Renin-angiotensin-aldosterone system (RAAS.)

The juxtaglomerular apparatus (JGA) is involved in the regulation of blood volume and pressure. The proteolytic enzyme renin formed in the granules of JGA cells catalyzes the conversion of angiotensinogen (one of the plasma proteins) into decapeptide angiotensin I, which does not have pressor activity. Under the action of angiotensin-converting enzyme (ACE), it is broken down (mainly in the lungs, kidneys, brain) to angiotensin II octapeptide, which acts as a powerful vasoconstrictor, and also stimulates the production of aldosterone by the adrenal cortex. Aldosterone enhances the reabsorption of Na + in the tubules of the kidneys and stimulates the production of antidiuretic hormone. As a result, there is a retention of Na + and water, which leads to an increase in blood pressure. In addition, blood plasma contains angiotensin III (a heptapeptide that does not contain aspartic acid), which also actively stimulates the release of aldosterone, but has a less pronounced pressor effect than angiotensin II. It should be noted that the more angiotensin II is formed, the more pronounced the vasoconstriction and, therefore, the more pronounced the increase in blood pressure.

Renin secretion is regulated by the following mechanisms, which are not mutually exclusive:

• 1) baroreceptors of the renal vessels, which obviously respond to changes in the wall tension of the afferent arterioles,
• 2) macula densa receptors, which seem to be sensitive to changes in the rate of entry or concentration of NaCl in the distal tubules,
• 3) negative feedback between the concentration of angiotensin in the blood and secretion of renin
• 4) the sympathetic nervous system, which stimulates the secretion of renin as a result of activation of the β-adrenergic receptors of the renal nerve.

Sodium homeostasis maintenance system. It includes the glomerular filtration rate (GFR) and natriuresis factors (excretion of sodium ions in the urine). With a decrease in BCC, GFR also decreases, which, in turn, leads to an increase in sodium reabsorption in the proximal nephron. Natriuresis factors include a group of peptides with similar properties and a common name - natriuretic peptide (or atriopeptide) produced by the atrial myocardium in response to their expansion. The effect of the atriopeptide is to reduce sodium reabsorption in the distal tubules and vasodilation.

The system of renal vasodepressor substances includes: prostaglandins, kallikrein-kinin system, NO, platelet activating factor, which by their action balance the vasopressor effect of angiotensin.

In addition, a certain role in the manifestation of hypertension is played by such environmental factors (Fig. 1 point 6), as physical inactivity, smoking, chronic stress, excessive consumption of salt with food.

Etiology of arterial hypertension:

The etiology of primary or essential hypertension is unknown. And it is unlikely that one reason could explain such a variety of hemodynamic and pathophysiological disorders that are observed in this disease. Currently, many authors adhere to the mosaic theory of the development of hypertension, according to which the maintenance of high blood pressure is due to the participation of many factors, even if any one of them initially dominated (for example, the interaction of the sympathetic nervous system and the renin-angiotensin-aldosterone system).

There is no doubt that there is a genetic predisposition to hypertension, but its exact mechanism is still not clear. It is possible that environmental factors (such as the amount of sodium in food, diet and lifestyle that contribute to obesity, chronic stress) have an effect only on genetically predisposed individuals.

The main reasons for the development of essential hypertension (or essential hypertension), which accounts for 85-90% of cases of all hypertension, are as follows:

• - activation of the renin-angiotensin-aldosterone system with changes in the genes encoding angiotensinogen or other RAAS proteins,
• - activation of the sympathetic nervous system, which leads to an increase in blood pressure mainly through vasoconstriction,
• - violation of Na + transport through the cell membranes of smooth muscle cells of blood vessels (as a result of inhibition of the Na + -K + pump or an increase in membrane permeability for Na + with an increase in the content of intracellular Ca2 +),
• - deficiency of vasodilators (such as NO, components of the kallikrein-kinin system, prostaglandins, atrial natriuretic factor, etc.).

Among the main causes of symptomatic hypertension are:

• - primary bilateral kidney damage (which may be accompanied by hypertension due to both increased secretion of renin and activation of the RAAS with sodium and fluid retention, and decreased secretion of vasodilators) in diseases such as acute and chronic glomerulonephritis, chronic pyelonephritis, polycystic kidney disease, amyloidosis, kidney tumors , obstructive uropathy, collagenosis, etc.
• - endocrine (potentially curable) diseases, such as primary and secondary hyperaldosteronism, Itsenko-Cushing's disease and syndrome, diffuse thyrotoxic goiter (Basedow's disease or Graves' disease), pheochromocytoma, renin-producing kidney tumors.
• - neurogenic diseases, including those accompanied by an increase in intracranial pressure (trauma, tumor, abscess, hemorrhage), damage to the hypothalamus and brain stem, associated with psychogenic factors.
• - vascular diseases (vasculitis, coarctation of the aorta and other vascular anomalies), polycythemia, an increase in BCC of an iatrogenic nature (with excessive transfusion of blood products and solutions).

Morphology of arterial hypertension:

Benign form of hypertension:

In the early stages of hypertension, no structural changes can be detected. Ultimately, generalized arteriolar sclerosis develops.

Given the long course of the disease, there are three stages that have certain morphological differences and are consistent with the stages proposed by WHO experts (indicated in brackets):

• 1) preclinical (mild course),
• 2) widespread changes in the arteries (moderate),
• 3) changes in organs due to changes in arteries and impaired organ blood flow (severe) preclinical stage.

It is clinically manifested by transient hypertension (episodes of increased blood pressure). At the early, labile stage of the disease, CO is increased, TPVR remains within the normal range for some time, but is inadequate for this level of CO. Then, probably as a result of autoregulation processes, OPVR begins to increase, and CO returns to normal levels.

In the arterioles and small arteries, hypertrophy of the muscle layer and elastic structures is revealed > gradual increase in the thickness of the vessel wall with a decrease in its lumen, which is clinically manifested in the OPSS. After some time, against the background of catecholemia, hematocrit, hypoxia (elements of the arterial wall and arterioles), vascular permeability increases, which leads to plasma impregnation of the vascular wall > a decrease in its elasticity and an even greater ^ OPSS. Morphological changes at this stage are completely reversible, and with the timely initiation of antihypertensive therapy, it is possible to prevent the development of target organ damage.

In the heart, due to transient ^ afterload, moderate compensatory hypertrophy of the left ventricle occurs, in which the size of the heart and the thickness of the wall of the left ventricle ^, and the size of the cavity of the left ventricle does not change or may decrease slightly - concentric hypertrophy (characterizes the stage of compensation of cardiac activity).

Stage of widespread changes in the arteries. Clinically manifested by a persistent increase in blood pressure.

In the arterioles and small arteries of the muscular type, widespread hyalinosis is detected, which developed as a result of plasma impregnation (a simple type of vascular hyaline), or arteriolosclerosis of the media and intima of arterioles in response to the release of plasma and proteins. Arteriologialinosis is noted in the kidneys, brain, retina, pancreas, intestines, adrenal capsule. Macroscopically hyalinized vessels look like vitreous tubes with thick walls and pinpoint lumen, dense consistency. Microscopically, homogeneous eosinophilic masses are detected in the wall of arterioles, the layers of the wall can be practically indistinguishable.

In the arteries of the elastic, musculo-elastic and muscular types, the following develop: - elastofibrosis - hyperplasia and splitting of the internal elastic membrane, sclerosis - atherosclerosis, which has a number of features:

• a) is more common, captures the arteries of the muscular type,
• b) fibrous plaques are circular in nature (rather than segmental), which leads to a more significant narrowing of the vessel lumen.

In the heart, the degree of myocardial hypertrophy increases, the mass of the heart can reach 900-1000 g, and the wall thickness of the left ventricle is 2-3 cm (cor bovinum). However, due to the relative insufficiency of blood supply (an increase in the size of cardiomyocytes, hyalinosis of arterioles and arteries) and increasing hypoxia, fatty degeneration of the myocardium and myogenic expansion of cavities develop - eccentric myocardial hypertrophy, diffuse small-focal cardiosclerosis, signs of cardiac decompensation appear.

3) The stage of changes in organs due to changes in arteries and impaired organ blood flow.

Secondary organ changes in uncomplicated arteriological disease and atherosclerosis can develop slowly, leading to parenchymal atrophy and stromal sclerosis.

With the addition of thrombosis, spasm, fibrinoid necrosis during a crisis, acute circulatory disorders occur - hemorrhages, heart attacks.

Changes in the brain:

Multiple small focal hemorrhages (hemorragia per diapedesin).

Hematomas - hemorrhages with destruction of brain tissue (hemorragia per rhexin microanaurisms, which occur more often against the background of hyalinosis with fibrinoid necrosis of the wall of small perforating arteries of the brain, mainly subcortical nuclei and the subcortical layer). As a result of hemorrhages, rusty cysts form in the brain tissue (the color is due to hemosiderin).

In the kidneys, arteriolosclerotic nephrosclerosis or primary wrinkling of the kidneys develops, which is based on arteriologialinosis > desolation with sclerosis and hyalinosis of the glomerular capillaries > stromal sclerosis due to prolonged hypoxia > atrophy of the epithelium of the tubules of the kidneys.

Macroscopic picture: the kidneys are significantly reduced in size (a type of local atrophy due to lack of blood supply), the surface is fine-grained, dense, thinning of the cortical and medulla is noted on the cut, proliferation of fatty tissue around the pelvis. Areas of retraction on the surface of the kidneys correspond to atrophied nephrons, and bulging foci correspond to functioning nephrons in a state of compensatory hypertrophy.

Microscopic picture: the walls of the arterioles are significantly thickened due to the accumulation of homogeneous weakly oxyphilic structureless masses of hyaline in the intima and middle shell (in some cases, the structural components of the arteriole wall, with the exception of the endothelium, are not differentiated), the lumen is narrowed (up to complete obliteration). The glomeruli are collapsed (collapsed), many are replaced by connective tissue or hyaline masses (in the form of weakly oxyphilic homogeneous "medallions"). The tubules are atrophied. The amount of interstitial tissue is increased. The surviving nephrons are compensatory hypertrophied.

Arteriolosclerotic nephrosclerosis can result in the development of chronic renal failure.

Malignant form of hypertension:

Rarely seen at present.

Occurs primarily or complicates benign hypertension (hypertensive crisis).

Clinically: Rdiast level? 110-120 mmHg Art., visual disturbances (due to bilateral edema of the optic disc), severe headaches and hematuria (less often - anuria).

The level of renin and angiotensin II in the blood serum is high, significant secondary hyperaldsteronism (accompanied by hypokalemia).

It occurs more often in middle-aged men (35-50 years, rarely up to 30 years).

It progresses rapidly, without treatment leads to the development of chronic renal failure (CRF) and death within 1-2 years.

Morphological picture:

A short stage of plasma impregnation is followed by fibrinoid necrosis of the arteriole wall > endothelial damage > thrombosis addition > organ changes: ischemic dystrophy and heart attacks, hemorrhages.

From the side of the retina: bilateral edema of the optic disc, accompanied by proteinaceous effusion and retinal hemorrhages

In the kidneys: malignant nephrosclerosis (Fara), which is characterized by fibrinoid necrosis of the walls of arterioles and capillary loops of the glomeruli, edema of the interstitium, hemorrhages > cellular reaction and sclerosis in arterioles, glomeruli and stroma, proteinaceous degeneration of the epithelium of the tubules of the kidneys.

Macroscopic picture: the appearance of the kidneys depends on the duration of the pre-existing phase of benign hypertension. In this regard, the surface can be smooth or granular. Petechial hemorrhages are very characteristic, which give the kidney a mottled appearance. The progression of dystrophic and necrotic processes quickly leads to the development of CRF and death.

In the brain: fibrinoid necrosis of the walls of arterioles with the addition of thrombosis and the development of ischemic and hemorrhagic infarcts, hemorrhages, edema.

Hypertensive crisis - a sharp increase in blood pressure associated with spasm of arterioles - can occur at any stage of hypertension.

Morphological changes in hypertensive crisis:

Spasm of arterioles: corrugation and destruction of the basement membrane of the endothelium with its location in the form of a palisade.

Plasma impregnation.

Fibrinoid necrosis of the walls of arterioles.

Diapedetic hemorrhages.

Clinical and morphological forms of AH:

Depending on the predominance of vascular, dystrophic, necrotic, hemorrhagic and sclerotic processes in a particular organ, the following forms are distinguished:

Cardiac form - is the essence of coronary heart disease (like the cardiac form of atherosclerosis)

Brain form - underlies most cerebrovascular diseases (as well as cerebral atherosclerosis)

The renal form is characterized by both acute (arteriolonecrosis - a morphological manifestation of malignant hypertension) and chronic changes (arteriolosclerotic nephrosclerosis).

Rice. 1

List of abbreviations for the lecture "Hypertension"

AG - arterial hypertension.

BP - blood pressure.

BCC is the volume of circulating blood.

CO - cardiac output.

OPSS - total peripheral vascular resistance.

SV - stroke volume.

HR - heart rate.

SNS - sympathetic nervous system.

PSNS - parasympathetic nervous system.

RAAS - renin-angiotensin-aldosterone system.

JUGA - juxtaglomerular apparatus.

ACE is an angiotensin-converting enzyme.

GFR - glomerular filtration rate.

WHO is the world health organization.

CRF - chronic renal failure.

Aldosterone in humans is the main representative of mineralocorticoid hormones derived from cholesterol.

Synthesis

It is carried out in the glomerular zone of the adrenal cortex. Formed from cholesterol, progesterone undergoes sequential oxidation on its way to aldosterone. 21-hydroxylase, 11-hydroxylase and 18-hydroxylase. Ultimately, aldosterone is formed.

Scheme of the synthesis of steroid hormones (complete scheme)

Regulation of synthesis and secretion

Activate:

• angiotensin II released during activation of the renin-angiotensin system,
• increased concentration potassium ions in the blood (associated with membrane depolarization, opening of calcium channels and activation of adenylate cyclase).

Activation of the renin-angiotensin system

1. There are two starting points to activate this system:

• pressure reduction in the afferent arterioles of the kidneys, which is determined baroreceptors cells of the juxtaglomerular apparatus. The reason for this may be any violation of the renal blood flow - atherosclerosis of the renal arteries, increased blood viscosity, dehydration, blood loss, etc.
• decrease in the concentration of Na + ions in the primary urine in the distal tubules of the kidneys, which is determined by the osmoreceptors of the cells of the juxtaglomerular apparatus. Occurs as a result of a salt-free diet, with prolonged use of diuretics.

The secretion of renin (basic) is maintained by the sympathetic nervous system, constant and independent of renal blood flow.

1. When performing one or both items of the cell juxtaglomerular apparatus are activated and from them the enzyme is secreted into the blood plasma renin.
2. There is a substrate for renin in plasma - a protein of the α2-globulin fraction angiotensinogen. As a result of proteolysis, a decapeptide called angiotensin I. Further, angiotensin I with the participation angiotensin converting enzyme(ACE) turns into angiotensin II.
3. The main targets of angiotensin II are smooth myocytes. blood vessels And glomerular cortex adrenal glands:

• stimulation of blood vessels causes their spasm and recovery blood pressure.
• secreted from the adrenal glands after stimulation aldosterone acting on the distal tubules of the kidneys.

When exposed to aldosterone, the tubules of the kidneys increase reabsorption Na + ions, following sodium moves water. As a result, the pressure in the circulatory system is restored and the concentration of sodium ions increases in the blood plasma and, therefore, in the primary urine, which reduces the activity of the RAAS.

Activation of the renin-angiotensin-aldosterone system

Mechanism of action

Cytosolic.

Targets and effects

It affects the salivary glands, the distal tubules and the collecting ducts of the kidneys. Enhances in the kidneys reabsorption of sodium ions and loss of potassium ions through the following effects:

• increases the amount of Na +, K + -ATPase on the basement membrane of epithelial cells,
• stimulates the synthesis of mitochondrial proteins and an increase in the amount of energy produced in the cell for the operation of Na +, K + -ATPase,
• stimulates the formation of Na-channels on the apical membrane of renal epithelial cells.

Pathology

hyperfunction

Conn syndrome(primary aldosteronism) - occurs with adenomas of the glomerular zone. It is characterized by a triad of signs: hypertension, hypernatremia, alkalosis.

Secondary hyperaldosteronism - hyperplasia and hyperfunction of juxtaglomerular cells and excessive secretion of renin and angiotensin II. There is an increase in blood pressure and the appearance of edema.

plays a central role in the development of renal hypertension. Any damage to the renal parenchyma (sclerosis, cysts, scarring, microangiopathic lesions, tubulo-interstitial or glomerular inflammation) causes impaired glomerular perfusion and increases renin secretion.

Hyperreninemia leads to angiotensin II-dependent vasoconstriction as well as aldosterone-dependent sodium retention. Thus, both the total peripheral resistance and the volume of circulating blood increase. In 90% of patients with ESRD, AH is volume-dependent, and in 10% the leading factor is an increase in RAS activity. In addition, high levels of angiotensin II trigger inflammation, myocardial hypertrophy, endothelial damage, mesangial cell proliferation, and interstitial fibrosis.

A significant impact on the volume of extracellular fluid and blood pressure has an uncontrolled intake of sodium with food. Sodium retention in CKD may be due to both a decrease in GFR and an increase in its reabsorption in the tubules, independent and independent of RAAS activation (in glomerulonephritis with nephrotic syndrome).

In hypertensive children on dialysis, diuresis is usually less than in normotensive patients of the same age, and interdialytic weight gain moderately correlates with interdialytic BP increase (r = 0.41). Nephrectomy in dialysis children with renin-dependent hypertension reduces mean BP, and hypertension becomes volume-dependent.

An important mechanism of hypertension is an increase in the activity of the sympathetic nervous system, which is noted in patients with CKD and especially in CKD. The mechanisms underlying this phenomenon are not yet clear and may include afferent signals from the kidneys, dopaminergic disturbances, and leptin accumulation. Not only blockade of β-receptors, but also inhibition of angiotensin-converting enzyme (ACE) can reduce sympathetic hyperactivation in CKD. It appears that renal ischemia of any origin (including local) causes sympathetic hyperactivation.

Drugs used in the treatment of patients with CKD can cause iatrogenic arterial hypertension. For example, the use of erythropoietin for several weeks leads to a rise in blood pressure in 20% of patients. Glucocorticoids cause fluid retention due to their mineralocorticoid activity. Cyclosporin A causes an increase in glomerular afferent arterioles and hyperplasia of the juxtaglomerular apparatus, followed by increased release of renin and angiotensin II.

Thus, all children with CKD are at risk for developing AH. The high-risk group includes patients with ESRD, kidney transplant recipients, patients with rapidly progressive glomerulonephritis.

Early diagnosis of hypertension is an extremely important task to prevent long-term effects of hypertension. For this purpose, it is necessary to use active screening methods, since clinical symptoms of hypertension are often absent.

The simplest screening method for the detection of hypertension is the regular measurement of blood pressure, at least at each examination of the patient by a doctor. The diagnosis of hypertension is valid if at least 3 clinical measurements of blood pressure are above the 95th percentile for age and height. (Annex 1.). Currently, the method of 24-hour (daily) monitoring of blood pressure (ABPM) has become widespread.

This study allows you to diagnose "hidden hypertension", i.e. not detectable by single clinical measurements of blood pressure, for example, at night, exclude white coat hypertension, which occurs even in children who are in the hospital for a long time. In the latter case, it is advisable to conduct ABPM on an outpatient basis, when the child is in his usual home environment throughout the study.

ABPM is indicated for all children with CKD annually. If hypertension is detected, it is also necessary to conduct an ophthalmological examination (to assess the state of the retinal vessels) and echocardiography (to exclude systolic and diastolic dysfunction, assess the degree of myocardial hypertrophy). In the future, these studies should be performed at least once a year.

The main goal of antihypertensive therapy is to prevent damage to target organs (especially left ventricular hypertrophy) and slow the progression of CKD. All children with CKD complicated by hypertension are indicated for antihypertensive therapy until BP levels are below the 90th percentile for age and height.

Therapy for hypertension includes lifestyle and dietary modifications and drug treatment.

In the diet of children with CKD complicated by hypertension, first of all, it is necessary to limit sodium intake to 1-2 g/day. Food is prepared without the addition of salt, which is dispensed in doses to add salt to food on a plate; all foods with a high sodium content (canned food, sausages, rye bread, etc.) should be excluded. Such restrictions are often difficult to tolerate by patients, but uncontrolled sodium intake significantly reduces the effectiveness of antihypertensive drug therapy.

Obesity is not common in children with CKD and is usually associated with steroid treatment. A gradual decrease in body weight against the background of a low-calorie diet and dosed physical activity contributes to the normalization of blood pressure. In practice, the implementation of a low-calorie diet is difficult due to the dietary restrictions already present in children with CKD, and it is rarely effective. However, in obese children with sodium retention, a combined low-calorie, low-sodium diet may be beneficial.

In hypertensive patients receiving RRT, changing the dialysis regimen may improve BP control prior to initiation of pharmacological treatment. In most cases, normalization of blood pressure in dialysis patients can be achieved by adequate duration of dialysis, careful control of extracellular fluid balance, and more aggressive achievement of dry weight. It is believed that dietary sodium reduction combined with low dialysate sodium is comparable in effectiveness to an increase in dialysis time and can achieve a modest reduction in blood pressure.

At all stages of CKD, the basis of antihypertensive therapy is pharmacological treatment. BP control below the 90th percentile can be achieved with monotherapy in no more than 75% of children with stage 2 CKD. Other patients require the use of 2 or more drugs. In children with ESRD, it is difficult to achieve adequate BP control, and 50% of children on dialysis have uncontrolled hypertension.

In children with hypertension, it is recommended to start treatment with a single drug at a low or moderate therapeutic dose and gradually increase it until BP is controlled. In the absence of a sufficient effect of monotherapy, the use of a combination of 2 or more drugs is indicated. An exception is emergency conditions in hypertension, such as hypertensive crisis, hypertensive encephalopathy, when treatment should be started with intravenous administration of drugs until a clinical effect is achieved.

Currently, a wide range of drugs is used in the treatment of arterial hypertension (Table 2.1).

First of all, drugs of the following groups are used:

Angiotensin-converting enzyme inhibitors (ACE inhibitors)

Angiotensin II receptor blockers (ARBs)

calcium channel blockers

β-blockers

diuretics

Reserve drugs include:

α β - blockers

central α-antagonists

peripheral α-antagonists

peripheral vasodilators.

In children with chronic kidney disease, it is most reasonable to start therapy with an ACE inhibitor or ARB. These drugs not only have an antihypertensive effect, but also slow down the progression of renal failure more effectively than drugs of other pharmacological groups. The renoprotective effect of RAAS blockade is due to a decrease in intraglomerular hypertension through selective dilatation of the efferent arteriole, a decrease in proteinuria, and a weakening of the pro-inflammatory and prosclerotic action of angiotensin II. An additional effect of RAAS blockade is to reduce sympathetic hyperactivity.

Since proteinuria is an independent factor in the progression of CKD, patients with CKD and proteinuria should receive RAAS blockers even in the absence of hypertension. There was no clear advantage of using ARBs over ACE inhibitors. If proteinuria persists on monotherapy, then a combination of ACE inhibitors and ARBs may be considered, as this combination is effective in reducing proteinuria and slowing the progression of CKD.

The use of ACE inhibitors and ARBs is contraindicated in patients with a decrease in GFR ≤ 20 ml / min, with hyperkalemia, and with bilateral renal artery stenosis. When prescribing these groups of drugs to children with stage 3-4 CKD, it is necessary to control the level of azotemia and potassium after the start of therapy and with each dose increase. Therapy with a combination of ACE inhibitors and ARBs increases the risk of falling glomerular filtration rate and hyperkalemia. In children with chronic renal failure, it may be advisable to use fosinopril (monopril), because. this drug (unlike others and ACE) is metabolized mainly in the liver, and is not excreted in the urine and is safer for patients with significant impairment of renal function. It is noted that ACE-induced cough in children is less common than in adults; if this side effect occurs, it is possible to replace the ACE inhibitor with an ARB.

b-blockers are second-line drugs for the treatment of children with renal hypertension. β-blockers should be used with caution in heart failure and in diabetic patients due to negative metabolic effects. Non-selective b-blockers are contraindicated in lung diseases accompanied by bronchial obstruction. In infants, propranolol has a good effect. The retarded form of this drug allows you to prescribe it once a day in older children. It is preferable to prescribe selective b1-blockers, such as atenolol, which also has a prolonged action.

The use of b-blockers is indicated in the presence of symptoms of hyperactivation of the sympathetic nervous system: tachycardia, vasoconstriction, high heart rate.

Calcium channel blockers (CCBs) are used as adjunctive therapy in children with resistant hypertension. Dihydropyridine drugs (nifedipine, amlodipine, etc.) act mainly as vasodilators. Doses of amlodipine are designed for pediatrics and do not require adjustment depending on renal function, however, dihydropyridine CCBs (nifedipine) increase intraglomerular pressure and may increase proteinuria, therefore, without having a renoprotective effect. Non-dihydropyridine CCBs (phenylalkylamine derivatives - verapamil, benzodiazepine - diltiazem) have an additional antiproteinuric effect.

In studies in elderly patients with type 2 diabetes mellitus, non-digropyridine CCBs have shown themselves to be effective in reducing proteinuria and blood pressure and slowing the progression of CKD, their effectiveness in this regard was comparable to the ACE inhibitor - lisinopril. Since such studies have not been conducted among children, non-digdropyridine CCBs should be used with caution in childhood, given their side effects (prolongation of the PQ interval, bradyarrhythmias).

In studies in patients with diabetes mellitus, hypertension and proteinuria, the combination of an ACE inhibitor with a third-generation dihydropyridine CCB, manidipine, had an additional antiproteinuric effect compared to ACE inhibitor monotherapy. The beneficial effect of manidipine on renal hemodynamics and proteinuria has been shown.

Intravenous nicardipine is the treatment of choice for the treatment of a hypertensive crisis, especially when renal function is unknown or rapidly changing. This drug can be safely used even in very young children with hypertension.

Diuretics are indicated primarily for patients with sodium retention, hypervolemia and edema and are not first-line drugs in the treatment of hypertension in children with CKD. It must be remembered that thiazide diuretics become ineffective in GFR.

Which is formed in special cells of the juxtaglomerular apparatus of the kidney (JUGA). The secretion of renin is stimulated by a decrease in the volume of circulating blood, a decrease in blood pressure, b 2 -agonists, prostaglandins E 2, I 2, potassium ions. An increase in renin activity in the blood causes the formation of angiotensin I - a 10-amino acid peptide that is cleaved from angiotensinogen. Angiotensin I under the action of angiotensin-converting enzyme (ACE) in the lungs and in the blood plasma is converted into angiotensin II.

It causes the synthesis of the hormone aldosterone in the glomerular zone of the adrenal cortex. Aldosterone enters the bloodstream, is transported to the kidney and acts through its receptors on the distal tubules of the renal medulla. The total biological effect of aldosterone is the retention of NaCl, water. As a result, the volume of fluid circulating in the circulatory system is restored, including an increase in renal blood flow. This closes the negative feedback and renin synthesis stops. In addition, aldosterone causes loss of Mg 2+ , K + , H + with urine. Normally, this system maintains blood pressure (Fig. 25).

Rice. 25. Renin-angiotensin-aldoster system

Too much aldosterone - aldosteronism , is primary and secondary. Primary aldosteronism can be caused by hypertrophy of the glomerular zone of the adrenal glands, endocrine epithology, tumor (aldosteronoma). Secondary aldosteronism is observed in liver diseases (aldosterone is not neutralized and not excreted), or in diseases of the cardiovascular system, as a result of which the blood supply to the kidney worsens.

The result is the same - hypertension, and in the chronic process, aldosterone causes proliferation, hypertrophy and fibrosis of blood vessels and myocardium (remodeling), which leads to chronic heart failure. If it is associated with an excess of aldosterone, aldosterone receptor blockers are prescribed. For example, spironolactone, eplerenone are potassium-sparing diuretics, they promote the excretion of sodium and water.

Hypoaldosteronism is a lack of aldosterone that occurs with certain diseases. The causes of primary hypoaldosteronism can be tuberculosis, autoimmune inflammation of the adrenal glands, tumor metastases, and abrupt withdrawal of steroids. As a rule, this is insufficiency of the entire adrenal cortex. Acute failure can be caused by glomerular necrosis, hemorrhage, or acute infection. In children, a fulminant form can be observed in many infectious diseases (flu, meningitis), when a child can die in one day.

With insufficiency of the glomerular zone, the reabsorption of sodium and water decreases, the volume of circulating plasma decreases; increases the reabsorption of K + , H + . As a result, blood pressure drops sharply, electrolyte balance and acid-base balance are disturbed, the condition is life-threatening. Treatment: intravenous saline and aldosterone agonists (fludrocortisone).

The key link in the RAAS is angiotensin II, which:

Acts on the glomerular zone and increases the secretion of aldosterone;

Acts on the kidney and causes retention of Na + , Cl - and water;

Acts on sympathetic neurons and causes the release of norepinephrine, a powerful vasoconstrictor;

Causes vasoconstriction - constricts blood vessels (tens of times more active than norepinephrine);

Stimulates salt appetite and thirst.

Thus, this system brings blood pressure to normal when it decreases. Excess angiotensin II affects the heart, as well as an excess of CA and thromboxanes, causes myocardial hypertrophy and fibrosis, contributes to hypertension and chronic heart failure.

With an increase in blood pressure, three hormones begin to work mainly: NUP (natriuretic peptides), dopamine, adrenomedullin. Their effects are opposite to those of aldosterone and AT II. NUP cause the excretion of Na + , Cl - , H 2 O, vasodilation, increase vascular permeability and reduce the formation of renin.

Adrenomedullin acts in the same way as NUP: it is the excretion of Na +, Cl -, H 2 O, vasodilation. Dopamine is synthesized by the proximal tubules of the kidneys and acts as a paracrine hormone. Its effects: excretion of Na + and H 2 O. Dopamine reduces the synthesis of aldosterone, the action of angiotensin II and aldosterone, causes vasodilation and an increase in renal blood flow. Together, these effects lead to a decrease in blood pressure.

The level of blood pressure depends on many factors: the work of the heart, the tone of peripheral vessels and their elasticity, as well as on the volume of the electrolyte composition and viscosity of the circulating blood. All this is controlled by the nervous and humoral system. Hypertension in the process of chronicization and stabilization is associated with late (nuclear) effects of hormones. In this case, vascular remodeling, their hypertrophy and proliferation, vascular and myocardial fibrosis occur.

Currently, effective antihypertensive drugs are inhibitors of vasopeptidase ACE and neutral endopeptidase. Neutral endopeptidase is involved in the destruction of bradykinin, NUP, adrenomedullin. All three peptides are vasodilators, reduce blood pressure. For example, ACE inhibitors (perindo-, enalopril) reduce blood pressure by reducing the formation of AT II and delaying the breakdown of bradykinin.

Neutral endopeptidase inhibitors (omapatrilat), which are both ACE inhibitors and neutral endopeptidase inhibitors, have been discovered. They not only reduce the formation of AT II, ​​but also prevent the breakdown of hormones that reduce blood pressure - adrenomedullin, NUP, bradykinin. ACE inhibitors do not completely turn off the RAAS. A more complete shutdown of this system can be achieved with angiotensin II receptor blockers (losartan, eprosartan).

The pharmacodynamic action of ACE inhibitors is associated with blocking ACE, which converts angiotensin I to angiotensin II in the blood and tissues, which leads to the elimination of pressor and other neurohumoral effects of ATII, and also prevents the inactivation of bradykinin, which enhances the vasodilating effect.

Most ACE inhibitors are prodrugs (except captopril, lisinopril), the action of which is carried out by active metabolites. ACE inhibitors differ in their affinity for ACE, their effect on tissue RAAS, lipophilicity, and elimination pathways.

The main pharmacodynamic effect is hemodynamic, associated with peripheral arterial and venous vasodilation, which, unlike other vasodilators, is not accompanied by an increase in heart rate due to a decrease in SAS activity. The renal effects of ACE inhibitors are associated with dilatation of glomerular arterioles, increased natriuresis and potassium retention as a result of a decrease in aldosterone secretion.

The hemodynamic effects of ACE inhibitors underlie their hypotensive action; in patients with congestive heart failure - in reducing the dilatation of the heart and increasing cardiac output.

ACE inhibitors have an organoprotective (cardio-, vaso- and nephroprotective) effect; favorably affect carbohydrate metabolism (reduce insulin resistance) and lipid metabolism (increase HDL levels).

ACE inhibitors are used to treat arterial hypertension, left ventricular dysfunction and heart failure, are used in acute myocardial infarction, diabetes mellitus, nephropathy and proteinuria.

Class-specific side effects - cough, hypotension of the first dose and angioedema, azotemia.

Keywords: angiotensin II, ACE inhibitors, hypotensive effect, organoprotective effect, cardioprotective effect, nephroprotective effect, pharmacodynamics, pharmacokinetics, side effects, drug interactions.

STRUCTURE AND FUNCTIONS OF THE RENIN-ANGIOTENSINALDOSTERONE SYSTEM

The renin-angiotensin-aldosterone system (RAAS) has an important humoral effect on the cardiovascular system and is involved in the regulation of blood pressure. The central link of the RAAS is angiotensin II (AT11) (Scheme 1), which has a powerful direct vasoconstrictor effect mainly on the arteries and a mediated effect on the central nervous system, the release of catecholamines from the adrenal glands and causes an increase in total peripheral vascular resistance, stimulates the secretion of aldosterone and leads to fluid retention and an increase in BCC ), stimulates the release of catecholamines (norepinephrine) and other neurohormones from sympathetic endings. The effect of AT11 on the level of blood pressure is due to the effect on vascular tone, as well as through structural restructuring and remodeling of the heart and blood vessels (Table 6.1). In particular, ATII is also a growth factor (or growth modulator) for cardiomyocytes and vascular smooth muscle cells.

Scheme 1. The structure of the renin-angiotensin-aldosterone system

Functions of other forms of angiotensin. Angiotensin I is of little importance in the RAAS system, as it quickly turns into ATP, in addition, its activity is 100 times less than that of ATP. Angiotensin III acts like ATP, but its pressor activity is 4 times weaker than ATP. Angiotensin 1-7 is formed as a result of the conversion of angiotensin I. In terms of functions, it differs significantly from ATP: it does not cause a pressor effect, but, on the contrary, leads to a decrease in blood pressure due to the secretion of ADH, stimulation of prostaglandin synthesis, and natriuresis.

RAAS has a regulatory effect on renal function. ATP causes a powerful spasm of the afferent arteriole and a decrease in pressure in the capillaries of the glomerulus, a decrease in filtration in the nephron. As a result of the decrease in filtration, sodium reabsorption in the proximal nephron decreases, which leads to an increase in the sodium concentration in the distal tubules and activation of Na-sensitive receptors in the densus macula in the nephron. By fur-

According to feedback, this is accompanied by inhibition of renin release and an increase in glomerular filtration rate.

The functioning of the RAAS is associated with aldosterone and through a feedback mechanism. Aldosterone is the most important regulator of extracellular fluid volume and potassium homeostasis. Aldosterone does not have a direct effect on the secretion of renin and ATP, but an indirect effect is possible through sodium retention in the body. ATP and electrolytes are involved in the regulation of aldosterone secretion, with ATP stimulating, and sodium and potassium reducing its formation.

Electrolyte homeostasis is closely related to RAAS activity. Sodium and potassium not only affect the activity of renin, but also change the sensitivity of tissues to ATP. At the same time, in the regulation of activity

renin, sodium plays a large role, and in the regulation of aldosterone secretion, potassium and sodium have the same influence.

Physiological activation of the RAAS is observed with the loss of sodium and fluid, a significant decrease in blood pressure, accompanied by a drop in filtration pressure in the kidneys, an increase in the activity of the sympathetic nervous system, and also under the influence of many humoral agents (vasopressin, atrial natriuretic hormone, antidiuretic hormone).

A number of cardiovascular diseases can contribute to pathological stimulation of the RAAS, in particular, in hypertension, congestive heart failure, and acute myocardial infarction.

It is now known that RAS functions not only in plasma (endocrine function), but also in many tissues (brain, vascular wall, heart, kidneys, adrenal glands, lungs). These tissue systems can work independently of the plasma, at the cellular level (paracrine regulation). Therefore, there are short-term effects of ATII, due to its freely circulating fraction in the systemic circulation, and delayed effects, regulated through tissue RAS and affecting the structural-adaptive mechanisms of organ damage (Table 6.2).

Table 6.2

Different fractions of the RAAS and their effects

The key enzyme of the RAAS is the angiotensin-converting enzyme (ACE), which ensures the conversion of ΑTI to ATII. The main amount of ACE is present in the systemic circulation, providing the formation of circulating ATII and short-term geodynamic effects. The conversion of AT to ATII in tissues can be carried out not only with the help of ACE, but also with other enzymes.

tami (chymases, endoperoxides, cathepsin G, etc.); believe that they play a leading role in the functioning of tissue RAS and the development of long-term effects of modeling the function and structure of target organs.

ACE is identical to the kininase II enzyme involved in the degradation of bradykinin (Scheme 1). Bradykinin is a powerful vasodilator involved in the regulation of microcirculation and ion transport. Bradykinin has a very short lifespan and is present in the bloodstream (tissues) at low concentrations; therefore it will show its effects as a local hormone (paracrine). Bradykinin promotes an increase in intracellular Ca 2 +, which is a cofactor for NO synthetase involved in the formation of endothelial relaxing factor (nitric oxide or NO). The endothelium-relaxing factor, which blocks vascular muscle contraction and platelet aggregation, is also an inhibitor of mitosis and proliferation of vascular smooth muscle, which provides an anti-atherogenic effect. Bradykinin also stimulates the synthesis of PGE in the vascular endothelium. 2 and PGI 2 (prostacycline) - powerful vasodilators and platelet antiplatelet agents.

Thus, bradykinin and the entire kinin system are anti-RAAS. Blocking ACE potentially increases the level of kinins in the tissues of the heart and vascular wall, which provides antiproliferative, antiischemic, antiatherogenic and antiplatelet effects. Kinins contribute to an increase in blood flow, diuresis and natriuresis without a significant change in the glomerular filtration rate. PG E 2 and PGI 2 also have diuretic and natriuretic effects and increase renal blood flow.

The key enzyme of the RAAS is the angiotensin-converting enzyme (ACE), which provides the conversion of ATI to ATII, and is also involved in the degradation of bradykinin.

MECHANISM OF ACTION AND PHARMACOLOGY OF ACE INHIBITORS

The pharmacodynamic effects of ACE inhibitors are associated with ACE blocking and a decrease in the formation of ATS in the blood and tissues,

elimination of pressor and other neurohumoral effects. At the same time, according to the feedback mechanism, the level of plasma renin and ATI can increase, as well as a transient decrease in the level of aldosterone. ACE inhibitors prevent the destruction of bradykinin, which complements and enhances their vasodilating effect.

There are many different ACE inhibitors and several important characteristics that distinguish the drugs in this group (Table 6.3):

1) chemical structure (presence of Sff-group, carboxyl group, phosphorus-containing);

2) drug activity (drug or prodrug);

3) influence on tissue RAAS;

4) pharmacokinetic properties (lipophilicity).

Table 6.3

Characterization of ACE inhibitors

The nature of distribution in tissues (tissue specificity) of ACE inhibitors depends on the degree of lipophilicity, which determines penetration into different tissues, and on the strength of binding to tissue ACE. The relative potency (affinity) of ACE inhibitors has been studied in vitro. Data on the comparative potency of different ACE inhibitors are presented below:

Quinaprilat = Benazeprilat = Trandaloprilat = Cilazaprilat = Ramiprilat = Perindoprilat > Lisinopril > Enalaprilat > Fosinoprilat > Captopril.

The strength of binding to ACE determines not only the strength of the action of ACE inhibitors, but also their duration of action.

The pharmacodynamic effects of ACE inhibitors are class-specific and are associated with blocking ACE and reducing the formation of ATP in the blood and tissues while eliminating its pressor and other neurohumoral effects, as well as preventing the destruction of bradykinin, which contributes to the formation of vasodilatory factors (PG, NO), complements the vasodilator Effect.

PHARMACODYNAMICS OF ACE INHIBITORS

The main pharmacodynamic effect of ACE inhibitors is hemodynamic, associated with peripheral arterial and venous vasodilation and developing as a result of complex changes in the neurohumoral regulation of the cardiovascular system (suppression of RAAS and SAS activity). According to the mechanism of action, they fundamentally differ both from direct vasodilators and calcium antagonists acting directly on the vascular wall, and from receptor-acting vasodilators (α- and β-blockers). They reduce peripheral vascular resistance, increase cardiac output and do not affect the heart rate due to the elimination of the stimulating effect of ATP on the SAS. The hemodynamic effect of ACE inhibitors is observed regardless of the activity of renin in the blood. The vasodilating effect of ACE inhibitors is manifested by an improvement in regional blood flow in the organs and tissues of the brain, heart, and kidneys. In the kidney tissue, ACE inhibitors have a dilating effect on the efferent (efferent) arterioles of the glomeruli and reduce intraglomerular hypertension. They also cause natriuresis and potassium retention as a result of a decrease in aldosterone secretion.

HEMODYNAMIC EFFECTS OF ACE INHIBITORS ARE THE BASIS OF THEIR HYPOTENSIVE ACTION

The hypotensive effect is due not only to a decrease in the formation of ATP, but also to the prevention of the degradation of bradykinin, which potentiates endothelium-dependent relaxation of vascular smooth muscles, through the formation of vasodilating prostaglandins and endothelial relaxing factor (NO).

For most ACE inhibitors, the hypotensive effect begins after 1-2 hours, the maximum effect develops on average after 2-6 hours, the duration of action reaches 24 hours (except for the shortest-acting captopril and enalapril, the effect of which lasts 6-12 hours) (Table 6.4 ). The rate of onset of the hemodynamic effect of inhibitors directly affects the tolerability and severity of "first dose" hypotension.

Table 6.4

Duration of hypotensive action of ACE inhibitors

The distribution of the hypotensive effect of ACE inhibitors over time is not always exactly dependent on pharmacokinetics, and not all drugs, even long-acting, are characterized by a high T / p index (Table 6.5).

Table 6.5

T/p ratio of ACE inhibitors

ACE inhibitors reduce the release of norepinephrine and the reactivity of the vascular wall to vasoconstrictor sympathetic activation, which is used in patients with coronary heart disease in acute myocardial infarction and the threat of reperfusion arrhythmias. In patients with congestive heart failure, a decrease in peripheral systemic resistance (afterload), pulmonary vascular resistance, and capillary pressure (preload) leads to a decrease in dilatation of the heart cavities, an improvement in diastolic filling, an increase in cardiac output, and an increase in exercise tolerance. In addition, the neurohumoral effects of ACE inhibitors slow down the remodeling of the heart and blood vessels.

By blocking the neurohumoral effects of ATII, ACE inhibitors have a pronounced organoprotective effect: cardioprotective, vasoprotective, and nephroprotective; they cause a number of beneficial metabolic effects, improving carbohydrate and lipid metabolism. Potential effects of ACE inhibitors are presented in table. 6.6.

ACE inhibitors exhibit a cardioprotective effect, causing regression of LVH, preventing remodeling, ischemic and reperfusion injury of the myocardium. The cardioprotective effect is class-specific for all ACE inhibitors and is due, on the one hand, to the elimination of the trophic effect of AT11 on the myocardium, and on the other hand, to the modulation of sympathetic activity, since AT11 is an important regulator of the release of

Table 6.6

Pharmacodynamic effects of ACE inhibitors

catecholamines, and inhibition of ATP leads to a decrease in the sympathetic effect on the heart and blood vessels. In the implementation of the cardioprotective effects of ACE inhibitors, a certain place belongs to kinins. Bradykinin and prostaglandins due to anti-ischemic action, dilatation of capillaries and increase

delivery of oxygen to the myocardium contributes to increased microcirculation, restoration of metabolism and pumping function of the myocardium against the background of regression of LVH and in the postinfarction period.

The predominant role of ACE inhibitors in reducing LVH over other classes of antihypertensive drugs has been proven, and there is no relationship between the severity of the hypotensive effect and regression of LVH (they can prevent the development of LVH and myocardial fibrosis even in the absence of a decrease in blood pressure).

ACE inhibitors exhibit a vasoprotective effect, canceling the effects of ATII on AT 1 receptors of blood vessels, on the one hand, and on the other hand, activating the bradykinin system, improving endothelial function and exerting an antiproliferative effect on vascular smooth muscle.

ACE inhibitors have an anti-atherogenic effect, the mechanism of which is anti-proliferative and anti-migration effects on vascular smooth muscle cells and monocytes, a decrease in the formation of a collagen matrix, an antioxidant and anti-inflammatory effect. The anti-atherogenic effect is complemented by potentiation of endogenous fibrinolysis by ACE inhibitors and antiplatelet action (inhibition of platelet aggregation); decrease in plasma atherogenicity (decrease in LDL and triglycerides and increase in HDL); they prevent atherosclerotic plaque rupture and atherothrombosis. Anti-atherogenic properties in clinical studies are shown for ramipril, quinapril.

ACE inhibitors have an important nephroprotective effect, preventing the progression of renal failure and reducing proteinuria. The nephroprotective effect is class-specific and is characteristic of all drugs. Dilatation of predominantly efferent arterioles of the renal glomerulus is accompanied by a decrease in intraglomerular filtration pressure, filtration fraction and hyperfiltration, resulting in a decrease in proteinuria (mainly low molecular weight proteins) in patients with diabetic and hypertensive nephropathy. Renal effects, due to the high sensitivity of the renal vessels to the vasodilating effect of ACE inhibitors, appear earlier than the decrease in peripheral vascular resistance and are only partially mediated by the hypotensive effect. The mechanism of the antiproteinuric effect of ACE inhibitors is based on the anti-inflammatory effect on the glomerular basement membrane and the antiproliferative effect.

on the mesangial cells of the glomerulus, which reduces its permeability to medium and high molecular weight proteins. In addition, ACE inhibitors eliminate the trophic effects of ATII, which, by stimulating the growth of mesangial cells, their production of collagen and epidermal growth factor of the renal tubules, accelerates the development of nephrosclerosis.

It has been established that the lipophilicity of ACE inhibitors determines the effect on tissue RAS, and, possibly, organoprotective effects (Table 6.8).

Comparative pharmacokinetics of ACE inhibitors are presented in table. 6.9.

A distinctive pharmacokinetic feature of most ACE inhibitors (except captopril and lisinopril) is

Table 6.8

Lipophilicity index of active forms of major ACE inhibitors

Note. A negative value indicates hydrophilicity.

pronounced metabolism in the liver, including presystemic, leading to the formation of active metabolites and accompanied by significant individual variability. This pharmacokinetics makes ACE inhibitors similar to "prodrugs", the pharmacological action of which, after oral administration, is due to the formation of active metabolites in the liver. In Russia, a parenteral form of enalapril is registered - a synthetic analogue of enalaprilat, which is used to relieve hypertensive crises.

The maximum concentration of ACE inhibitors is reached in blood plasma after 1-2 hours and affects the rate of development of hypotension. ACE inhibitors are highly bound to plasma proteins (70-90%). The half-life is variable: from 3 hours to 24 hours or more, although pharmacokinetics have less effect on the duration of the hemodynamic effect. There are three phases of early

her rapid decline, reflecting the stage of distribution (T 1/2 a); the initial phase of elimination, reflecting the elimination of the fraction not associated with tissue ACE (T 1/2 b); a long terminal elimination phase, reflecting the elimination of the dissociated fraction of active metabolites from the complex with ACE, which can reach 50 hours (for ramipril) and determines the dosing interval.

Drugs are further metabolized to form glucuronides (except lisinopril and cilazapril). The routes of elimination of ACE inhibitors are of the greatest clinical importance:

predominantly renal (more than 60%) - lisinopril, cilazapril, enalapril, quinapril, perindopril; biliary (spirapril, trandolapril) or mixed. Biliary excretion is an important alternative to renal elimination, especially in the presence of CKD.

INDICATIONS

arterial hypertension(Table 6.9). ACE inhibitors have a hypotensive effect in almost all forms of hypertension, regardless of plasma renin activity. Baroreflex and other cardiovascular reflexes do not change, there is no orthostatic hypotension. This class of drugs is classified as first-line drugs in the treatment of hypertension. Monotherapy is effective in 50% of patients with hypertension. In addition to their hypotensive effect, ACE inhibitors in hypertensive patients reduce the risk of cardiovascular events (perhaps more than other antihypertensive drugs). ACE inhibitors are the drugs of choice in the combination of hypertension and diabetes mellitus due to a significant reduction in cardiovascular risk.

Left ventricular systolic dysfunction and chronic heart failure. ACE inhibitors should be prescribed to all patients with left ventricular dysfunction, regardless of the presence of symptoms of heart failure. ACE inhibitors prevent and slow down the development of CHF, reduce the risk of AMI and sudden death, and reduce the need for hospitalization. ACE inhibitors reduce left ventricular dilatation and prevent myocardial remodeling, reduce cardiosclerosis. The effectiveness of ACE inhibitors increases with the severity of left ventricular dysfunction.

Acute myocardial infarction. The use of ACE inhibitors in the early stages in acute myocardial infarction reduces the mortality of patients. ACE inhibitors are especially effective against the background of hypertension, diabetes mellitus and high-risk patients.

Diabetes mellitus and diabetic nephropathy. All ACE inhibitors slow down the progression of kidney damage in type I and type II diabetes mellitus, regardless of blood pressure levels. ACE inhibitors slow down the progression of chronic renal failure in other nephropathies. Long-term use of ACE inhibitors is accompanied by a decrease in the incidence of complications of diabetes mellitus and cardiovascular

Table 6.9

Indications for ACE inhibitors

complications. The use of ACE inhibitors is accompanied by a lower incidence of new cases of diabetes mellitus than other antihypertensive drugs (diuretics, β-blockers, calcium antagonists).

CONTRAINDICATIONS

ACE inhibitors are contraindicated in patients with bilateral renal artery stenosis or stenosis in a single kidney, as well as after kidney transplantation (risk of developing renal failure); in patients with severe renal failure; hyperkalemia; with severe aortic stenosis (with impaired hemodynamics); with angioedema, including after the use of any of the ACE inhibitors.

ACE inhibitors are contraindicated in pregnancy. The use of ACE inhibitors during pregnancy leads to embryotoxic effects: in the first trimester, malformations of the heart, blood vessels, kidneys, and brain are described; in the II and III trimesters - leads to fetal hypotension, skull hypoplasia, renal failure, anuria and even fetal death, so ACE inhibitors should be canceled immediately after pregnancy is established.

Caution is required in autoimmune diseases, collagenoses, especially systemic lupus erythematosus or scleroderma

(the risk of developing neutropenia or agranulocytosis increases); bone marrow depression.

Dosing principles. Dosing of ACE inhibitors has its own characteristics associated with the risk of a pronounced hemodynamic (hypotensive) effect and involves the use of the dose titration method - the use of an initial low dose of the drug, followed by its increase at intervals of 2 weeks until the average therapeutic (target) dose is reached. It is important to achieve the target dose both for the treatment of hypertension, CHF, and nephropathies, since it is at these doses that the maximum organoprotective effect of ACE inhibitors is observed.

Table 6.10

Dosing of ACE inhibitors

SIDE EFFECTS OF ACE INHIBITORS

ACE inhibitors, due to the common mechanism of action associated with non-selective blocking of the ACE enzyme, have the same class-specific side effects (PE). K class-specific

Kim PE ACE inhibitors include: 1) the most frequent - hypotension, cough, rash, hyperkalemia; 2) less frequent - angioedema, disorders of hematopoiesis, taste and impaired renal function (in particular, in patients with bilateral stenosis of the renal arteries and with congestive heart failure receiving diuretics).

"First dose" hypotension and associated dizziness are common to all ACE inhibitors; they are a manifestation of the hemodynamic effect (frequency up to 2%, with heart failure - up to 10%). Especially frequent after taking the first dose, in elderly patients, in patients with high plasma renin activity, with chronic heart failure, with hyponatremia and concomitant use of diuretics. To reduce the severity of "first dose" hypotension, slow titration of drug doses is recommended.

Cough is a class-specific PE of ACE inhibitors; the frequency of its occurrence varies widely from 5 to 20%, more often does not depend on the dose of drugs, mainly occurs in women. The mechanism of cough development is associated with the activation of the kinin-kallikrein system due to ACE blocking. At the same time, bradykinin can accumulate locally in the bronchial wall and activate other pro-inflammatory peptides (for example, substance P, neuropeptide Y), as well as histamine, which affect bronchomotor function and provoke coughing. Cancellation of ACE inhibitors completely stops the cough.

Hyperkalemia (above 5.5 mmol / l) is the result of a decrease in aldosterone secretion that occurs when blocking the formation of ATP, can be observed in patients with chronic renal failure, while taking potassium-sparing diuretics, potassium preparations.

Skin rash and angioedema (Quincke's edema) are associated with an increase in bradykinin levels.

Impaired renal function (increased creatinine and residual nitrogen in the blood plasma) can be observed at the beginning of treatment with ACE inhibitors, is transient. A significant increase in plasma creatinine can be observed in patients with CHF and renal artery stenosis, accompanied by high plasma renin activity and spasm of efferent arterioles; in these cases, drug withdrawal is necessary.

Neicopenia, thrombocytopenia and agranulocytosis are extremely rare (less than 0.5%).

Table 6.11

ACE inhibitor drug interactions

DRUG INTERACTIONS

ACE inhibitors do not have pharmacokinetic interactions; all drug interactions with them are pharmacodynamic.

ACE inhibitors interact with non-steroidal anti-inflammatory drugs, diuretics, potassium preparations, antihypertensive drugs (Table 6.11). The combination of ACE inhibitors with diuretics and other antihypertensive drugs can lead to an increase in the hypotensive effect, while diuretics are used to potentiate the hypotensive effect of ACE inhibitors. When combined with non-steroidal anti-inflammatory drugs (except for aspirin in antiplatelet doses less than 150 mg / day), this can lead to a weakening of the hypotensive effect of ACE inhibitors due to fluid retention and blocking of PG synthesis in the vascular wall. Potassium-sparing diuretics and other K+-containing agents (eg, KCl, potassium supplements) may increase the risk of hyperkalemia. Estrogen-containing drugs can reduce the hypotensive effect of ACE inhibitors. Caution is required when co-administering drugs with myelodepressive effects.

Table 6.12

Pharmacokinetics of ACE inhibitors