of which cardiac denervation and immunosuppressive therapy play a major role, is a frequent companion to heart transplantation.
The main drugs for lowering blood pressure in patients undergoing cardiac surgery are sodium nitroprusside, nitroglycerin, labetalol, b-blockers and calcium antagonists. There is evidence of the effective use of fenoldopam for this purpose, including after coronary artery bypass surgery. After heart surgery, it is not recommended to prescribe hydralazine and diazoxide, which, by causing tachycardia, increase the load on the myocardium.

Hypertensive crises caused by
increased sympathetic activity
nervous system
Pheochromocytoma in 85-90% of cases is a benign tumor of the adrenal medulla that produces catecholamines. In approximately 70% of cases, arterial hypertension with pheochromocytoma is of a crisis nature. Hypertensive crises are characterized by palpitations, headache, sweating, pale skin, and polyuria. Leukocytosis, eosinophilia, and hyperglycemia are often detected in the blood.
To relieve a hypertensive crisis in pheochromocytoma, 5-10 mg of phentolamine is administered intravenously (the use of b-blockers without a-blockers is contraindicated). Backup drugs may include sodium nitroprusside and labetalol. At the same time, according to some data, the use of labetalol for this purpose is inappropriate due to insufficient effectiveness or even an increase in blood pressure.
Sudden cessation of taking certain antihypertensive drugs that affect the activity of the sympathetic nervous system (clonidine, b-blockers) can also cause a significant increase in blood pressure (“rebound” hypertension) and the appearance of a number of other symptoms, such as tachycardia, cardiac arrhythmias, etc. d. Treatment of rebound hypertension consists of continuing interrupted antihypertensive therapy after rapidly lowering blood pressure with phentolamine, sodium nitroprusside, or labetalol. It must be remembered that the use of b-blockers in patients taking clonidine negatively affects the course of “rebound” hypertension.
Some other clinical situations also lead to a significant increase in adrenergic activity and the appearance of severe hypertension:
1) use of drugs with sympathomimetic activity (cocaine, amphetamines, phencyclidine, phenylpropanolamine, etc.);
2) interaction of monoamine oxidase inhibitors with foods containing tyramine (we talked about them earlier);
3) Guillain-Barre syndrome (inflammatory disease of the nervous system);
4) spinal cord damage.
When treating these arterial hypertension (as in patients with pheochromocytoma), monotherapy with b-blockers should be avoided, because inhibition of vasodilation associated with stimulation of b-adrenergic receptors leads to the elimination of the counterbalance of a-adrenergic vasoconstriction and a further increase in blood pressure. High blood pressure is reduced by intravenous administration of phentolamine, sodium nitroprusside, fenoldopam, labetalol. However, data on the effectiveness of the latter in these patients are contradictory and require clarification.

Kidney failure
For antihypertensive therapy in patients with renal failure, drugs that do not negatively affect renal blood flow and glomerular filtration are used: calcium antagonists, fenoldopam, labetalol, sodium nitroprusside, a-blockers. Diuretics (mostly loop diuretics and often in fairly high doses) are used only in the presence of hypervolemia. Thiazide diuretics are ineffective when the glomerular filtration rate is less than 30 ml/min. Since b-blockers can reduce renal blood flow, their use should be avoided in renal failure. Potassium-sparing diuretics are contraindicated in patients with this pathology, aggravated by hyperalemia. Dose adjustment of antihypertensive drugs excreted by the kidneys is necessary.
A number of controlled clinical studies have shown that, compared with sodium nitroprusside, fenoldopam infusion improves diuresis, natriuresis, and creatinine clearance. When administering sodium nitroprusside to patients with renal failure, the risk of intoxication with cyanide and thiocyanate increases (it is necessary to reduce the initial rate of drug administration and monitor their levels in the blood plasma). In connection with the above, it is probably necessary to give preference to fenoldopam rather than sodium nitroprusside when emergency treatment of hypertension due to renal failure is necessary. Some patients may require emergency hemodialysis to control blood pressure. Bilateral nephrectomy followed by continuous hemodialysis or kidney transplantation is also used as a method of treating hypertension refractory to pharmacotherapy.

Literature
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PART II. PHARMACOTHERAPY AND SPECIAL ISSUES OF PHARMACOLOGY. Chapter 10. ARTERIAL HYPERTENSION

PART II. PHARMACOTHERAPY AND SPECIAL ISSUES OF PHARMACOLOGY. Chapter 10. ARTERIAL HYPERTENSION

10.1. ARTERIAL HYPERTENSION SYNDROME

Arterial hypertension (AH)- syndrome, which consists of an increase in blood pressure (systolic blood pressure >140 mm Hg and/or diastolic blood pressure >90 mm Hg).

Hypertension syndrome can accompany a number of diseases, but more often a single etiological cause of increased blood pressure cannot be identified - this is the so-called essential(primary or idiopathic) AG. Other names for this disease are also common - hypertension, arterial hypertension. The causes of essential hypertension are still not well understood, although among all patients with high blood pressure, essential hypertension occurs in 90-94% of cases.

If the reasons for the increase in blood pressure are known, it is customary to talk about secondary or symptomatic hypertension.

Epidemiology of hypertension. Hypertension is the most important risk factor for major cardiovascular diseases and is one of the most common pathological conditions of the cardiovascular system. Increased blood pressure is observed in approximately 25% of the total adult population in industrialized countries. High blood pressure is diagnosed in 40% of the adult population of the Russian Federation. In the United States alone, hypertension causes 100 million visits to medical care annually, and an average of $31.7 billion is spent on treating patients with hypertension per year. Awareness of patients with hypertension about the presence of the disease in the Russian Federation is 77.9%. Antihypertensive drugs are taken by 59.4% of patients with hypertension, treatment is effective in 21.5%.

Etiology and pathogenesis of secondary hypertension. The cause of secondary hypertension can only be any disease (Table 10-1). Most often, blood pressure increases in kidney diseases that occur with retention of fluid and sodium ions in the body. Some tumors can produce large quantities of hormones (aldosterone, thyroxine, adrenocorticotropic hormone) or biologically active substances (renin), which have a pronounced pressor (increasing)

BP) effect. This group of diseases includes pheochromocytoma 1, a tumor of the adrenal glands that produces catecholamines. Blood pressure in this disease occasionally rises to very high levels. In pregnant women, the cause of increased blood pressure is considered to be an increase in the volume of circulating fluid and impaired renal function (nephropathy of pregnancy, eclampsia). Secondary hypertension is often caused by taking drugs - primarily glucocorticoids and oral contraceptives.

Table 10-1. Types and causes of hypertension

1 The use of beta blockers for pheochromocytoma causes a paradoxical increase in blood pressure due to the blockade of peripheral β-adrenergic receptors, which dilate blood vessels.

Etiology and pathogenesis of essential hypertension. The causes of this form of hypertension currently remain poorly understood. It is believed that a number of factors contribute to the development of the disease, among which the most important are excessive consumption of table salt, stress 1, a decrease in the number of functionally active nephrons 2, genetic defects and obesity. Thus, essential hypertension can be classified as a polyetiological disease.

A person's blood pressure level depends on cardiac output and peripheral vascular resistance. In patients with hypertension, an increase in cardiac output may be due to two main reasons:

An increase in fluid volume caused by an excess of sodium ions (increased sodium consumption, impaired excretion by the kidneys, increased synthesis of aldosterone);

Increased contractility of the heart muscle under the influence of catecholamines and excessive sympathetic innervation (stress).

On the other hand, catecholamines, angiotensin II and sodium ions cause peripheral vasoconstriction and irreversible hypertrophy of the muscular layer of the vascular wall, which leads to increased peripheral vascular resistance and endothelial dysfunction.

The pathogenesis of hypertension mainly involves the pressor systems of the body - the sympathoadrenal and renin-angiotensin-aldosterone system (RAAS) - Fig. 10-1. At the same time, a long-term increase in blood pressure is counteracted by central (CNS) and peripheral (kallikrein-kinin system) 3 depressor systems. However, long-term high activity of pressor factors leads to irreversible changes in the structure of the kidneys and vascular wall and to the “fixation” of elevated blood pressure levels.

The RAAS is of particular importance in the regulation of blood pressure; it determines blood volume, blood pressure and the functions of the cardiovascular system. The RAAS is activated in response to a decrease in blood volume, a decrease in blood pressure, and an increase in the activity of the sympathetic nervous system.

1 Stress is a pathological condition characterized by excessive activation of the sympathoadrenal system and increased production of catecholamines under the influence of external or internal stimuli.

2 Nephron is the structural and functional unit of the kidneys.

3 The kallekrein-kinin system synthesizes kinins (bradykinin) - active compounds that have a hypotensive effect. The synthesis of these compounds occurs in the kidneys.

Rice. 10-1. Renin-angiotensin-aldosterone system

The RAAS is involved in the regulation of blood pressure and fluid volume, as renin catalyzes the conversion of angiotensinogen to angiotensin I, which is transformed by ACE 1 into angiotensin II. Angiotensin II, acting through four types of receptors - AT 1, AT 2, AT 3, AT 4, serves as the central active component of the RAAS. The first two are the most well studied - angiotensin II receptors type 1 (AT 1) and type 2 (AT 2). In the human body, there are significantly more AT 1 receptors than AT 2, thus, the effects of stimulation with angiotensin II are mainly due to stimulation of AT 1 receptors: arterial vasoconstriction and especially an increase in hydraulic pressure in the renal glomeruli (vasoconstriction of the afferent and, to an even greater extent, efferent arterioles), reduction of mesangial cells and decreased renal blood flow, increased sodium reabsorption in the proximal renal tubules, secretion of aldosterone

1 ACE - angiotensin-converting enzyme.

adrenal cortex, secretion of vasopressin, endothelin-1, release of renin, increased release of norepinephrine from sympathetic nerve endings, activation of the sympathoadrenal system (central at the presynaptic level and peripheral in the adrenal glands), stimulation of vascular and myocardial remodeling processes (proliferation and migration of vascular smooth muscle cells, hyperplasia intima, hypertrophy of cardiomyocytes and myocardial fibrosis).

The cardiovascular effects of angiotensin II mediated by AT 2 receptors are opposite to the effects caused by stimulation of AT 1 receptors and are less pronounced. AT 2 type receptors are abundantly present in fetal tissues; in adult tissues they are found in the myocardium, adrenal medulla, kidneys, reproductive organs, and brain; cell apoptosis is regulated through them. Stimulation of AT 2 receptors is accompanied by vasodilation, inhibition of cell growth, suppression of cell proliferation (endothelial and smooth muscle cells of the vascular wall, fibroblasts), inhibition of cardiomyocyte hypertrophy. In addition, the production of nitric oxide (NO) increases. There is also prorenin, a precursor to renin, which was previously considered an inactive molecule. However, recent research suggests that prorenin may have angiotensin I-forming activity. Renin and prorenin also have direct effects through interaction with recently discovered (pro)renin receptors.

Elevated blood pressure levels in patients with hypertension are dangerous due to a number of complications. In such patients, the risk of atherosclerosis and the development of coronary heart disease (see Chapter 11) or cerebrovascular diseases [acute cerebrovascular accident (ACVA)] is increased. Elevated blood pressure causes damage, death of nephrons and the development of renal failure; damage to retinal vessels and diseases of the arteries of the lower extremities. An increase in afterload causes myocardial hypertrophy, the progression of which leads to the development of heart failure (see Chapter 14). The organs in which pathological changes most often develop are called target organs(Table 10-2).

Risk factors for hypertension. Blood pressure level is considered the most important, but far from the only factor determining the severity of hypertension, its prognosis and treatment tactics. Of great importance is the assessment of overall cardiovascular risk, the degree of which depends on the value of blood pressure, as well as on the presence or absence of associated risk factors, target organ damage and concomitant clinical conditions.

Table 10-2. Factors whose presence negatively affects the prognosis in patients with hypertension

Classification of hypertension. The severity of the disease is assessed by blood pressure. The risk of complications and life expectancy of patients primarily depend on this indicator (Table 10-3). In addition, the presence of target organ damage and a number of concomitant conditions, as well as smoking and old age, negatively affect the prognosis of hypertension (see Table 10-2).

Symptom complex of hypertension. Usually the disease is asymptomatic, which makes its timely diagnosis difficult. Patients with hypertension most often complain of headache, dizziness, blurred vision, general poor health, sensory and motor disturbances, palpitations, shortness of breath, dry mouth, feeling of “hot flashes”, fever, cold extremities are also possible. At the same time, symptoms of other diseases (CHD, stroke, renal failure) that complicate the course of hypertension are often detected.

The disease can occur with sudden increases in blood pressure (BG) of varying duration (from several hours to several days). GK 1, as a rule, develops in patients who do not receive adequate treatment, or when taking antihypertensive drugs abruptly, as well as under stress, sudden meteorological changes, or due to excess salt and fluid intake.

GK - hypertensive crisis (see chapter 10.12).

Table 10-3. Classification of the degree of increase in blood pressure in patients with hypertension, proposed by WHO and the International Society of Arterial Hypertension in 1999.

Course and severity of the disease. Secondary hypertension usually develops at a young age and is characterized by rapid progression and frequent crises. Essential hypertension, on the contrary, is characterized by slow progression; the disease can be asymptomatic for many years (an increase in blood pressure in such patients is first noted after 30-40 years). Gradually, as the disease progresses, target organ damage appears and other diseases of the cardiovascular system develop. The appearance of complications indicates a severe course of the disease and an increased risk of developing

MI and ONMC.

The most prognostically unfavorable form of the course of hypertension, which produces a large number of complications, disability, loss of working capacity and deaths, is the crisis course.

Diagnosis and examination methods. The diagnosis of hypertension is made based on the presence of elevated blood pressure in the patient (increased blood pressure must be recorded at least twice on two consecutive visits with the patient in a sitting position). Avoid drinking coffee and strong tea 1 hour before the test; It is recommended not to smoke for 30 minutes before measuring blood pressure; stop taking sympathomimetics

kov, including nasal and eye drops; Blood pressure is measured at rest after resting for 5 minutes; if the blood pressure measurement procedure is preceded by significant physical or emotional stress, the rest period should be extended to 15-30 minutes.

Examination of patients has two main goals.

Exclusion of the secondary nature of hypertension:

Biochemical blood test (increased concentrations of urea and creatinine are characteristic of chronic renal failure);

Ultrasound examination (ultrasound) of the abdominal organs, as well as computed tomography and scintigraphy (allows us to identify some diseases of the kidneys and adrenal glands that cause hypertension);

Doppler ultrasound of the renal arteries: allows you to identify stenosis (narrowing) of the renal artery (with stenosis, blood flow to the kidneys decreases, which, in turn, causes activation of the RAAS) and contrast research methods (angiography);

Study of the concentration of thyroid hormones, cortisol (adrenal cortex hormone), catecholamine metabolites in urine (increases in pheochromocytoma);

X-ray of the skull (area of ​​the sella turcica) to exclude a pituitary tumor 1;

Measurement of blood pressure in the lower extremities and ultrasound of the abdominal aorta to exclude coarctation (congenital narrowing) of the aorta.

Determination of the state of target organs:

Echocardiography (EchoCG) (myocardial hypertrophy) and Dopplerography of large vessels (atherosclerosis);

ECG (myocardial hypertrophy, signs of ischemia and/or scar changes in the myocardium);

Examination of urine for the presence of protein;

Fundus examination;

Blood glucose concentration (excluding diabetes);

Neurological examination (detection of hypertensive encephalopathy), including magnetic resonance imaging of the brain, Doppler ultrasound of the main arteries.

1 The pituitary gland is an endocrine gland directly connected to the brain; the hormones secreted by this gland regulate the functions of other endocrine glands.

Daily blood pressure monitoring provides important information about the state of the cardiovascular system. Using this method, it is possible to determine daily blood pressure variability, nocturnal arterial hypotension and hypertension, and to trace the connection with the emotional background of the subject. All these factors are important when choosing antihypertensive drugs and when assessing their effectiveness. It should also be noted that some patients have “white coat” hypertension with a low risk of cardiovascular disease, which can also be detected using this method.

Clinical and pharmacological approaches to the treatment of arterial hypertension

Treatment of secondary hypertension consists primarily of correction of the underlying disease; drugs with antihypertensive effects serve as symptomatic therapy.

According to modern national recommendations, recommendations of the European Society of Arterial Hypertension and the European Society of Cardiology, the treatment tactics for essential hypertension depend on the level of blood pressure and the degree of risk of cardiovascular complications. The main goal of treatment is to minimize the risk of developing cardiovascular complications and death from them. The main goals of treatment are normalization of blood pressure, prevention of complications in the absence or minimal level of adverse drug reactions, correction of all modifiable risk factors (smoking, dyslipidaemia, hyperglycemia, obesity), prevention and slowdown of the rate of progression and/or reduction of target organ damage, as well as treatment associated and concomitant diseases (CHD, diabetes).

When treating patients with hypertension, it is necessary to maintain blood pressure below 140/90 mmHg. Art., what is called target level. If the prescribed treatment is well tolerated, it is advisable to reduce blood pressure to lower values. In patients with a high and very high risk of cardiovascular complications, it is necessary to reduce blood pressure to 140/90 mm Hg. Art. or less in 4 weeks. Then, subject to good tolerance, 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 mmHg. Art. In patients with diabetes and/or kidney disease, the target blood pressure level should be less than 130/85 mmHg. Art.

If the risk of complications is low, treatment begins with measures aimed at changing the patient’s lifestyle.

th. Lifestyle and dietary changes should be recommended to all patients, regardless of the severity of hypertension. An attempt should be made to eliminate all relatively reversible factors, as well as increased concentrations of cholesterol (C) and/or glucose in the blood. Among the recommendations for lifestyle changes, the following are especially relevant:

Reducing excess body weight [body mass index (BMI)<25 кг/ м 2 ];

Limiting table salt consumption to 5 g or less per day;

To give up smoking;

Reducing the consumption of alcoholic beverages -<30 г алкоголя в сутки для мужчин и 20 г для женщин;

Regular moderate-intensity physical exercise lasting at least 30-60 minutes outdoors 3-4 times a week;

Changing your diet to increase your intake of plant foods, potassium, calcium (found in vegetables, fruits, grains) and magnesium (found in dairy products), as well as reducing your intake of animal fats.

The listed measures allow, on the one hand, to reduce the rate of progression of the disease, and on the other, to reduce the dose of antihypertensive drugs.

It is necessary to explain to the patient the goals of treatment and teach the technique of measuring blood pressure (independently or with the help of loved ones), teach him to make the right decisions in specific clinical situations (for example, first aid for a hypertensive crisis). The patient should be explained the importance of non-drug therapeutic measures (limiting table salt, reducing body weight, etc.).

If in a patient with a low risk of complications these measures do not allow normalization of blood pressure levels within 6-12 months, one should proceed to the prescription of antihypertensive drugs. In patients with stage II-III hypertension, a high risk of developing cardiovascular complications, target organ damage and the presence of concomitant diseases, drug treatment is started immediately and non-drug treatment is carried out in parallel.

Classification of drugs used to treat arterial hypertension

ACEI 1 - captopril, enalapril, perindopril, lisinopril, fosinopril, quinapril, trandolapril, etc.

AT 1 receptor blockers (ARBs) - valsartan, losartan, telmi-sartan, candesartan, irbesartan, etc.

BMKK 2 - nifedipine, amlodipine.

BAB 3 - carvedilol, bisoprolol, nebivolol, metoprolol, atenolol.

Thiazide and thiazide-like diuretics - hydrochlorothiazide, indapamide, etc.

As additional classes of antihypertensive drugs for combination treatment, α-blockers (prazosin, doxazosin), imidazoline receptor agonists (moxonidine), and direct renin inhibitor (aliskiren) can be used.

When choosing an antihypertensive drug, first of all, it is necessary to evaluate the effectiveness, the likelihood of side effects and the benefits of the drug in a certain clinical situation (Tables 10-4, 10-5).

The choice of drug is influenced by many factors, the most important of which are considered:

The patient has risk factors;

Target organ damage;

Concomitant clinical conditions, kidney damage, metabolic syndrome (MS), diabetes;

Concomitant diseases for which it is necessary to prescribe or limit the use of antihypertensive drugs of various classes;

Previous individual patient reactions to drugs of various classes;

The likelihood of interaction with drugs prescribed to the patient for other reasons;

Socioeconomic factors, including cost of treatment.

ACEIs are angiotensin-converting enzyme inhibitors. BMCC - blockers of slow calcium channels. BAB - β-adrenergic receptor blockers.

Table 10-4. Preferred indications for prescribing various groups of antihypertensive drugs

* MAU - microalbuminuria.

** ISAH - isolated systolic arterial hypertension.

Table 10-5. Absolute and relative contraindications to the prescription of various groups of antihypertensive drugs

* IGT - impaired glucose tolerance. ** DLP - dyslipoproteinemia.

It is necessary to begin treatment with the prescription of one drug in the minimum daily dose (this recommendation does not apply to patients with severe hypertension or those in whom previous treatment was ineffective). Taking new drugs should begin with low doses, the goal of each successive stage of treatment should be to reduce blood pressure by 10-15 mmHg. Art. In patients with stage II and III hypertension, it is recommended to begin treatment with a combination of two (and sometimes three) rationally selected drugs. If blood pressure does not decrease to the desired level, further treatment is carried out by gradually increasing doses or adding new drugs. Ineffective drugs (not causing a decrease in blood pressure by 10-15 mm Hg) and drugs that cause ADRs should be replaced.

There are no uniform recommendations regarding which drugs should be used to start treating a patient. The choice of drug depends on age, gender and the presence of concomitant diseases. In patients with severe hypertension and when treatment with one drug is ineffective, combinations of drugs are prescribed.

Combined antihypertensive therapy has many advantages.

Strengthening the antihypertensive effect through 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 due to both lower doses of combined antihypertensive drugs and mutual neutralization of these effects.

Providing the most effective organ protection and reducing the risk and frequency of cardiovascular complications.

The prescription of drugs in the form of combination treatment must meet the following conditions:

The drugs must have a complementary effect;

When used together, better results are achieved;

The drugs must have similar pharmacodynamic and pharmacokinetic parameters, which is especially important for fixed combinations.

The combination of two antihypertensive drugs is divided into rational (effective), possible and irrational. All the advantages of combination treatment are inherent only in rational combinations of antihypertensive drugs.

These include:

ACE inhibitor + diuretic;

ARB + ​​diuretic;

ACEI + dihydropyridine BMCC;

ARB + ​​dihydropyridine BMCA;

Dihydropyridine BMCC + BAB;

Dihydropyridine BMCC + diuretic;

beta blocker + diuretic;

BAB + α-adrenergic blocker.

For the combined treatment of hypertension, you can use both non-fixed and fixed combinations of drugs (two drugs in one tablet).

The advantages of fixed (official) combinations include:

Potentiation of the antihypertensive effect of drugs;

Ease of administration and dose titration process;

Reducing the incidence of side effects (low dose, mutual neutralization of NDR);

Increased patient adherence to treatment;

Reducing the cost of treatment.

Currently, there are quite a lot of official combination drugs: Capozide* (captopril + hydrochlorothiazide), Ko-Renitek* (enalapril + hydrochlorothiazide), Noliprel* (perindopril + indapamide), Accuside* (quinapril + hydrochlorothiazide), Co-diovan* (valsartan + hydrochlorothiazide), Gizaar* (losartan + hydrochlorothiazide), Exforge* (valsartan + amlodipine), Equator* (lisinopril + amlodipine), Logimax* (metoprolol + felodipine), Tarka* (verapamil + trandolapril), etc.

Monitoring the effectiveness of arterial treatment

hypertension

When assessing the effectiveness of hypertension treatment, the following points are highlighted.

Short term goals:

Decrease in systolic and/or diastolic blood pressure by 10% or more;

Absence of hypertensive crises;

Maintaining or improving quality of life.

Medium-term goals:

Achieving target blood pressure values;

Absence of target organ damage or reverse dynamics of existing complications;

Elimination of modifiable risk factors.

Finally, the long-term goal of treatment is considered to be stable maintenance of blood pressure at the target level and the absence of progression of target organ damage.

The effectiveness of treatment is monitored based on regular blood pressure measurements and regular medical examinations of the patient (see section “Diagnosis and examination methods”).

Monitoring the safety of hypertension treatment. When prescribing prazosin, clonidine, guanethidine, there is a risk of developing orthostatic collapse, and blood pressure is measured with the patient lying and standing. The difference is 20 mmHg. Art. indicates a high probability of the patient developing orthostatic hypotension.

Most drugs that reduce vascular tone (nitrates, BMCCs, non-selective α-adrenergic blockers) cause reflex tachycardia, while some drugs can cause bradycardia, a decrease in the strength of heart contractions and intracardiac conduction (central α-adrenergic receptor agonists, sympatholytics, pyrroxane ).

When prescribing ACE inhibitors, ARBs, and indapamide, the concentration of potassium in the blood plasma should be monitored.

When taking methyldopa, terazosin, ACEI, the development of anemia, leukopenia is possible, and when nifedipine is prescribed, also thrombocytopenia.

In addition, when prescribing beta blockers, central α-adrenomimetics, sympatholytics, ACE inhibitors, one should remember the possibility of increased bronchial tone and the appearance of bronchospasm, and when treating with sympatholytics, the appearance of pain in the epigastric region.

10.2. CLINICAL PHARMACOLOGY OF ANGIOTENSIN-CONVERTING INHIBITORS

ENZYME

The search for drugs that regulate the activity of the RAAS began in the 60s of the 20th century, immediately after its importance in the pathogenesis of hypertension was clarified. The first effective regulator of RAAS activity was the ACE inhibitor captopril, which is used in clinical practice.

since 1979

There are five groups of drugs that regulate the activity of the RAAS.

BBs: block P1-adrenergic receptors of the juxtaglomerular apparatus of the kidneys, reduce the synthesis and release of renin and indirectly AT II.

ACE inhibitors: reduce the concentration of AT II by blocking the main enzyme that catalyzes the transition of AT I to AT II.

ARBs: prevent the interaction of AT II with target tissues through AT 1 receptors, but at the same time AT II interacts with AT 2 receptors.

Aldosterone receptor blockers: interfere with the interaction of aldosterone with target tissues.

Selective renin inhibitor: by binding to the renin molecule, it prevents the binding of renin to angiotensinogen and thereby reduces the formation of AT II.

Classification of angiotensin-converting enzyme inhibitors

The classification of ACEIs is based on the pharmacokinetic principle: a group of active drugs (captopril and lisinopril) and prodrugs (other ACEIs) are distinguished, from which active metabolites are formed in the liver, providing therapeutic effects (Table 10-6).

Table 10-6. ACEI classification according to Opie, 1999

Pharmacokinetics of angiotensin-converting enzyme inhibitors

The pharmacokinetic features of the most commonly prescribed ACE inhibitors are presented in Table. 10-7.

Pharmacodynamics of angiotensin-converting enzyme inhibitors

The pharmacodynamics of ACEIs are associated with the suppression of the main pathway of AT II synthesis, which determines their antihypertensive effect and a positive effect on cardiac function in CHF and ischemic heart disease (Table 10-8).

Table 10-8. Basic pharmacological properties of ACE inhibitors

Taking ACE inhibitors leads to a decrease in vascular tone, and in patients with hypertension - systemic blood pressure. It should be noted that the decrease in blood pressure under the influence of ACE inhibitors is not accompanied by the development of tachycardia. There are “acute” and “chronic” antihypertensive effects of drugs.

The “acute” effect is due to a decrease in the concentration of AT II in the circulation and the accumulation of bradykinin in the endothelium with a decrease in the rate of its degradation. Bradykinin directly causes a decrease in the tone of the smooth muscles of the vascular wall, and also promotes the release of endothelium-relaxing factors - nitric oxide and prostaglandin E 2. This can lead to a drop in renal perfusion pressure and an increase in renin production, which causes the "escape" phenomenon - a decrease

hypotensive effect of drugs for 7-10 days. With further use of ACE inhibitors, the formation of aldosterone decreases, the excretion of sodium and water increases, which stabilizes the antihypertensive effect.

The “chronic” antihypertensive effect of drugs occurs with long-term (several months or years) use and is due to their ability to reduce the severity of hypertrophy (mainly through connective tissue components) of the muscle layer of the vascular wall and myocardium. Inhibition of growth and proliferation of smooth muscle cells and fibroblasts in the media of arteries leads to an increase in their lumen, and also restores or improves the elasticity of the arterial wall. Restoration of the myocardial structure, on the one hand, contributes to the normalization of central hemodynamics, on the other, it reduces the level of peripheral vascular resistance through reflex mechanisms.

Long-term use of ACE inhibitors significantly reduces (by approximately 8% per year) the risk of developing myocardial infarction and patient mortality.

Because ACEIs increase uric acid excretion, they should be the first choice drugs in patients with gout. However, it should be remembered that a strong uricosuric effect can contribute to the formation of uric acid stones.

Clinical use of angiotensin-converting enzyme inhibitors

The main indications for prescribing ACE inhibitors include the following:

Arterial hypertension of any etiology (as monotherapy and in combination with diuretics and antihypertensive drugs of other groups);

Relief of hypertensive crises (for captopril);

CHF;

LV systolic and diastolic dysfunction;

IHD (to reduce the infarct area, dilatation of coronary vessels and reduce dysfunction during reperfusion, reduce the risk of recurrent MI);

Diabetic angiopathy (in particular, to slow the progression of diabetic nephropathy);

Diagnosis of renovascular hypertension and primary aldosteronism (single dose of captopril).

Monitoring the effectiveness and safety of prescribing angiotensin-converting enzyme inhibitors

The effectiveness of treatment with ACE inhibitors for hypertension is determined by the dynamics

HELL.

To monitor the safety of treatment, it is also necessary to measure blood pressure to exclude possible hypotension. Hypotension develops more often in patients with CHF, renal failure, or renal artery stenosis, which is why the first dose of the drug must be taken while sitting or lying down. The development of hypotension requires a reduction in the dose of the drug, followed by titration under the control of blood pressure levels.

To exclude the growth of urate stones in patients with urolithiasis, it is necessary to determine the concentration of urate in the urine, and to exclude hypoglycemia in patients with diabetes, to monitor the concentration of glucose in the blood.

ACEIs are one of the safest antihypertensive drugs. Men tolerate long-term treatment with these drugs better than women.

The most common ADR (from 1 to 48% during treatment with different ACE inhibitors) is considered to be a dry cough, which in some cases requires discontinuation of the drug. The mechanism of its occurrence is most often associated with an increase in the concentration of bradykinin in bronchial tissue. As a rule, cough does not depend on the dose of the drug.

The second most common (from less than 1 to 10-15% in heart failure) ADR of ACE inhibitors is the development of orthostatic hypotension, the so-called “first dose effect,” which occurs in patients with high RAAS activity. The simultaneous use of diuretics and other antihypertensive drugs also contributes to the development of a hypotensive reaction.

In patients with heart failure (less commonly, hypertension), ACEIs can impair glomerular filtration and other renal functions, and the incidence of these ADRs increases with prolonged use. Most often this occurs against the background of hidden renal pathology and (or) in patients receiving diuretics and NSAIDs.

Clinically significant hyperkalemia (more than 5.5 mmol/l) is observed mainly in patients with kidney pathology. Thus, with renal failure, its frequency ranges from 5 to 50%.

In 0.1-0.5% of cases, during treatment with ACE inhibitors, angioneurotic edema (Quincke's edema) develops, and in women it is 2 times more likely than in men.

In some cases, ACE inhibitors can cause cytopenia (usually leukopenia, less often thrombo- and pancytopenia). The mechanism of this NDR is due to the fact that one of the substrates for ACE is the peptide N-acetyl-seryl-aspartyl-lysyl-proline circulating in the blood, which functions as a negative regulator of hematopoiesis. When the enzyme is blocked, the amount of this peptide in the blood may increase. When taking ACEIs, nonspecific side effects may also develop, such as dizziness, headache, fatigue, weakness, dyspeptic symptoms (nausea, diarrhea), taste disturbances and skin rashes.

Taking ACE inhibitors in the second and third trimesters of pregnancy leads to the development of arterial hypotension, cranial hypoplasia, anuria, reversible and irreversible renal failure and fetal death. In addition, a decrease in the amount of amniotic fluid, the development of joint contractures, craniofacial deformities and pulmonary hypoplasia are possible.

Contraindications to the use of ACE inhibitors

Absolute: drug intolerance; allergic reactions; pregnancy and lactation; bilateral renal artery stenosis (increases the possibility of severe hypotension), severe chronic renal failure (creatinine concentration in serum more than 300 mmol/l), severe hyperkalemia (more than 5.5 mmol/l); hypertrophic cardiomyopathy with obstruction of the LV outflow tract, hemodynamically significant stenosis of the aortic or mitral valves, constrictive pericarditis, internal organ transplantation.

Relative: hypotension; moderate chronic renal failure, moderate hyperkalemia (5.0-5.5 mmol/l), gouty kidney (having a uricosuric effect, ACE inhibitors can accelerate the growth of urate stones); liver cirrhosis, chronic active hepatitis; obliterating atherosclerosis of the arteries of the lower extremities; severe obstructive pulmonary diseases.

Interaction of ACE inhibitors with other drugs

The most significant pharmacokinetic interaction of ACE inhibitors is observed with antacids containing aluminum and/or magnesium hydroxide. These antacids interfere with the absorption of captopril and fosinopril from the digestive tract.

The pharmacodynamic interaction of ACE inhibitors with other groups of drugs that differ from them in their mechanism of action is considered more important for clinical practice (Table 10-9).

Captopril(Capoten*). The strength with which captopril binds to the angiotensin-converting enzyme is low, which necessitates the administration of large doses. Captopril in the ACE inhibitor group has the shortest duration of action (6-8 hours compared to 24 hours for other drugs), but the earliest onset of effect, which allows it to be used sublingually for emergency treatment of hypertensive conditions. When captopril is taken sublingually, the antihypertensive effect occurs within 5-15 minutes. An important difference between captopril and other ACE inhibitors is the presence of the SH group, which determines its main side effects - nephrotoxicity and associated proteinuria (at a dose of more than 150 mg/day), cholestasis, neutropenia (usually in patients with diffuse connective tissue diseases and impaired renal function with long-term use). At the same time, the presence of an SH group in captopril promotes the manifestation of an antioxidant effect, increases coronary blood flow and increases tissue sensitivity to insulin.

The use of captopril in patients with acute MI leads to a significant reduction in mortality. Long-term use of the drug - more than 3 years - reduces the risk of developing recurrent myocardial infarction by 25%, and the risk of death from it by 32%.

The captopril test is used in the radioisotope diagnosis of renovascular hypertension and biochemical diagnosis of primary hyperaldosteronism (Conn's disease).

Enalapril(Renitek*) is transformed in the liver into enalaprilat (40-60% of the dose taken orally), which has a high degree of binding to the angiotensin-converting enzyme.

When prescribing enalapril for the treatment of hypertension, diuretics should be temporarily discontinued within 2-3 days; if this is not possible, the initial dose of the drug (5 mg) should be reduced by half. Also, the first doses of enalapril should be minimal in patients with initially high RAAS activity. The effectiveness of the prescribed dose is assessed every two weeks. The drug is prescribed 1-2 times a day.

Lisinopril(Diroton*) is an active metabolite of enalapril. A decrease in blood pressure is noted 1 hour after taking the drug. When appointing

When taking lisinopril once a day, its stable concentration in the blood is achieved after 3 days. The drug is excreted unchanged by the kidneys; in case of renal failure, it exhibits pronounced cumulation (the half-life increases to 50 hours). In elderly patients, its concentration in the blood is 2 times higher than in young patients. When lisinopril is administered intravenously, its antihypertensive effect begins within 15-30 minutes, which makes it possible to use it to relieve hypertensive crises.

Perindopril(Prestarium*) is a prodrug, in the liver it is transformed into the active metabolite perindoprilat (20% of the administered perindopril), which has a high degree of binding to the angiotensin-converting enzyme. The drug reduces hypertrophy of the vascular wall and myocardium. In the heart, while taking it, the amount of subendocardial collagen decreases.

Ramipril(Tritace*) is transformed in the liver into ramiprilat, which has a high degree of binding to angiotensin-converting enzyme. Two pharmacokinetic features of ramipril are of important clinical importance - slow elimination from the body and a double elimination route (up to 40% of the drug is excreted in the bile). However, in case of severe renal failure (glomerular filtration rate 5-55 ml/min), it is recommended to reduce its dose by half.

Trandolapril(Hopten*) has a 6-10 times greater effect on tissue ACE than enalapril. Although trandolapril is considered a prodrug, it has pharmacological activity in itself, but trandolaprilat is 7 times more active than trandolapril. The hypotensive effect of the drug with a single dose lasts up to 48 hours.

Moexipril(Moex*) becomes active after biotransformation in the liver into moexiprilat. Unlike most ACE inhibitors, it has a dual elimination route: up to 50% of moexipril is excreted in bile, which makes it safer in patients with renal failure.

Moexipril is primarily prescribed for the treatment of hypertension; its antihypertensive effect lasts up to 24 hours.

Fosinopril(Monopril*) is a prodrug, being converted in the liver into the active substance fosinoprilat.

The drug has a dual route of elimination: its elimination occurs equally through the kidneys and the liver. In case of renal failure, the release of fosinopril from the body through the liver increases, and in case of hepatic failure - through the kidneys, which makes it possible not to

adjust the dose of the drug if patients have these diseases.

The drug is used 1 time per day.

Fosinopril rarely causes a dry cough; If this complication occurs while taking any ACE inhibitors, it is recommended to switch to fosinopril.

10.3. CLINICAL PHARMACOLOGY OF ANGIOTENSIN II RECEPTOR BLOCKERS

Taking ACE inhibitors does not completely stop the formation of AT II in the organs and tissues of sick people due to the existence of an ACE-independent pathway for the formation of AT II from AT I. It can occur with the help of cathepsin G, tonin, tissue plasminogen activator, endothelial peptidyl dipeptidase, renal carboxypeptidase, chymostatin-sensitive AT II-forming enzyme (CAGE) and chymase. The latter enzyme is a cardiac serine protein kinase and contributes to the formation of up to 80% of myocardial AT II. Because of this, in some patients the therapeutic effect of ACEI is insufficient, and in this case, ARBs become of great importance, limiting its biological effect in tissues.

Currently, several synthetic non-peptide selective AT 1 blockers are used in world medical practice - valsartan, irbesartan, candesartan, losartan, telmisartan and eprosartan.

There are several classifications of angiotensin II receptor antagonists: according to chemical structure, pharmacokinetic properties, mechanism of binding to receptors, etc.

Based on the mechanism of binding to receptors, ARBs (as well as their active metabolites) are divided into competitive and non-competitive angiotensin II antagonists. Thus, losartan and eprosartan reversibly bind to AT 1 receptors and are competitive antagonists (i.e., under certain conditions, for example, when the level of angiotensin II increases in response to a decrease in blood volume, they can be displaced from the binding sites), while valsartan, irbesartan, candesartan, telmisartan, as well as the active metabolite of losartan EXP-3174 act as non-competitive antagonists and bind irreversibly to receptors.

Pharmacokinetics of angiotensin receptor blockers

All ARBs act gradually, the antihypertensive effect develops smoothly, within several hours after taking a single dose, and lasts up to 24 hours. With regular use, a pronounced therapeutic effect is usually achieved after 2-4 weeks (up to 6 weeks) of treatment.

The pharmacokinetic features of drugs in this group make them convenient for patients to take. These medications can be taken with or without food. A single dose is enough to provide a good hypotensive effect throughout the day. They are equally effective in patients of different sexes and ages, including patients over 65 years of age.

Pharmacodynamics of angiotensin receptor blockers

The main mechanism of action of drugs in this group is associated with the blockade of AT 1 receptors. ARBs have high affinity and selectivity for the AT 1 receptor subtype, through which the main effects of angiotensin II are realized. According to various authors, their affinity for AT 1 receptors exceeds that for AT 2 receptors by thousands of times: for losartan and eprosartan more than 1 thousand times, telmisartan - more than 3 thousand, irbesartan - 8.5 thousand, active metabolite of losartan EXP-3174 and candesartan - 10 thousand, valsartan - 20 thousand times.

They block the main negative effects of angiotensin II, which underlie the pathogenesis of cardiovascular diseases: increased blood pressure, release of aldosterone, renin, vasopressin and norepinephrine, development of hypertrophy of the LV myocardium and vascular smooth muscle.

The antihypertensive action and other pharmacological effects of ARBs are based on several mechanisms - one direct and at least two indirect (mediated).

The direct mechanism of the antihypertensive effect of ARBs is associated with the weakening of the effects of angiotensin II, which are mediated by AT 1 receptors. By blocking AT 1 receptors, ARBs reduce arterial vasoconstriction caused by angiotensin II, reduce increased hydraulic pressure in the renal glomeruli, and also reduce the secretion of such vasoconstrictor and antinatriuretic substances as aldosterone, arginine vasopressin,

endothelin-1 and norepinephrine. With long-term use, ARBs weaken the proliferative effects of angiotensin II, as well as aldosterone, arginine vasopressin, endothelin-1 and norepinephrine on cardiomyocytes and smooth muscle cells of the vascular wall, as well as fibroblasts and mesangial cells.

The indirect mechanisms of the pharmacological effects of ARBs are associated with reactive hyperactivation of the RAAS under conditions of blockade of AT 1 receptors, which leads, in particular, to increased formation of angiotensin II and angiotensinogen. These RAAS effector peptides, under conditions of AT 1 receptor blockade, cause additional stimulation of AT 2 and AT x receptors, causing arterial vasodilation, exerting an antiproliferative effect and increasing sodium excretion by the kidneys.

Recent studies of endothelial dysfunction in hypertension suggest that the cardiovascular effects of ARBs may also be associated with endothelial modulation and effects on nitric oxide (NO) production. The experimental data obtained and the results of individual clinical studies are quite contradictory. Against the background of blockade of AT 1 receptors, the endothelium-dependent synthesis and release of nitric oxide increases, which promotes vasodilation, a decrease in platelet aggregation and a decrease in cell proliferation.

Thus, specific blockade of AT 1 receptors allows for a pronounced antihypertensive and organoprotective effect. Against the background of blockade of AT 1 receptors, the adverse effects of angiotensin II (and angiotensin III, which has an affinity for angiotensin II receptors) on the cardiovascular system are inhibited and its protective effect is presumably manifested (by stimulating AT 2 receptors), and the effect of angiotensin is also developing. (I-VII) by stimulating AT x receptors. All these effects contribute to vasodilation and weakening of the proliferative effect of angiotensin II on vascular and cardiac cells.

ARBs can penetrate the blood-brain barrier and inhibit the activity of mediator processes in the sympathetic nervous system. By blocking presynaptic AT 1 receptors of sympathetic neurons in the central nervous system, they inhibit the release of norepinephrine and reduce the stimulation of adrenergic receptors in vascular smooth muscle, which leads to vasodilation. According to experimental studies, this additional mechanism of vasodilating action is more characteristic of eprosartan. Action Data

losartan, irbesartan, valsartan and other drugs of this group on the sympathetic nervous system (which manifested itself at doses exceeding therapeutic ones) are very contradictory.

Indications for the use of receptor blockers

angiotensin

The indications for prescribing ARBs are hypertension and CHF.

Adverse drug reactions

The results of multicenter placebo-controlled studies indicate high efficacy and good tolerability of AT 1 angiotensin II receptor antagonists. ARBs are among the safest antihypertensive drugs. Their main side effects (headache, dizziness, asthenia, dry cough) are comparable to those of placebo. There is no withdrawal syndrome observed.

Contraindications to the use of blockers

angiotensin receptors

Contraindications for ARBs are drug intolerance, pregnancy, lactation.

Characteristics of basic drugs

Valsartan(Diovan*). The most studied drug of the group. The total number of patients included in clinical trials reaches 100 thousand, of which more than 40 thousand were included in studies studying morbidity and mortality (hard endpoints).

The bioavailability of the drug is 23%. Although food intake slows its absorption, this does not lead to a decrease in clinical effectiveness. Communication with plasma proteins - 94-97%. Valsartan is excreted unchanged by the liver (70%) and kidneys (30%). Patients with impaired liver and kidney function do not require dose adjustment.

For the treatment of hypertension, valsartan is prescribed once a day. In most patients, the onset of its antihypertensive effect is noted within 2 hours, maximum - 4-6 hours, duration - more than 24 hours.

More than 150 clinical studies have been conducted, examining more than 45 points of efficacy assessment. The drug is effective both in patients with newly diagnosed hypertension and in those with ineffective previous treatment. Valsartan has at least comparable effectiveness to antihypertensive drugs from other groups. In a number of studies, valsartan has demonstrated advantages over other ARBs - losartan, telmisartan, irbesartan and candesartan. The number of patients who responded to the prescription of valsartan at a dose of 80-160 mg/day reaches 75%. In addition to antihypertensive effectiveness, valsartan significantly reduces the concentration of high-sensitivity C-reactive protein, a marker of inflammation and endothelial dysfunction; The nephroprotective properties of valsartan have been confirmed in patients with severe chronic renal failure, as well as in patients on hemodialysis. While taking valsartan, a decrease in the risk of diabetes by 23% was noted compared with amlodipine and a decrease in the risk of heart failure. Studies have shown the cardioprotective effect of valsartan, expressed in a decrease in the coefficient of LV hypertrophy and improvement in LV diastolic function. The inclusion of valsartan in the standard treatment regimen for hypertension reduces the risk of cardiovascular complications and mortality by 39% compared with a treatment regimen that did not include an ARB. According to various studies, when using valsartan, the risk of primary and recurrent stroke decreased by 40%.

Losartan(Kozaar *). The drug is well absorbed after oral administration and undergoes carboxylation in the intestine to form the active metabolite E-3174. The bioavailability of the drug is 33%, the maximum concentration in the blood is achieved within 1 hour, 92% of losartan is bound to albumin. Losartan is excreted 90% by the liver.

In comparative studies in elderly patients, losartan caused a relative reduction in the risk of death that was 46% greater than captopril. .

In patients with renal failure, the drug reduces the severity of proteinuria, maintains an acceptable glomerular filtration rate and renal blood flow.

Losartan increases the excretion of uric acid by the kidneys (by inhibiting tubular reabsorption), reducing its concentration in the blood and tissues.

Irbesartan(Aprovel*). The bioavailability of the drug is 60-80%. The maximum concentration in the blood is achieved within 1.5-2 hours. T 1 / 2 -11-15 hours. Plasma protein binding - 96%. Irbesartan is excreted by the liver and kidneys both unchanged and in the form of metabolites (6%). Patients with impaired liver and kidney function do not require dose adjustment.

The maximum effect of the drug after a single dose develops after 3-6 hours. A stable clinical effect is achieved after 1-2 weeks of administration.

Candesartan(Atakand *). The absolute bioavailability of the tablet form of the drug is 14%. Food intake does not affect bioavailability. The maximum concentration in the blood is reached after 3-4 hours. T 1 / 2 -9 hours, cumulation is not observed. Plasma protein binding is more than 99%. Candesartan is excreted in bile and urine mainly unchanged and to a small extent in the form of metabolites. Patients with severe renal impairment and patients on hemodialysis require a 2-fold dose reduction.

Eprosartan(Teveten *) is a selective non-peptide blocker of angiotensin II receptors, which provides an additional pharmacodynamic effect mediated by presynaptic angiotensin receptors: additional vasodilation without reflex tachycardia as a result of blockade of not only the RAAS, but also the sympathoadrenal system. Eprosartan does not interact with cytochrome P-450 isoenzymes and, therefore, has a low potential for interaction with other drugs. The drug has a pronounced effect on systolic blood pressure.

After oral administration of a single dose of 300 mg, the bioavailability of the drug is approximately 13%; intake with food reduces absorption. Plasma protein binding is high (98%) and remains constant after reaching therapeutic concentrations. Cmax is reached in 1-2 hours. Practically does not accumulate. T 1/2 -5-9 hours. Excreted mainly unchanged through the intestines and kidneys.

Telmisartan(Micardis*). The bioavailability of the drug is about 50%; food intake slightly reduces the rate of absorption. T 1/2 -20 hours. Plasma protein binding - 99%. Telmi-sartan is excreted by the liver. Patients with impaired liver function require dose adjustment.

The main indication is the treatment of hypertension. The effect after a single dose of the drug lasts 24-48 hours. The maximum clinical effect develops 4-8 weeks after the start of treatment.

10.4. CLINICAL PHARMACOLOGYβ -ADRENOBLOCKERS

Beta blockers are drugs that block β-adrenergic receptors.

The first adrenergic blockers appeared in the early 60s of the 20th century, they were mainly prescribed for the treatment of acute cardiac arrhythmias, and then for the treatment of hypertension, angina pectoris, acute myocardial infarction, and CHF.

Classificationβ - adrenergic blockers

More than 30 beta blockers are used in clinical practice, which are divided into the following groups.

Drugs acting on β 1 - and β 2 -adrenergic receptors or non-selective (propranolol, nadolol) and acting on β 1 -adrenergic receptors or cardioselective (atenolol, metoprolol, bisoprolol, nebivolol).

Drugs with internal sympathomimetic activity (pin-dolol) and without internal sympathomimetic activity (propranolol, nadolol, metoprolol, bisoprolol, nebivolol).

Drugs with a membrane-stabilizing effect (propranolol, pindolol, talinolol) and without a membrane-stabilizing effect (nadolol).

Drugs with a combined mechanism of action:

Blockade of α- and β-adrenergic receptors (labetalol®);

Non-selective β-blockade + blockade of α1-adrenergic receptors (carvedilol);

Non-selective β-blockade + α2-adrenergic stimulation (dilevalol);

Highly selective blockade of β 1 receptors + direct vasodilating effect associated with activation of the nitric monoxide system of endothelial origin (nebivolol).

There is another classification that characterizes BAB by generation (Table 10-10).

Table 10-10. Classification of BAB according to M.R. Bristow, 1998

Pharmacokineticsβ - adrenergic blockers

The pharmacokinetics of beta blockers depends largely on solubility in fats and water (Table 10-11). On this basis, all biologically active substances are divided into three groups: fat-soluble (lipophilic); water-soluble (hydrophilic); fat- and water-soluble.

Table 10-11. Pharmacokinetic characteristics of fat-soluble and water-soluble biologically active substances

Lipophilic biologically active substances(betaxolol, carvedilol, metoprolol, oxprenolol®, propranolol, timolol, nebivolol) are quickly and well (more than 90%) absorbed from the gastrointestinal tract, binding to plasma proteins is 80-95%. 80-100% undergo metabolic transformation in the liver. Because of this, in patients with reduced hepatic blood flow (elderly and senile age, severe heart failure) and liver diseases (hepatitis, cirrhosis), doses of lipophilic beta blockers should be reduced. Drugs in this group themselves can reduce hepatic blood flow (for example, propranolol - by 30%), which leads to a slowdown in its own metabolism in the liver, lengthening the half-life, especially with long-term use. Lipophilic beta blockers usually have a short half-life (from 1 to 5 hours) and because of this they must be prescribed at least 2-3 times a day (sometimes up to 4-6). Lipophilic beta blockers bind more strongly to β-adrenergic receptors. The disadvantage of these drugs is their ability to cause mild depressive disorders due to their penetration through the blood-brain barrier.

Hydrophilic BAB(atenolol, nadolol, sotalol) are not completely absorbed into the gastrointestinal tract (30-70%), excreted, as a rule, unchanged (40-70%) or in the form of metabolites by the kidneys and only insignificantly.

to a significant extent (up to 20%) undergo biotransformation in the liver. Hydrophilic drugs have a longer half-life (from 6 to 24 hours). They are usually prescribed 1-3 times a day. It should be noted that there are no significant differences in the half-life and duration of action of hydrophilic and prolonged forms of lipophilic biologically active substances. However, significant differences in elimination pathways remain, which should be taken into account when choosing drugs for long-term treatment. For example, the half-life of hydrophilic beta blockers increases in renal failure, in elderly and senile people, when the glomerular filtration rate decreases. Some lipophilic biologically active agents (propranolol) have active metabolites, which, like hydrophilic drugs, are excreted through the kidneys and can accumulate in renal failure. Lipophilic biologically active agents such as metoprolol or timolol do not have active metabolites. Thus, in chronic renal failure they are more preferable for long-term treatment. If you are prone to depression, especially in old age, it is more advisable to prescribe water-soluble drugs.

Lipo- and water-soluble biologically active substances soluble in both fats and water (bisoprolol, pindolol, celiprolol®). These drugs have two approximately equivalent elimination routes - hepatic and renal. Up to 40-60% of the absorbed drug undergoes biotransformation in the liver, the rest is excreted unchanged through the kidneys. Typically, drugs have a short half-life - from 3 to 12 hours. However, the effects caused by the blockade of β-adrenergic receptors can be longer, and the degree and duration of the adrenergic blocking effect increases as the dose of the drug increases.

The main indicators of the pharmacokinetics of some beta blockers are presented in table. 10-12.

BABs with a long half-life are considered promising. This is especially important in the treatment of hypertension, CHF, when drugs are needed to control blood pressure levels when taken 1-2 times a day.

Pharmacodynamicsβ - adrenergic blockers

Blockade of β-adrenergic receptors reduces the activity of adenylate cyclase, due to which the intracellular concentration of calcium decreases, the cell relaxes, and becomes less excitable.

Myocardium. BABs are competitive antagonists of catecholamines, reduce sympathetic effects on the cardiovascular system, and reduce blood pressure. Heart rate, myocardial contractility, and therefore myocardial oxygen demand decreases. This determines the antianginal activity of the drugs, although their use increases ejection time and LV volume, while coronary blood flow does not change or even decreases. In response to physical or psychoemotional stress, beta blockers help stabilize lysosomal membranes and increase cell resistance to ischemia. Thanks to the blockade of β-adrenergic receptors, the current of sodium ions in phases 0 and 4 decreases, the activity of the sinus node and ectopic foci decreases.

The membrane-stabilizing effect is associated with the ability of some beta blockers to influence membrane potassium channels and stabilize the intracellular potassium content. However, it is not of great importance and is not expressed when taking therapeutic doses of drugs.

Kidneys. With blockade of the juxtaglomerular apparatus by beta blockade, renin production decreases by 60%.

Vessels. Blockade of β 2 -adrenergic receptors first leads to the predominance of the vasoconstrictor effects of α-adrenergic receptors and an increase in peripheral vascular tone. Then vascular tone returns to normal or decreases through inverse autoregulatory reactions, which also explains the mechanism of the longer-term hypotensive effect of beta blockers.

Blood. BBs inhibit platelet aggregation and make red blood cells better “give” oxygen to ischemic cells.

DYS. Some dietary supplements eliminate symptoms of anxiety. Possible development of depressive disorders, impaired concentration, decreased reaction speed, and drowsiness. Beta blockers also reduce tremors.

Uterus. The drugs enhance the rhythmic and contractile activity of the myometrium.

Bronchi. Increases bronchial tone. In addition, beta blockers increase the tone of the lower esophageal sphincter. The effect is more pronounced in non-selective beta blockers; it is used for the treatment and prevention of reflux esophagitis. BBs can also enhance gastrointestinal motility and relax the muscle that pushes urine out (impaired bladder emptying). Some beta blockers (propranolol) inhibit the formation of active forms of thyroid hormones at the level of peripheral tissues.

In general, all beta blockers have similar pharmacological properties and their differences are not always significant. Cardioselective drugs have a predominant effect on β 1 -adrenergic receptors. However, the selectivity of most beta blockers is relative; it is leveled out with increasing doses of the drug. Nebivolol has the most pronounced cardioselectivity. The cardioselectivity coefficient of nebivolol is 288, that of bisoprolol is 75, while atenolol is only 19. Because of this, nebivolol and bisoprolol, unlike atenolol, do not reduce exercise tolerance, do not cause fatigue and do not affect the maximum performance, in addition, the drugs have little effect on bronchial patency and metabolic rate (can be prescribed to patients with MS and diabetes).

The presence of intrinsic sympathomimetic activity has long been of great importance. (Such drugs, along with blockade of receptors, can excite them somewhat.) Drugs with internal sympathomimetic activity (pindolol, acebutolol ®) have little effect on heart rate at rest, but reduce the degree of tachycardia during exercise. There was an assumption that these drugs reduce cardiac output less, dilate peripheral arteries, and cause peripheral circulatory disorders less frequently than other blockers. However, experience with the use of these drugs indicates that the intrinsic sympathomimetic activity of beta blockers is not of key importance for their effectiveness.

Clinical Applicationβ - adrenergic blockers

Arterial hypertension is the most important indication for the use of beta blockers. The drugs reduce the risk of cardiovascular complications, myocardial hypertrophy, reduce mortality, and increase the life expectancy of patients with hypertension. They can be prescribed as monotherapy or in combination with other antihypertensive drugs: diuretics, slow calcium channel blockers (dihydropyridine), and 1-adrenergic blockers. The combination with an ACE inhibitor is considered in some guidelines to be a less effective combination, but there are no evidence-based clinical studies on this topic.

When treating hypertension, preference should be given to beta blockers with vasodilating properties (carvedilol, nebivolol) and cardioselective drugs (bisoprolol, metoprolol, betaxolol, atenolol). The former are recommended to be prescribed due to increased peripheral vascular resistance in most patients. The latter have

less negative impact on vascular tone. For hypertension, it is advisable to use long-acting drugs (nebivolol, bisoprolol, metoprolol, betaxolol, talinolol). Firstly, due to the convenience of taking it once a day (in rare cases, 2 times), and secondly, the administration of long-acting beta blockers makes it possible to maintain a constant concentration of the drug in the blood, and therefore avoid fluctuations in the activity of the sympathoadrenal system.

A stable hypotensive effect of beta blockers develops 3-4 weeks after starting the drug. It is stable and does not depend on the physical activity and psycho-emotional state of the patient.

When prescribed as monotherapy, beta blockers significantly reduce blood pressure in 50-70% of patients. The hypotensive effect of beta blockers is enhanced in combination with diuretics, slow calcium channel blockers, α-blockers, and ACE inhibitors.

The principles for selecting beta blockers in patients with hypertension depending on concomitant diseases, syndromes or conditions are given in Table. 10-13.

Monitoring the effectiveness and safety of the use of biologically active substances

Since the initial level of sympathetic activity in different patients is unknown, at the beginning of treatment the drugs are prescribed in minimal therapeutic doses, gradually increasing them until a clinical effect is obtained (dose titration). The criterion for correctly selected dose is the blood pressure level. Interval extension PQ ECG indicates a violation of atrioventricular conduction and requires discontinuation or dose adjustment of the drug. It is necessary to monitor the contractile function of the heart using additional research methods (EchoCG). In elderly and senile patients, at the beginning of treatment, the dose of beta blockers is reduced by 2-4 times from the average therapeutic value. The selected dose can be prescribed long-term as maintenance therapy due to the fact that tolerance to beta blockers does not occur.

Efficacy and safety criteria

Clinical:

Heart rate at rest should be about 60 per minute (at least 50); with moderate physical activity (squats, bicycle exercises), heart rate should not increase above 100-120 per minute;

Decreased blood pressure;

No increase in signs of heart failure.

Laboratory, functional:

Determining the concentration of beta blockers in the blood is of no practical importance due to the individual variability of the response to the drug and the rate of biotransformation;

ECG: increasing interval PQ on an ECG more than 25% is considered dangerous;

Study of external respiration function with a tendency to bronchospasm;

Monitoring blood glucose concentration and lipid spectrum

(LDL and VLDL, as well as HDL). Adverse drug reactions

Side effects reflect nonspecific blockade of β 1 or β 2 adrenergic receptors. To eliminate them, it is necessary to completely discontinue the drug or limit the dose. The main NDRs associated with beta-blockers are listed below.

Caused mainly by blockade of β 2 -adrenergic receptors:

Bronchospasm;

Disorders of the peripheral vascular system (cold extremities; exacerbation of Raynaud's syndrome, intermittent claudication);

Deterioration of cerebral blood flow, manifested in some cases by a feeling of fatigue and drowsiness;

Possibility of a hypoglycemic state in patients with diabetes (beta blockers are adrenaline antagonists in relation to its hyperglycemic effect, in particular, glycogenolysis in the liver is inhibited). It is acceptable to prescribe beta blockers, especially cardioselective ones, to patients with compensated diabetes;

An increase in the concentration of cholesterol in the blood due to antagonism with adrenaline, which has a lipolytic effect (the concentration of total cholesterol does not change, the content of HDL cholesterol decreases, and VLDL cholesterol increases). However, these changes do not necessarily lead to atherogenesis.

Caused mainly by blockade of β 1-adrenergic receptors:

AV block.

Caused by blockade of β 1 - and β 2 -adrenergic receptors:

Direct effect on the central nervous system (for fat-soluble drugs) - insomnia, disturbing dreams, hallucinations, rarely - depression;

Postural hypotension;

Impotence.

The following pharmacological effects of beta blockers are of less importance.

Increased gastrointestinal motility, which can manifest as abdominal pain, vomiting, diarrhea, and less commonly, constipation.

Relaxation of the muscle that pushes urine out. This can cause discomfort for patients with prostatic hyperplasia; it is useful in the treatment of urinary incontinence, especially of a neurogenic nature.

Oculocutaneous syndrome. There may be a decrease in the secretion of the lacrimal glands (this effect can lead to the development of conjunctivitis or keratoconjunctivitis, especially in patients wearing contact lenses).

Contraindications for useβ - adrenergic blockers

BA.

Insulin-dependent diabetes.

Obstructive peripheral vascular diseases.

Impaired cardiac conduction.

Breastfeeding is a relative contraindication. Some biologically active substances accumulate in breast milk (nadolol). Taking beta blockers in an adequate dose, 1-2 times a day, and prescribing cardioselective drugs reduce the risk of undesirable effects.

Pheochromocytoma. The development of GC is possible when drugs without α-blocking activity are prescribed.

With the advent of highly selective beta blockers, pregnancy is no longer a contraindication for the use of this group of drugs.

The possibility of a sharp deterioration in the course of coronary artery disease and hypertension should be taken into account when suddenly stopping the use of beta blockers (withdrawal syndrome). In this case, an increase in angina attacks, an increase in blood pressure, and an increase in platelet aggregation are observed. BB should be discontinued gradually, with a dose reduction of 50% per week.

Interactionβ - adrenergic blockers with others

medicines

The antianginal effect is enhanced when beta-blockers are combined with nitrates, the side effects of nifedipine, which are associated with

associated with activation of the sympathoadrenal system. The combination with verapamil is considered effective, but as a result of the additive effect, undesirable effects are possible (bradycardia, AV block, arterial hypotension, heart failure). Bradycardia caused by digoxin increases. The effect of barbiturates is enhanced. The negative inotropic effect of quinidine and procainamide is potentiated. When a beta blocker is prescribed with clonidine, a decrease in blood pressure and bradycardia are observed, especially when the patient is in an upright position. Combination with amiodarone enhances the antiarrhythmic and antianginal effect. It is recommended to avoid inhalation anesthesia with diethyl ether, cyclopropane, chloroform due to the enhanced β-blocking effect (halothane is safe).

In addition to this, it should be noted that drugs that reduce the activity of microsomal liver enzymes (cimetidine, chlorpromazine) slow down the elimination of lipophilic beta blockers. Drugs that increase the activity of microsomal liver enzymes (barbiturates, phenytoin, rifampicin), as well as smoking, on the contrary, accelerate the elimination of lipophilic biologically active substances and have virtually no effect on the metabolism of hydrophilic biologically active substances.

Characteristics of basic drugs

Non-selectiveβ - adrenergic blockers

Propranolol(Obzidan*) is a kind of standard of drugs with β-adrenergic blocking activity. Bioavailability when taken orally is 36x10%. Approximately 93% of the drug in the blood is in a protein-bound state. T1/2 is 2-3 hours (in patients with liver failure, T1/2 increases). Volume of distribution - 3.9 l/kg. The drug undergoes biotransformation in the liver with the formation of active metabolites. Only 0.5% of the dose is excreted by the kidneys. The drug is taken at intervals of 4-6 hours.

Nadolol(Korgard *). It differs from other drugs in this group in its long-lasting action and ability to improve kidney function. Antianginal activity is higher than that of propranolol. The cardiodepressive effect is less pronounced. The bioavailability of nadolol when taken orally is 30x10%. Only 30% of the drug in the blood is in a protein-bound state. T1/2 of nadolol is 20-24 hours (in patients with renal failure T1/2 increases). Effective Concentration

is achieved after 6-9 days of administration. Volume of distribution - 2.1 l/kg. During metabolism, inactive metabolites are not formed. Up to 76% of the dose is excreted by the kidneys.

Pindolol(Wisken *). Causes a less pronounced negative inotropic effect than propranolol. To a lesser extent than other non-selective beta blockers, it affects β 2 -adrenergic receptors. Safer for bronchospasm and diabetes. In hypertension, the effect of pindolol is lower than that of propranolol.

Pindolol is almost completely absorbed from the gastrointestinal tract, its bioavailability when taken orally is 95%, only 40% of the drug in the blood is in a protein-bound state. T 1/2 of pindolol is 3-4 hours. The volume of distribution is 2.0 l/kg. During metabolism, inactive metabolites are not formed. About 35-40% of the dose is excreted by the kidneys. The drug is taken orally 3-4 times a day.

Cardioselective beta blockers

Atenolol(Tenoretic*) is a selective β 1 -blocker without its own sympathomimetic and membrane-stabilizing activity. The drug can be taken 2 times a day, it has weak cardioselectivity, and is practically free of central side effects. The advantages of the drug include low cost.

The bioavailability of atenolol when taken orally is 40±10%. Only 5% of the drug in the blood is in a bound state. T1/2 is 6-7 hours, T1/2 increases significantly in patients with chronic renal failure. Volume of distribution - 0.7 l/kg. About 85% of the drug is excreted by the kidneys, and in case of chronic renal failure, dose adjustment is necessary.

Metoprolol(Betalok*, Betalok-ZOK*). Cardioselective β 1 -blocker with its own sympathomimetic activity. Bioavailability when taken orally is 50%, undergoes intensive first-pass metabolism in the liver, has no active metabolites. Penetrates well through the blood-brain barrier and is found in high concentrations in breast milk. T1/2 ranges from 3 to 7 hours; an increase in T1/2 is noted in individuals belonging to the category of “slow” metabolizers (see Chapter 9). Volume of distribution - 5.6 l/kg. Only 5% of the dose is excreted by the kidneys, and in case of renal failure, significant accumulation in the body is not observed; in patients with liver cirrhosis, biotransformation slows down. The hypotensive effect occurs quickly: systolic blood pressure begins to decrease after 15 minutes. Prescribed for hypertension and angina pectoris 2 times a day.

Bisoprolol(Concor *) is one of the most selective β 1 -blockers. Has hypotensive, antiarrhythmic,

antianginal effect. In therapeutic doses it does not have internal sympathomimetic activity and clinically significant membrane-stabilizing properties. Absorption - 80-90%, food intake does not affect absorption, time to reach Cmax - 2-4 hours, protein binding - 26-33%, biotransformation in the liver, T1/2 -9-12 hours, excretion - by the kidneys (50% unchanged), less than 2% in feces. Penetration through the blood-brain barrier (BBB) ​​and placental barrier is low, secretion into breast milk is low.

Bisoprolol provides a controlled decrease in blood pressure, depending on the dose of the drug, smoothly reduces blood pressure throughout the day, including in the early morning hours, it can be taken for a long time without developing tolerance. High β-selectivity allows the use of bisoprolol in special groups of patients: patients with diabetes, lipid metabolism disorders; two routes of elimination make it possible to prescribe bisoprolol to patients with impaired liver and kidney function, as well as for the treatment of CHF (causes regression of myocardial hypertrophy).

Betaxolol(Lokren *). Does not have internal sympathomimetic activity. When prescribed in high doses, it has a membrane-stabilizing effect. About 89-95% is absorbed from the gastrointestinal tract, approximately half of the drug in the blood is in a protein-bound state. T 1/2 of betaxolol is 14-22 hours. The volume of distribution is 6.1 l/kg. It undergoes biotransformation in the liver; the metabolites do not have pharmacological activity and are excreted by the kidneys. About 15% of the dose is excreted unchanged by the kidneys. Betaxolol is prescribed once a day.

Drugs with a combined mechanism of action

Bioavailability when taken orally is 25%, reaching maximum concentration in the blood after 2 hours. 50% bound to plasma proteins. T 1/2 of labetolol® is 6-8 hours. The volume of distribution is 9.4 l/kg. Subject to biotransformation in the liver. During metabolism, inactive products are not formed. Only 5% of the dose is excreted by the kidneys. In renal failure, drug excretion does not change significantly.

Carvedilol(Dilatrend*) - blocker of α 1 - and β 12 -adrenergic receptors. Blockade of β 1-adrenergic receptors leads to a decrease in the frequency and strength of heart contractions without severe bradycardia and decreased conductivity. As a result of blockade of α 1 -adrenergic receptors, peripheral vessels dilate. Blockade of β 2 -adrenergic receptors causes a slight increase in the tone of the bronchi, microvasculature, increased tone and intestinal motility.

Rapidly absorbed when taken orally; food intake can reduce the degree of adsorption, but does not reduce its intensity. When taken simultaneously with food, the risk of developing orthostatic hypotension is reduced. The bioavailability of carvedilol is 25-35%. There is a first-pass effect through the liver; the intensity of metabolism may be affected by CYP2D6 inhibitors. T 1/2 is 7-10 hours.

The most serious ADR when taking carvedilol is considered to be orthostatic hypotension (about 2% of cases), because of this, after the first prescription of the drug, the patient must remain in a sitting or lying position for several hours. Sometimes after taking carvedilol, chest pain and impaired glucose tolerance occur; drowsiness that goes away after 7-10 days of regular use of the drug. Carvedilol is taken orally 1-2 times a day.

Nebivolol(Nebilet *) is a new generation beta blocker that has high selectivity for β 1 -adrenergic receptors, differing from other drugs of this class in its direct vasodilatory effect by stimulating the endothelial production of nitric oxide. It is prescribed for the treatment of hypertension, ischemic heart disease, and heart failure. Side effects typical of other beta blockers are observed much less frequently. No dose titration is required to obtain the desired effect.

10.5. CLINICAL PHARMACOLOGY OF SLOW CALCIUM BLOCKERS

CHANNELS

BMCC are drugs that, by blocking cell membrane channels, prevent the flow of calcium ions.

Classification of slow blockers

calcium channels

There are several options for classifying BMCC. A. By chemical nature.

Phenylalkylamines (verapamil).

Benzothiazepines (diltiazem).

Dihydropyridines (nifedipine, nisoldipine* 3, amlodipine).

Diphenylpiperazines (cinnarizine, flunarizine®).

The structural features of drugs from different chemical groups determine differences in tissue selectivity (Table 10-14). Thus, phenylalkylamines (verapamil) act predominantly on the heart (especially on the conduction system) and to a lesser extent on arterial vessels. Diltiazem has an approximately equal effect on the conduction system of the heart and blood vessels. Dihydropyridines (nifedipine), on the contrary, predominantly affect arterial vessels and to a lesser extent the heart. Diphenylpiperazines (cinnarizine, flunarizine®) selectively affect the arterial vessels of the brain.

Table 10-14. Selectivity (vessels/myocardium) and pharmacological action of various BMCCs

B. There is a division of BMKK according to the duration of action.

Short-acting drugs: verapamil, nifedipine, dil-tiazem.

Long-acting drugs: isoptin SR 240*, altiazem RR*, adalat SR, amlodipine.

The disadvantage of short-acting BMCC is considered to be frequent daily fluctuations in the concentration of the drug in the blood, therefore, an unstable effect. Long-acting drugs are represented by two subgroups.

Special dosage forms with sustained release of a short-acting drug:

Retard form in the form of tablets or capsules with a slow release of the drug from the dosage form (isoptin SR 240 *, altiazem RR *);

Rapid retard form with two-phase release of the drug (adalat CL*>);

Daily action medicinal therapeutic systems (adalat GITS* 3).

New dihydropyridine derivatives: nitrendipine, amlodipine, etc.

There is also a division of BMKK by generation. In particular, the first generation includes short-acting drugs, and the second generation includes long-acting drugs.

Pharmacokinetics of slow calcium channel blockers

Pharmacokinetic parameters of the main BMCCs are presented in table. 10-15 and 10-16.

Table 10-15. Pharmacokinetic parameters of some BMCCs (part 1)

Table 10-16. Pharmacodynamic parameters of some BMCCs (part 2)

Pharmacodynamics of slow calcium channel blockers

Calcium ions perform a special function in maintaining the functional activity of cells. They regulate the contraction of muscle fibers, the release of mediators by nerve cells, and the secretion of enzymes and hormones. The importance of extracellular and intracellular calcium in the contraction of different types of muscles is different. For example, to contract skeletal muscle, only calcium found in the sarcoplasmic reticulum is consumed. Contraction of the heart muscle is 95% provided by calcium from the sarcoplasmic reticulum, and 5% by extracellular “seed” calcium. In vascular smooth muscle cells, the sarcoplasmic reticulum is not developed, and contraction is almost entirely dependent on extracellular calcium. For calcium to enter the cell, ion channels are used: voltage-dependent and receptor-dependent. Voltage-gated channels open when the membrane potential changes. There are several types of voltage-gated calcium channels: L, T, N, P, R.

BMCCs block L- and T-calcium-conducting channels of smooth muscle cells and reduce the flow of calcium into them. This mechanism leads to a decrease in cardiac output (phenylalkylamines and benzothiazepines), a decrease in peripheral arteriolar resistance (dihydropyridines) and a decrease in blood pressure. Then the sympathoadrenal system and RAAS are activated. At the same time, phenylalkylamines and benzothiazepines neutralize the stimulating effect of catecholamines on the myocardium through a direct cardiodepressive effect, and the use of dihydropyridines (especially short-acting ones) can lead to tachycardia and an increase in myocardial oxygen demand.

Drugs in this group reduce the tone of the coronary vessels and increase coronary blood flow. Relaxation of arterioles under the influence of BMCC significantly reduces the afterload on the heart. The listed effects create gentle conditions for cardiac activity and increase the delivery of oxygen to the myocardium. These drugs have cardioprotective properties: they reduce mitochondrial damage in cardiomyocytes, increase the concentration of ATP, and stimulate collateral blood flow in ischemic myocardium. In hypertension, they cause reverse development of LV hypertrophy.

Verapamil and diltiazem reduce the automaticity of the sinus AV node and ectopic foci, reduce conduction in the AV node and increase the effective refractory period of the atria.

BMCC have a beneficial effect on the kidneys. They reduce the tone of the renal arteries, improve glomerular filtration and increase sodium excretion by the kidneys, which contributes to the hypotensive effect.

Drugs in this group inhibit platelet aggregation and have antiatherogenic properties. BMCC is prescribed for hypertension, coronary artery disease, arrhythmias, hypertrophic cardiomyopathy, and cerebrovascular accidents.

Monitoring the effectiveness and safety of BMKK

When prescribing BMCC, it is necessary to monitor blood pressure, heart rate, conductivity (dihydropyridines increase the rhythm, phenylalkylamines and benzothiazepines slow the rhythm, reduce conductivity and prolong the interval PQ), as well as myocardial contractility (EchoCG).

In addition, it must be taken into account that when using short-acting dihydropyridines (nifedipine) for the treatment of hypertension, the risk of death or the development of cardiovascular complications increases. Prescribing short-acting drugs to patients who have had a MI should be avoided. It is not recommended to take short-acting forms of nifedipine during hypertensive crises, since they cause a sharp decrease in blood pressure and thereby can provoke the development of myocardial, cerebral and kidney ischemia. Long-acting forms of verapamil, diltiazem, nifedipine are better tolerated. Long-term use of BMCC is undesirable for LV systolic dysfunction, sick sinus syndrome, II-III degree AV block, at the beginning of pregnancy and during lactation.

Adverse drug reactions

Significant adverse reactions when prescribing BMCC in therapeutic doses are rarely observed. The main NLRs are divided into three groups.

Effect on blood vessels: headache, dizziness, hot flashes in 7-10% of patients, palpitations, swelling of the feet in 5-15% of patients, transient hypotension.

Effect on the heart: decreased conductivity and force of heart contractions (especially with verapamil), bradycardia (verapamil and diltiazem - in 25% of patients).

Gastrointestinal disorders (constipation in 20% of patients, diarrhea, nausea in 3%).

The drugs are not prescribed for cardiogenic shock, severe bradycardia, arterial hypotension, or heart failure.

Interactions of slow calcium channel blockers with other drugs

means

Drug interactions are presented in table. 10-17.

Characteristics of basic drugs

Verapamil(Isoptin*) is a derivative of phenylalkylamines. The first BMKK. It has antiarrhythmic, antianginal and hypotensive effects, reduces myocardial oxygen demand by reducing myocardial contractility and heart rate. Causes dilatation of the coronary arteries and an increase in coronary blood flow. As an antiarrhythmic it is effective for supraventricular arrhythmias (for more details, see Chapter 13).

Diltiazem- benzothiazepine derivative. In terms of pharmacodynamic properties, diltiazem occupies an intermediate position between verapamil and nifedipine. It reduces the activity of the sinus node and inhibits atrioventricular conduction to a lesser extent than verapamil, and has less effect on total peripheral vascular resistance (TPVR) than nifedipine.

Diltiazem undergoes biotransformation in the liver with the formation of an active metabolite - desacetyldiltiazem, is excreted by the kidneys, mainly in the form of metabolites and only 2-4% of the drug is excreted unchanged.

The drug is prescribed for hypertension, for the prevention of angina attacks, including vasospastic (Prinzmetal angina), supraventricular arrhythmias (paroxysmal supraventricular tachycardia, atrial fibrillation, atrial flutter, extrasystole).

The drug is contraindicated in sick sinus syndrome and atrioventricular conduction disorders.

Continuation of the table. 10-17

End of table. 10-17

Nifedipine(Adalat*, Corinfar*) - a derivative of dihydropyridine. Reduces the tone of coronary and peripheral vessels and blood pressure, increases coronary blood flow in atherosclerotic obstruction. The drug has a negative inotropic effect, does not affect conductivity in the myocardium, and does not have antiarrhythmic properties. With long-term use, it reduces the incidence of new atherosclerotic damage to the coronary vessels and blocks platelet aggregation.

In elderly patients, the drug is 2 times more than in young patients. When administered sublingually, the effect begins within 5-10 minutes, reaching a maximum after 15-30 minutes. The drug is less lipophylic compared to verapamil and penetrates tissue less. Nifedipine undergoes biotransformation in the liver; inactive metabolites are excreted by the kidneys.

The administration of short-acting forms of nifedipine leads to tachycardia and an increase in myocardial oxygen demand, which significantly limits its use in hypertension and coronary artery disease. The disadvantage of nifedipine is its short duration of action, as well as the need for repeated administration, which not only creates inconvenience for patients, but also causes significant daily fluctuations in blood pressure. For long-term treatment of hypertension, it is recommended to prescribe retard forms of nifedipine or second-generation dihydropyridine BMCCs.

Adalat SL * is a dosage form with a two-phase release of nifedipine, containing microgranules of a fast-release drug (5 mg) and delayed release nifedipine (15 mg). The result of this combination is a rapid onset of action and an increased duration of the therapeutic effect (up to 8-10 hours).

Adalat GITS* 3 (GITS - gastrointestinal therapeutic system)- long-acting therapeutic systems. Such therapeutic systems are based on the release of the drug from the dosage form under the influence of osmosis. The GITS system consists of two layers: the first contains the drug, and the second contains a polymeric osmotic active substance. Such a two-layer tablet is covered with a water-permeable insoluble membrane, in which a hole is punched with a laser on the side of the drug. When the system enters the stomach, water, penetrating through the membrane, converts the active substance into a suspension, while simultaneously binding to the osmotically active filler. The filler forces the nifedipine suspension through the laser hole at a constant speed.

The duration of action of such a drug is 24 hours. In this case, due to the slow development of the vasodilating effect, the sympatho-drenal system is slightly activated. When using long-acting drugs, the concentration of norepinephrine in the blood practically does not change. This can significantly reduce the severity of reflex tachycardia and accelerate the reverse development of LV hypertrophy. In general, the use of long-acting medications can reduce the incidence of

NLR 3-4 times.

When taking nifedipine, allergic reactions (skin rashes and fever), sleep disturbances, and vision disorders may develop. Very rarely, hematological disorders (thrombocytopenia, leukopenia, anemia), allergic hepatitis, gingivitis, depression and paranoid syndrome, fainting, temporary impairment of liver function are noted. Short-acting nifedipine is characterized by tachycardia, increased myocardial oxygen demand, and blood pressure fluctuations.

When prescribing nifedipine in combination with cardiac glycosides, the dose of the latter should be reduced by 40-50%. The combination of nifedipine with beta blockers can provoke the development of hypotension. Cimetidine and diltiazem increase the concentration of nifedipine in the blood.

Amlodipine(Norvasc*) is a long-acting BMCC. The drug is well absorbed from the gastrointestinal tract. Food intake does not affect the absorption of amlodipine. Bioavailability - 60-80%. The maximum concentration in the blood is observed after 6-12 hours, a stable concentration in plasma is achieved after 7-8 days of continuous use of the drug. Amlodipine undergoes biotransformation in the liver with the formation of inactive metabolites, T1/2 - up to 50 hours. For ischemic heart disease, amlodipine can be prescribed as monotherapy and in combination with other antianginal drugs. It is possible to use amlodipine for diastolic myocardial dysfunction.

Nitrendipine(Octidipine *) is a long-acting dihydropyridine derivative. Has hypotensive and antianginal activity. Bioavailability - 60-70%. T 1/2 -8-12 hours.

Felodipin(Plendil*) is a drug with high vasoselectivity, 7 times higher than that of nifedipine. Has a moderate diuretic (natriuretic) effect. The drug has low bioavailability - 15%. The latent period for intravenous administration is 10-15 minutes, for enteral administration - 45 minutes.

10.6. CLINICAL PHARMACOLOGYα -ADRENOBLOCKERS

α-adrenergic receptor blockers have been used for the treatment of hypertension for more than 40 years; currently they are considered as additional drugs in combination with drugs of the main classes.

The classification of drugs is based on their selectivity towards various receptors.

Non-selective α-blockers: dihydrogenated ergot alkaloids, tropodiphene, phentolamine;

Selective α1-blockers: prazosin, doxazosin, terazosin.

Currently, for hypertension, selective α1-adrenergic blockers are prescribed, which, when used for a long time, have a hypotensive effect comparable to thiazide diuretics, beta blockers, BMCCs and ACE inhibitors. The drugs, by blocking α1-adrenergic receptors, reduce systemic vascular resistance, cause reverse development of LV hypertrophy, and improve blood lipid composition. They significantly reduce the concentration of total cholesterol in the blood due to LDL and at the same time increase the concentration of HDL. The drugs increase tissue sensitivity to insulin and cause a slight decrease in glucose concentration. The presence of a large number of a 1 -adrenergic receptors in the smooth muscles of the prostate gland and the bladder neck makes it possible to prescribe drugs to patients with prostate adenoma to improve urination.

Prazosin- a selective a 1 -adrenergic blocker of short action, when taken orally it is quickly absorbed into the gastrointestinal tract. Bioavailability - 60%. More than 90% of prazosin is bound to plasma proteins. The maximum concentration in the blood is determined after 2-3 hours. T 1 / 2 -3-4 hours. The effect of the drug begins after 30-60 minutes, duration - 4-6 hours. Prazosin undergoes biotransformation in the liver. 90% of the drug and its metabolites are excreted through the intestines, the rest through the kidneys. The frequency of administration is 2-3 times a day. Prazosin is characterized by a “first dose” effect - a sharp decrease in blood pressure after taking the first dose of the drug, because of this it is taken lying down, especially for the first time, and treatment is started with small doses (0.5-1 mg). The drug causes postural hypotension, weakness, drowsiness, dizziness, and headache. Due to the short duration of action and NDRs of prazosin

is not widely used for the treatment of hypertension.

Doxazosin(Kardura*) is a long-acting α1-adrenergic blocker, does not cause the “first dose” effect. Doxazosin is almost completely absorbed from the gastrointestinal tract. Food slows down the absorption of the drug by about 1 hour. Bioavailability is 65-70%. The maximum concentration in the blood is determined 2-3.5 hours after administration. T 1 / 2 -16-22 hours. Duration of action - 18-36 hours. Doxazosin is prescribed 1 time per day. When taking the drug at night, the maximum effect occurs during the morning rise in blood pressure, which is associated with circadian activation of the sympathoadrenal system. According to long-term clinical observations, doxazosin monotherapy is effective in 66% of patients. Doxazosin reverses the development of LV hypertrophy and reduces the increased risk of cardiovascular complications in patients with hypertension. The drug facilitates the passage of urine in patients with prostate adenoma. The following ADRs are characteristic of doxazosin: dizziness, weakness, drowsiness, arterial hypotension. If the effectiveness is insufficient, doxazosin is combined with BMCC, beta blockers, ACE inhibitors, and diuretics.

Phentolamine- non-selective a-blocker. Mainly indicated in the treatment of hypertensive crises associated with overproduction of catecholamines, for example, in patients with pheochromocytoma. In addition, phentolamine is prescribed for diagnostic purposes in cases of suspected pheochromocytoma. Phentolamine and other non-selective α-blockers are currently not used for the treatment of hypertension due to the frequent development of orthostatic hypotension, tachycardia, dizziness, and weakness.

10.7. USE OF DIURETICS FOR TREATMENT OF ARTERIAL HYPERTENSION

Diuretics have been prescribed for hypertension for a long time; at first they were used as auxiliaries. Currently, thiazide and thiazide-like diuretics are considered the drugs of choice for long-term combination treatment and monotherapy of hypertension.

The role of increasing the concentration of sodium ions in the plasma and vascular wall in the pathogenesis of hypertension is well known, and saluretics - drugs, mechanism - are of primary importance in the treatment of hypertension

which is associated with inhibition of sodium and chlorine reabsorption. These include benzothiadiazine derivatives and thiazide-like diuretics. As monotherapy, thiazide and thiazide-like diuretics in low doses are effective in 25-65% of patients with mild and moderate hypertension. In emergency situations, for example during a hypertensive crisis, “loop” diuretics are used: furosemide and ethacrynic acid. Sometimes potassium-sparing diuretics are prescribed as monotherapy. This group often serves a supportive role and is usually prescribed with thiazide and loop diuretics to reduce potassium loss.

The initial decrease in blood pressure with saluretics is associated with an increase in sodium excretion, a decrease in plasma volume, and a decrease in cardiac output. After 2 months of treatment, the diuretic effect decreases and cardiac output normalizes. This is due to a compensatory increase in the concentration of renin and aldosterone, which prevent fluid loss. The hypotensive effect of diuretics at this stage is explained by a decrease in peripheral vascular resistance, most likely due to a decrease in the concentration of sodium ions in vascular smooth muscle cells. Diuretics reduce both systolic and diastolic blood pressure and have a slight effect on cardiac output.

When using diuretics as blood pressure lowering agents, the duration of their action should be taken into account (Table 10-18) to ensure the constancy of the hypotensive effect of these drugs throughout the day.

Table 10-18. Duration of the hypotensive effect of some diuretics

The use of diuretics for hypertension reduces the likelihood of developing stroke. The possibility of developing stroke and decompensation of CHF is more markedly reduced with long-term use of comparable doses of thiazide and thiazide-like diuretics (at least 25 mg of hydrochlorothiazide per day). When prescribing thiazide and thiazide-like

These diuretics may reduce the glomerular filtration rate, and these drugs (with the exception of indapamide) are not recommended for use as monotherapy in patients with impaired renal function. It is undesirable to prescribe thiazide diuretics for long-term monotherapy of hypertension in patients with insulin-dependent diabetes. According to various studies, the use of thiazide diuretics in such patients significantly increases their mortality. When treating hypertension in patients with non-insulin-dependent diabetes, the prescription of thiazide diuretics is permissible in small doses (no more than 25 mg of hydrochlorothiazide or clopamide per day). Diuretics cause reversal of LV hypertrophy. As monotherapy, thiazide and thiazide-like diuretics are prescribed in low doses. Increasing the dose of a diuretic leads to an increase in the hypotensive effect, but also increases the risk of ADR. Diuretics enhance the hypotensive effect of beta blockers, ACE inhibitors, and AT 1 receptor blockers.

10.8. CLINICAL PHARMACOLOGY OF CENTRAL HYPOTENSIVE DRUGS

ACTIONS

Centrally acting drugs reduce the activity of the vasomotor center of the medulla oblongata; they are currently prescribed as additional drugs for the treatment of hypertension.

Clonidine(Gemiton*®, clonidine*) is an imidazoline derivative, a stimulator of central α2-adrenergic and β-receptors. Not recommended for continuous use, except in cases of treatment-refractory or malignant hypertension.

Pharmacokinetics of clonidine. The drug is well absorbed from the gastrointestinal tract. When taken orally, the effect of the drug occurs within 30-60 minutes, intravenous administration - 3-6 minutes. When administered enterally, the maximum concentration in the blood is recorded after 3-5 hours, T1/2 -12-16 hours, with impaired renal function it increases to 41 hours. Clonidine is excreted from the body by the kidneys mainly in the form of metabolites.

Pharmacodynamics of clonidine. The drug stimulates the receptors of the nuclei of the solitary tract of the medulla oblongata, which leads to inhibition of neurons of the vasomotor center and a decrease in sympathetic innervation. The hypotensive effect of the drug is due to a decrease in cardiac output and peripheral vascular resistance. When administering the drug intravenously,

That hypotensive effect may be preceded by a short-term increase in blood pressure due to stimulation of vascular α2-adrenergic receptors.

NLR. When you stop taking the drug, a “withdrawal” syndrome occurs - a sharp increase in blood pressure. Clonidine has a sedative and hypnogenic effect, potentiates the central effects of alcohol, sedatives, and depressants. When clonidine is combined with tricyclic antidepressants, blood pressure increases. The drug reduces appetite, secretion of the salivary glands, and retains sodium and water.

Contraindications. Clonidine is contraindicated in cerebral atherosclerosis, depression, decompensated CHF, as well as in patients whose profession requires increased attention.

Methyldopa(Dopegit*) is converted into α-methylnorepinephrine, which stimulates central α2-adrenergic receptors in the solitary tract.

Pharmacokinetics of methyldopa. When taken orally, 20-50% of the drug is absorbed. The maximum hypotensive effect develops after 4-6 hours, duration of action is up to 24 hours, binding to plasma proteins is 20%. It undergoes biotransformation in the liver and is excreted by the kidneys.

Pharmacodynamics of methyldopa. An indirect decrease in the activity of the vasomotor center leads to a decrease in peripheral vascular resistance and a decrease in blood pressure. The drug has a slight effect on cardiac activity. Increases glomerular filtration rate and renal blood flow. Has a slight sedative effect. Experimental studies have not revealed any adverse effects of the drug on the fetus, so methyldopa can be considered as the drug of choice in the treatment of hypertension in pregnant women.

NLR. Methyldopa can cause drowsiness, dry mouth, sodium and water ion retention, and rarely - agranulocytosis, myocarditis, hemolytic anemia. Methyldopa is not combined with tricyclic antidepressants and sympathomimetic amines due to the possibility of increasing blood pressure.

Moxonidine(Physiotens*) - agonist of ^-receptors.

Pharmacokinetics of moxonidine. The drug is well absorbed from the gastrointestinal tract and has high bioavailability (88%). The maximum concentration in the blood is recorded after 0.5-3 hours. 90% of the drug is excreted by the kidneys, mainly (70%) unchanged. Despite the short half-life (about 3 hours), it controls blood pressure throughout the day.

Pharmacodynamics. Activation of imidazoline receptors in the central nervous system leads to a decrease in the activity of the vasomotor center and a decrease in peripheral vascular resistance. Moxonidine is effective as monotherapy for hypertension. It is safer than clonidine, propranolol, captopril, nifedipine. The sedative effect is significantly less pronounced than that of other centrally acting drugs.

NLR. Moxonidine may cause fatigue, headaches, dizziness, and sleep disturbances.

Contraindications for use the drug - sick sinus syndrome, AV block of II and III degrees, severe bradycardia, severe arrhythmias, unstable angina.

Interaction of moxonidine with other drugs. The combination of moxonidine with other antihypertensive drugs enhances their antihypertensive effect. The drug potentiates the effects of drugs that depress the central nervous system - ethanol, tranquilizers, barbiturates.

10.9. CLINICAL PHARMACOLOGY

VASODILATORS

Vasodilators for the treatment of hypertension are represented by drugs of two groups: with a predominant effect on the arteries (hydralazine, minoxidil) and mixed action (sodium nitroprusside) - Table. 10-19. Arteriolar vasodilators dilate resistive vessels (arterioles and small arteries) and reduce peripheral vascular resistance. In this case, a reflex increase in heart rate and cardiac output occurs. The asset increases

Table 10-19. Effects of vasodilators

activity of the sympathoadrenal system and renin secretion. The drugs cause sodium and water retention. Mixed-action vasodilators also cause dilation of capacitance vessels (venules, small veins) with a decrease in venous return of blood to the heart.

Hydralazine due to the large number of adverse reactions (tachycardia, pain in the heart, facial flushing, headache, lupus-like syndrome) they are prescribed rarely and only in the form of ready-made combinations of drugs (adelfan-esidrex *). It is contraindicated for stomach ulcers and autoimmune processes.

Diazoxide- arteriolar vasodilator, potassium channel activator. The effect on potassium channels leads to hyperpolarization of the muscle cell membrane, which reduces the influx of calcium ions necessary to maintain vascular tone. The drug is prescribed intravenously for hypertensive crisis. Duration of action is approximately 3 hours. Undesirable reactions during use include hyperglycemia, cerebral or myocardial ischemia. The drug is contraindicated in cases of cerebrovascular accidents and in the acute period of myocardial infarction.

Minoxidil(Regaine *) - arteriolar vasodilator, potassium channel activator. The drug is well absorbed from the gastrointestinal tract. T 1/2 - 4 hours. Minoxidil is taken orally 2 times a day, gradually increasing the dose. When applied topically, it causes active hair growth, which can be used to treat baldness.

Sodium nitroprusside- mixed arteriovenous vasodilator. The hypotensive effect is associated with the release of nitric oxide from the drug molecule, which acts similarly to the endogenous endothelium-relaxing factor. Thus, its mechanism of action is similar to nitroglycerin. Sodium nitroprusside causes an increase in heart rate without increasing cardiac output. However, with a decrease in LV contractile function, the drug increases cardiac output and can be prescribed for heart failure and pulmonary edema. Sodium nitroprusside is prescribed intravenously because it does not have a hypotensive effect when taken orally. When administered intravenously, the latent period of the drug is 1-5 minutes, after the end of administration it acts for another 10-15 minutes. Sodium nitroprusside is used for hypertensive crises and acute left ventricular failure. ADRs include headache, anxiety, and tachycardia.

10.10. CLINICAL PHARMACOLOGY

RENIN INHIBITOR

Currently, the first selective renin inhibitor of a non-peptide structure with pronounced activity, aliskiren, has undergone clinical trials and is registered in many countries of the world, including the Russian Federation.

Aliskiren(Rasilez *) acts by binding to the active site of the renin molecule, thereby preventing the binding of renin to angiotensinogen and blocking the formation of angiotensin I, the precursor of angiotensin II. The optimal initial dose of Aliski-Ren is 150 mg once a day; if necessary, the dose is increased to 300 mg. For mild and moderate hypertension, aliskiren can be prescribed as monotherapy once a day, providing a significant dose-dependent reduction in blood pressure. The antihypertensive effect of aliskiren persists for more than 24 hours after administration.

Aliskiren has at least comparable effectiveness to antihypertensive drugs from other groups. Its antihypertensive effect is enhanced when co-administered with ACE inhibitors, ARBs, BMCCs or diuretics. In addition, three studies demonstrated additional cardioprotective and nephroprotective properties of the drug. The addition of aliskiren to the standard treatment of patients with hypertension and CHF leads to a significantly greater decrease in the concentration of brain natriuretic peptide in the blood plasma (a marker of the severity of heart failure). Aliskiren reduces LV myocardial hypertrophy in patients with hypertension comparable to losartan, and when added to losartan, provides an additional decrease in the albumin/creatinine ratio in the urine compared to placebo in patients with hypertension, diabetes and nephropathy, which indicates the pronounced nephroprotective properties of the drug. The severity of the antihypertensive effect of aliskiren does not depend on age, gender, race and body mass index.

10.11. CLINICAL PHARMACOLOGY

SYMPATHOLYTICS

In modern cardiological practice, these drugs are rarely used. Sympatholytics include reserpine and guanethidine. These drugs disrupt the transmission of excitation by acting presynaptically

chesically By acting on the endings of adrenergic nerve fibers, these substances reduce the amount of norepinephrine released in response to nerve impulses. They do not affect adrenergic receptors.

Reserpine- Rauwolfia alkaloid. The drug disrupts the deposition of norepinephrine in vesicles, which leads to its destruction by cytoplasmic monoamine oxidase. Reserpine reduces the content of norepinephrine in the heart, blood vessels, central nervous system and other organs. The hypotensive effect of reserpine when taken orally develops gradually over 7-10 days, after intravenous administration of the drug - within 2-4 hours. Reserpine has a hypotensive effect only in 25% of patients, even in conditions of “mild” hypertension.

NLR: drowsiness, depression, stomach pain, diarrhea, bradycardia, bronchospasm. The drug causes sodium and water retention in the body. With long-term use, the development of drug-induced parkinsonism is possible.

For the treatment of hypertension, official combinations of drugs containing sympatholytics are still used: reserpine, hydralazine and hydrochlorothiazide; reserpine, dihydralazine®, hydrochlorothiazide, potassium chloride; reserpine, α-blockers - dihydroergocristine and clopamide.

Guanethidine disrupts the process of norepinephrine release and prevents the reuptake of the transmitter by sympathetic endings. The decrease in blood pressure is due to a decrease in cardiac output and a decrease in peripheral vascular resistance. Bioavailability of the drug is 50%. T 1/2 - about 5 days.

NLR: the drug causes postural hypotension, severe bradycardia, sodium and water retention in the body, dizziness, weakness, swelling of the nasal mucosa, and diarrhea.

Contraindications: severe atherosclerosis, stroke, myocardial infarction, renal failure, pheochromocytoma.

10.12. PRINCIPLES OF PHARMACOTHERAPY

HYPERTENSION CRISIS

HA is an acute, pronounced increase in blood pressure, accompanied by clinical symptoms, requiring an immediate, controlled decrease in blood pressure to prevent or limit target organ damage.

Hypertensive crises are divided into two large groups - complicated (life-threatening) and uncomplicated (non-life-threatening).

GC is considered complicated in the following cases:

Hypertensive encephalopathy;

ONMK;

Acute coronary syndrome (ACS);

Acute left ventricular failure;

Dissecting aortic aneurysm;

GC for pheochromocytoma;

Preeclampsia or eclampsia;

Severe hypertension associated with subarachnoid hemorrhage or brain injury;

Hypertension in patients in the postoperative period and with the threat of bleeding;

GK while taking amphetamines, cocaine and other drugs. In most cases, HA develops during systolic

Blood pressure >180 mm Hg. Art. and/or diastolic blood pressure >120 mm Hg. Art., but the development of this emergency condition is possible even with a less pronounced increase in blood pressure. All patients with GC require a rapid reduction in blood pressure.

GK is usually accompanied by severe headache, dizziness, nausea, vomiting, feeling hot, sweating, palpitations, and a feeling of lack of air. A particularly pronounced increase in blood pressure can lead to the development hypertensive encephalopathy(drowsiness, drowsiness, cerebrovascular accident) or the development of acute left ventricular failure (pulmonary edema).

GK requires urgent treatment, since a sharp increase in blood pressure poses a threat of cerebrovascular accident and the development of acute heart failure.

In case of uncomplicated HA, intravenous or sublingual administration and oral administration of antihypertensive drugs are possible (depending on the severity of the increase in blood pressure and symptoms). Treatment should begin immediately, the rate of reduction in blood pressure should not exceed 25% in the first 2 hours, followed by achieving target blood pressure within several hours (no more than 24-48 hours) from the start of treatment. Drugs with a relatively quick and short action are administered orally or sublingually: captopril (25-50 mg), clonidine (0.1-0.2 mg), nifedipine (10-20 mg) and nitroglycerin (0.5 mg) were previously used. The patient can take these drugs independently, using the instructions of the attending physician. However, it should be remembered that with sublingual administration of clonidine, nifedipine, captopril, a sharp decrease in blood pressure and deterioration of cerebral circulation are possible, especially in elderly patients.

Treatment of patients with complicated HA is carried out in the emergency cardiology department or the intensive care unit of the cardiology, neurology or therapeutic department.

The following drugs are used to treat GC (Table 10-20):

Vasodilators:

Enalapril (preferred for acute LV failure);

Nitroglycerin at a dose of 5-100 mcg/min (preferred for ACS and acute LV failure);

Sodium nitroprusside 0.5-10 mcg/kg per minute (drug of choice for hypertensive encephalopathy, but note that it may increase intracranial pressure).

BAB.

Antiadrenergic drugs (phentolamine if pheochromocytoma is suspected).

Diuretics (furosemide for acute LV failure).

Neuroleptics (droperidol).

Ganglion blockers (pentamine).

Table 10-20. The main drugs used to relieve hypertensive crises, depending on the damage to target organs

When treating patients with GC, it should be remembered that a rapid decrease in blood pressure can provoke the development of cerebral circulatory failure or other dangerous complications.

When uncomplicated HA is first detected in patients with unclear genesis of hypertension, with intractable HA, and frequent repeated crises, hospitalization in the cardiology or therapeutic department of a hospital is indicated.

10.13. REFRACTORY AND MALIGNANT

ARTERIAL HYPERTENSION

According to current national recommendations, refractory or resistant to treatment consider hypertension in which the prescribed treatment (lifestyle changes and rational combined antihypertensive treatment with adequate doses of at least three drugs, including diuretics) does not lead to a sufficient reduction in blood pressure and achievement of its target level. In such cases, a detailed examination of target organs is indicated - with refractory hypertension, pronounced changes are often observed in them. It is necessary to exclude secondary forms of hypertension, which cause refractoriness to treatment. Inadequate doses of drugs and their irrational combinations can also lead to insufficient reduction in blood pressure. Refractory hypertension may be associated with pseudohypertension, such as “white coat hypertension” or the use of an inappropriately sized cuff.

Main causes of refractory hypertension

Lack of adherence to treatment (non-compliance with the regimen and doses of prescribed medications).

Volume overload due to the following reasons: excessive consumption of table salt, inadequate treatment with diuretics, progression of chronic renal failure, hyperaldosteronism.

Continued use of drugs that increase blood pressure or reduce the effectiveness of treatment (glucocorticoids, NSAIDs).

Undiagnosed secondary forms of hypertension.

Untreated obstructive sleep apnea syndrome.

Severe target organ damage.

A thorough analysis of all possible causes of refractory hypertension contributes to the rational choice of antihypertensive treatment. To control blood pressure in refractory hypertension, it may be necessary to prescribe more than three antihypertensive drugs.

The problem of combining three or more drugs has not yet been sufficiently studied, since there are no results of randomized, controlled, clinical studies studying the triple combination of antihypertensive drugs. However, in many patients, including

including in patients with refractory hypertension, only with the help of three or more drugs can the target blood pressure level be achieved.

ARB + ​​dihydropyridine BMCC + diuretic;

ACE inhibitor + dihydropyridine BMCC + diuretic;

ARB + ​​dihydropyridine BMCA + BAB;

ACE inhibitor + dihydropyridine BMCC + beta blocker;

ARB + ​​diuretic + beta blocker; ACE inhibitor + diuretic + beta blocker;

Dihydropyridine BMCC + diuretic + beta blocker. Malignant hypertension is rare. For malignant hypertension

extremely high blood pressure is observed (>180/120 mm Hg) with the development of severe changes in the vascular wall (fibrinoid necrosis), which leads to hemorrhages and/or swelling of the optic nerve nipple, tissue ischemia and dysfunction of various organs. The transition of hypertension into a malignant form is possible in all its forms, but more often it occurs in patients with secondary or severe hypertension. Various neurohormonal systems take part in the development of malignant hypertension. Activation of their activity increases sodium excretion, hypovolemia, and also damages the endothelium and causes proliferation of vascular smooth muscle cells. All these changes are accompanied by a continued release of vasoconstrictors into the bloodstream and an even greater increase in blood pressure. The syndrome of malignant hypertension is usually accompanied by symptoms from the central nervous system, progression of chronic renal failure, deterioration of vision, loss of body weight, changes in the rheological properties of the blood, up to the development of disseminated intravascular coagulation (DIC) or hemolytic anemia. Effective and timely treatment improves the prognosis, while without it, 50% of patients die within a year.

The presence of malignant hypertension is assessed as a serious condition and requires a reduction in diastolic blood pressure to 100-110 mm Hg. Art. within 24 hours. Patients with malignant hypertension are treated with three or more antihypertensive drugs. One should remember about the possibility of excessive excretion of sodium from the body, especially when prescribing diuretics, which is accompanied by further activation of the RAAS and an increase in blood pressure. A patient with malignant hypertension should be carefully examined for the presence of secondary hypertension.

10.14. ARTERIAL HYPERTENSION IN ELDERLY PEOPLE

According to modern international and national recommendations for the treatment of hypertension, the principles of treatment of elderly patients are the same as in the general population. Treatment should begin with lifestyle changes. Limiting the consumption of table salt and reducing body weight in this category of patients have a significant antihypertensive effect. For drug treatment, drugs of different classes can be used: thiazide diuretics, BMCC, beta blockers, ACE inhibitors and ARBs. Most elderly patients have other risk factors and concomitant diseases, which must be taken into account when choosing first-line drugs.

In general, as evidenced by the results of completed large-scale studies, thiazide diuretics, CBCBs and ARBs are most effective in the treatment of hypertension in old age. The initial dose of antihypertensive drugs may be reduced in some elderly patients; however, most patients in this category require standard doses to achieve target blood pressure. Elderly patients require special caution when prescribing and titrating the dose of antihypertensive drugs due to the greater risk of side effects. In this case, special attention should be paid to the possibility of developing orthostatic hypotension and blood pressure should also be measured in a standing position.

The target systolic blood pressure should be less than 140 mmHg. Art., and to achieve it often requires a combination of two or more antihypertensive drugs. The optimal value of diastolic blood pressure in elderly patients has not been precisely determined, but, according to the results of an analysis of a number of studies, its reduction is less than 70 mm Hg. Art. and especially less than 60 mmHg. Art. worsens the prognosis of the disease.

10.15. ARTERIAL HYPERTENSION

IN PREGNANT WOMEN

Hypertension and associated complications still remain one of the main causes of morbidity and mortality in mothers, fetuses and newborns. The goal of treatment for pregnant women with hypertension is to prevent the development of complications caused by high blood pressure, to ensure the continuation of pregnancy, normal fetal development and successful childbirth.

The target blood pressure level for pregnant women is less than 140/90 mm Hg. Art., but episodes of hypotension should be avoided, preventing disturbances in placental blood flow. Non-drug treatment is advisable when blood pressure is 140-149/90-94 mm Hg. Art. and active surveillance. Physical activity should be limited; There is insufficient data on the advisability of limiting salt intake in pregnant women. Weight loss during pregnancy is not recommended even for obese patients. In women with long-term hypertension, accompanied by target organ damage, and also requiring large doses of antihypertensive drugs before pregnancy, antihypertensive treatment should be continued during pregnancy. Women whose blood pressure was well controlled before pregnancy can take the same medications, with the exception of ACEIs and ARBs. Almost all antihypertensive drugs cross the placenta and have the potential to have undesirable effects on the fetus, newborn and/or further development of the child. Thus, the range of drugs used during pregnancy is limited. First-line drugs include methyldopa, dihydropyridine BMCC (nifedipine) and cardioselective beta blockers. Diuretics (hypothiazide) may be prescribed as additional drugs for combination treatment. The use of ACE inhibitors, ARBs and rauwolfia preparations is contraindicated due to the possible manifestation of malformations and fetal death. You should refrain from prescribing drugs that are little studied during pregnancy, such as indapamide and imidazoline receptor agonists.

According to modern international and national recommendations for the treatment of hypertension, systolic blood pressure >170 and diastolic blood pressure >110 mm Hg. Art. in a pregnant woman is regarded as an emergency condition requiring hospitalization. The main rule in the treatment of GC is a careful and controlled reduction in blood pressure by no more than 20% of the initial value. Methyldopa or nifedipine is prescribed orally; if ineffective, short-term administration of sodium nitroprusside or hydralazine is possible. For the treatment of preeclampsia with pulmonary edema, nitroglycerin is considered the drug of choice. Its administration is possible for no more than 4 hours, due to the negative effect on the fetus and the risk of developing cerebral edema in the mother. The use of diuretics is not justified - with preeclampsia, the volume of blood volume decreases.

10.16. ARTERIAL HYPERTENSION IN PATIENTS

WITH METABOLIC SYNDROME AND SUGAR SYNDROME

DIABETES

The combination of diabetes and hypertension deserves special attention, since both diseases significantly increase the risk of developing micro- and macrovascular lesions, including diabetic nephropathy, stroke, ischemic heart disease, myocardial infarction, heart failure, peripheral vascular disease, and contribute to an increase in cardiovascular mortality.

Lifestyle interventions, especially following a low-calorie diet, increasing physical activity and limiting salt intake, should be used to the maximum due to the fact that obesity is of great importance in the progression of type 2 diabetes. Reducing the body weight of patients with hypertension and diabetes helps to further reduce blood pressure and increase tissue sensitivity to insulin. Antihypertensive treatment in patients with hypertension and diabetes should be started at high normal blood pressure.

According to modern international and national recommendations for the treatment of hypertension, a target blood pressure level of less than 130/80 mmHg is set for patients with diabetes. Art. With high normal blood pressure, it is possible to achieve its target level with monotherapy. Other patients, as a rule, require a combined prescription of two or more drugs. ARBs or ACEIs are considered first-line drugs, due to their best nephroprotective effect. As a combination treatment, it is advisable to add BMCC, imidazoline receptor agonists, low-dose thiazide diuretics, nebivolol or carvedilol. The effectiveness of treatment with a fixed combination of perindopril and indapamide in patients with type II diabetes has also been proven to reduce the risk of cardiovascular complications and death from them. Given the greater risk of orthostatic hypotension, it is necessary to additionally measure blood pressure in a standing position. When treating patients with hypertension and diabetes, it is necessary to control all the patient’s risk factors.

The presence of diabetic nephropathy, in particular microalbuminuria, in patients with hypertension is associated with a very high risk of developing cardiovascular complications. Correction of nephropathy requires strict control of blood pressure at the level<130/80 мм рт. ст. и уменьшение протеинурии до минимально возможных значений. Наиболее эффективными классами ЛС для профилактики или лечения диабетической нефропатии в настоящее время считают БРА и ИАПФ.

Metabolic syndrome (MS) is discussed in detail in Chapter 16.

According to modern international and national recommendations, the basis of treatment for a patient with MS is non-drug measures aimed at reducing body weight, changing dietary patterns and increasing physical activity - creating a healthy lifestyle. If non-drug treatment methods are insufficiently effective or there are indications, drug or surgical correction of body weight is possible. Correction of existing disorders of carbohydrate, lipid and purine metabolism is considered mandatory.

The choice of tactics for managing patients with MS is individual and depends on the degree of obesity, the presence or absence of hypertension and other manifestations of MS. In patients with a high and very high risk of cardiovascular complications, it is necessary to immediately prescribe antihypertensive drugs and carry out treatment aimed at eliminating abdominal obesity, insulin resistance, hyperglycemia, and dyslipidemia.

When choosing a drug, it is necessary to take into account its effect on carbohydrate and lipid metabolism. Metabolically neutral drugs should be preferred. First-line drugs for the treatment of hypertension in patients with MS are considered to be ARBs or ACEIs, for which metabolic neutrality and organoprotective effects have been proven. If monotherapy is insufficiently effective to achieve the target blood pressure level, it is advisable to add BMCC or imidazoline receptor agonists to them. It has been proven that these combinations reduce blood pressure well, have a beneficial effect on target organs and reduce the risk of developing diabetes.

Without clear indications, patients with hypertension and MS should not be prescribed beta blockers, since many of them negatively affect insulin sensitivity, carbohydrate and lipid metabolism. An exception can be considered nebivolol and carvedilol, which have additional vasodilating properties, as well as highly selective bisoprolol. These drugs can be recommended to patients with hypertension and MS as part of combination treatment.

Thiazide or loop diuretics can also be prescribed to patients with hypertension and metabolic syndrome as part of combination treatment with ARBs or ACEIs. The thiazide-like diuretic indapamide is considered the safest diuretic drug. Patients with hypertension and the presence of metabolic disorders should avoid combining beta blockers

and diuretics due to the fact that both drugs adversely affect lipid, carbohydrate and purine metabolism.

Thus, when correcting hypertension in patients with MS, it is necessary to achieve complete normalization of blood pressure. The most important requirement when choosing antihypertensive therapy is the absence of negative metabolic effects of the drug.

Clinical pharmacology and pharmacotherapy: textbook. - 3rd ed., revised. and additional / ed. V. G. Kukesa, A. K. Starodubtseva. - 2012. - 840 p.: ill.

Goals and objectives of antihypertensive therapy

§ The goal of treatment for patients with hypertension: to minimize the risk of cardiovascular morbidity and mortality. The main thing in achieving this goal is to reduce high blood pressure to target values, correct all modifiable risk factors (smoking, dyslipidemia, hyperglycemia, obesity) and adequate treatment of concomitant diseases (diabetes mellitus, etc.).

§ Target blood pressure in the general population of patients with hypertension< 140/90 мм рт.ст.

§ When hypertension is combined with diabetes mellitus and/or renal dysfunction (serum creatinine > 1.5 mg/dl, proteinuria, GFR<60 мл/мин) целевое АД < 130/80 мм рт.ст.

Algorithm for the management of patients with hypertension depending on the risk category

§ In high and very high risk groups, along with the implementation of a non-drug treatment program, drug therapy is recommended to be started immediately.

§ In groups of patients with average risk, it is permissible to monitor the patient with regular blood pressure monitoring and conduct a non-drug treatment program for 3-6 months before deciding to start drug therapy. Antihypertensive drugs are prescribed for sustained blood pressure > 140/90 mmHg.

§ Early, active drug therapy is indicated for patients with high normal blood pressure (130-139/85-89 mm Hg), who have diabetes mellitus, renal or heart failure, as well as those who have had a stroke or transient cerebrovascular accident.

Tactics for starting antihypertensive therapy

There are two possible strategies for initial treatment of hypertension: monotherapy and combination therapy (Fig. 4).

Rice. 4. Hypertension treatment strategy

Rationale for choosing an antihypertensive drug to initiate treatment of arterial hypertension

Currently, seven classes of antihypertensive drugs are recommended for long-term treatment of hypertension:

§ thiazide and thiazide-like diuretics;

§ beta-blockers;

§ calcium antagonists;

§ ACE inhibitors;

§ angiotensin II receptor blockers;

§ imidazoline receptor agonists;

§ alpha-blockers.

Modern guidelines highlight the main indications for prescribing antihypertensive drugs, based on evidence-based medicine (Table 1).

Table 1. Indications for prescribing antihypertensive drugs

Drug class	Clinical situations in favor of use	Absolute contraindications	Relative contraindications
Thiazide diuretics	CHF ISAH AG in the elderly	Gout	Pregnancy Dyslipidemia
Loop diuretics	chronic renal failure chronic heart failure
Aldosterone antagonists	CHF After MI	Hyperkalemia CRF
Beta blockers	Angina pectoris After a MI CHF (starting with low doses) Pregnancy Tachyarrhythmias	AV block II-III stage. Bronchial asthma	Atherosclerosis of peripheral arteries IGT COPD Athletes and physically active individuals
Dihydropyridine calcium antagonists	ISAH hypertension in the elderly Angina pectoris Atherosclerosis of the carotid arteries Pregnancy		Tachyarrhythmias CHF
Non-dihydropyridine calcium antagonists	Angina pectoris Atherosclerosis of the carotid arteries Supraventricular tachycardia	AV block II-III p. CHF
ACEI	CHF LV dysfunction After MI Nephropathy Proteinuria
Angiotensin receptor blockers	Diabetic nephropathy in type 2 diabetes Diabetic MAU Proteinuria LVH Cough caused by ACE inhibitors	Pregnancy Hyperkalemia Bilateral renal artery stenosis
α1-blockers	Benign prostatic hyperplasia Dyslipidemia	Orthostatic hypotension	CHF
Imidazoline receptor agonists	Metabolic syndrome Diabetes mellitus		Severe CHF AV block II-III stage.

CHAPTER 3. HYPOTENSIVE DRUGS

Diuretics.

Diuretics are drugs whose direct effect on the kidneys leads to inhibition of sodium and water reabsorption and, consequently, to an increase in the volume of excreted fluid.

In accordance with the latest recommendations of the United States Joint National Committee on Hypertension Control (JNC VII, 2003) and additions to the recommendations of the World Health Organization and the International Society of Hypertension (WHO/IAS, 2003), diuretics as the initial therapy for hypertension should be prescribed to all patients with hypertension, with the exception of those who have contraindications.

Classification of diuretics

Diuretic drugs can be classified in different ways:

1) by chemical structure,

2) according to the mechanism of diuretic action,

3) by localization of action in the nephron.

According to the mechanism of action, the following groups of diuretics are distinguished:

§ carbonic anhydrase inhibitors;

§ osmotic diuretics;

§ increasing the release from the body mainly of Na +, K +, Cl - (loop diuretics);

§ increasing the release of Na +, Cl - from the body (thiazides and thiazide-like diuretics);

§ mineralocorticoid receptor antagonists;

§ renal epithelial sodium channel inhibitors (indirect aldosterone antagonists, potassium-sparing diuretics).

Most often, diuretics are divided into three groups depending on the site of their action in the nephron, which determines the severity of the natriuretic effect, expressed as a percentage of excreted sodium from the total amount of sodium filtered in the renal glomeruli.

§ Potent diuretics (i.e. causing excretion of more than 15-20% of filtered sodium):

Organic mercury compounds (not currently used in clinical practice);

Derivatives of sulfamonlanthranilic acid (furosemide, bumetanide, pyretanide, torasemide, etc.);

Derivatives of phenoxyacetic acid (ethacrynic acid, indacrinone, etc.).

§ Diuretics with a moderate natriuretic effect (i.e., causing the excretion of 5-10% of filtered sodium):

Benzothiadiazine derivatives (thiazides and hydrothiazides) - chlorothiazide, hydrochlorothiazide, bendroflumethiazide, polythiazide, cyclothiazide, etc.;

Heterocyclic compounds similar in the mechanism of tubular action to thiazide diuretics are chlorthalidone, metolazone, clopamide, indapamide, xipamide, etc.

§ Low-acting diuretics (i.e., those causing excretion of less than 5% of filtered sodium):

Potassium-sparing diuretics - amiloride, triamterene, spironolactone;

Carbonic anhydrase inhibitors - acetazolamide, etc. (not used in the treatment of arterial hypertension);

Osmotic diuretics - mannitol, urea, glycerin, etc. (not used in the treatment of arterial hypertension).

Thiazide, loop and potassium-sparing diuretics used in the treatment of hypertension are distinguished by the site of action at the level of the renal tubules.

§ Thiazide and thiazide-like diuretics suppress the reabsorption of sodium ions at the level of that part of the thick segment of the ascending limb of the loop of Henle, which is located in the renal cortex, as well as in the initial part of the distal tubules.

§ Loop diuretics affect the reabsorption of sodium ions in that part of the thick segment of the ascending limb of the loop of Henle, which is located in the renal medulla. In this section, the tubules are impermeable to water, but active transport of chlorine into the tubule cells occurs, which is accompanied by significant sodium reabsorption. It is the blockade of chlorine transport that leads to an increase in natriuresis and diuresis.

§ Potassium-sparing diuretics block the exchange of sodium ions for potassium ions at the level of the distal convoluted tubules and collecting ducts. This leads to potassium retention and suppression of sodium ion reabsorption.

The localization of the action of diuretics is shown in Figure 5.

H2O

Passive

Cl-

H2O

transport

ADH

Active

transport

Rice. 5. Localization of the action of diuretics.

Note: 1 – carbonic anhydrase inhibitors; 2 – osmotic diuretics; 3 – loop diuretics; 4 – thiazide and thiazide-like diuretics; 5 – potassium-sparing diuretics.

The effect of diuretics on renal hemodynamics and the excretion of major ions is shown in Table 2.

Table 2. Effect of diuretics on renal hemodynamics and excretion of major ions

Diuretics	KF	PC	Ion excretion
Na+	K+	Ca++	Mg++	Cl-	HCO3-
Carbonic anhydrase inhibitors	↓	#			#	#
Osmotic
Loop
Thiazides and thiazide-like	#	#			↓
Indirect aldosterone antagonists	#	#		↓	↓	↓		#
Direct aldosterone antagonists	#	#		↓	#	↓		#

Note: - increase; ↓ - decrease; # - lack of influence.

Pharmacokinetics of diuretics

Pharmacokinetic parameters of diuretics are presented in Table 3.

Table 3. Pharmacokinetic parameters of diuretics

Drugs	Dose, mg/day	DB, %	Elimination duration	Elimination routes
Thiazide and thiazide-like diuretics
Hydrochlorothiazide	12,5-50	60-80	6-18	kidneys
Chlorothiazide	250-500		6-12	kidneys
Indapamide	1,5-2,5		12-24	kidneys + liver
Xipamide	10-40		12-24	kidneys + liver
Metolazone	2,5-5	50-60	12-24	kidneys + liver
Chlorthalidone	12,5-50		24-72	kidneys + liver
Loop diuretics
Bumetanide	0,5-4	60-90	2-5	kidneys + liver
Torasemide	2,5-10	80-90	6-8	kidneys + liver
Furosemide	20-240	10-90	2-4	kidneys
Potassium-sparing diuretics
Amiloride	5-10		6-24	kidneys
Triamterene	50-150		8-12	kidneys + liver
Spironolactone	25-100		3-5 days	liver

Note: BD – bioavailability.

TDs are well absorbed from the gastrointestinal tract, so they are prescribed during or after meals, once in the morning or twice in the morning. During treatment, a diet rich in potassium and low in sodium is recommended. Loop diuretics are strong diuretics that cause a quick, short-lived effect. Their hypotensive effect is much less pronounced than that of thiazide drugs; increasing the dose is accompanied by dehydration. Prescribed in the morning on an empty stomach.

The mechanism of the hypotensive action of thiazide diuretics (TD)

The action of TD in relation to blood pressure is divided into 3 phases: acute, subacute and chronic. The acute phase lasts 3-4 weeks, and a decrease in blood pressure occurs due to an increase in natriuresis, a decrease in the volume of extracellular fluid and bcc and an associated decrease in CO. If large amounts of sodium are taken in food, the effectiveness of treatment for TD may be low or completely absent.

Subsequently, within 2-3 weeks (subacute phase), following a decrease in CO, an increase in the activity of the RAS and SAS is observed. This neurohumoral activation causes a compensatory increase in BCC, which still remains somewhat reduced.

In the chronic phase of taking TD, a decrease in OPSS is observed. This process is associated with changes in the activation of SMC ion channels and a decrease in vascular tone.

Features of thiazide diuretics

1) Moderate natriuretic (and diuretic) effect and longer action than loop diuretics.

2) The greatest diuretic and hypotensive effect is achieved when prescribing relatively low doses of TD (12.5 - 25 mg of hydrochlorothiazide per day or equivalent doses of other thiazide diuretics). With a further increase in dose, the antihypertensive effect does not increase.

3) Reduced effect in patients with renal failure (serum creatinine level above 2.0 mg/dl; glomerular filtration rate less than 30 ml/min).

4) Reducing the excretion of calcium ions in the urine (calcium-sparing effect).

A number of diuretic drugs, different in chemical structure from TD, have pharmacological properties similar to them, which gives reason to call them thiazide-like diuretics. Indapamide occupies a special place in the group of thiazide-like diuretics. Indapamide differs from other thiazide and thiazide-like diuretics in that, along with the diuretic effect, it has a direct vasodilator effect on the systemic and renal arteries. Peripheral vasodilation is associated with the ability of the drug to inhibit the entry of calcium ions into the SMC and stimulate the synthesis of prostacyclin. Indapamide is known to cause reversal of LVH. The incidence of side effects with indapamide is lower than with other thiazide diuretics.

Two more drugs are close to indapamide - xipamide and metolazone. These drugs have a significant sodium and diuretic effect even in patients with severe renal failure (glomerular filtration rate less than 30 ml/min).

Features of loop diuretics (LD)
1) Pronounced but short-term diuretic effect.

During the period of action of PD, the excretion of sodium ions in the urine increases significantly, but after the cessation of the diuretic effect of the drugs, the rate of excretion of sodium ions decreases to a level below the initial level. This phenomenon is called the “ricochet phenomenon” (or recoil). It is assumed that the basis of the “rebound phenomenon” is a sharp activation of the RAS and, possibly, other antinatriuretic neurohumoral systems in response to massive diuresis caused by PD. The existence of the “rebound phenomenon” explains why, when taken once daily, loop diuretics may not have a significant effect on the daily excretion of sodium ions. To achieve the removal of sodium ions from the body and achieve a hypotensive effect, short-acting PDs (furosemide and bumetanide) must be prescribed 2 times a day. Long-acting PDs (torsemide) do not have a rebound effect and are therefore more effective in the treatment of hypertension.

2) The diuretic effect increases significantly as the dose increases.

3) Maintaining effectiveness at a low glomerular filtration rate, which allows the use of PD for the treatment of hypertension in patients with renal failure.

4) Increased excretion of calcium ions in the urine.

5) Greater severity of adverse drug reactions.

Features of potassium-sparing diuretics (KD)

1) KDs prevent the loss of potassium in the urine, acting at the level of the distal convoluted tubules and collecting ducts as either a competitive antagonist of aldosterone (spironolactone) or direct inhibitors of the secretion of potassium ions (amiloride, triamterene).

2) Prescribed in combination with thiazide or loop diuretics as potassium-sparing drugs.

3) As monotherapy, spironolactone is used in the treatment of “idiopathic hyperaldosteronism”, when hypersecretion of aldosterone is caused by bilateral hyperplasia of the adrenal cortex.

4) Adverse drug reactions include: hyperkalemia, gynecomastia and impotence in men, menstrual irregularities and hirsutism in women.

Side effects of diuretics

1. Electrolyte disturbances:

§ hypokalemia, which can cause ventricular arrhythmias;

§ hypomagnesemia.

2. Metabolic influences:

§ impaired carbohydrate tolerance,

§ increased blood levels of TG, LDL cholesterol,

§ hyperuricemia.

3. Sexual dysfunction:

§ impotence.

4. Effect on blood:

§ thrombocytopenia,

§ leukopenia.

5. Ototoxicity (loop diuretics).

Contraindications to the use of diuretics

§ gout,

§ hypokalemia.

Interactions

Drug interactions involving beta blockers are presented in table. 4.

Table 4. Drug interactions involving diuretics