Treatment of arterial hypertension

Treatment of arterial hypertension associated with the kidneys has a number of general provisions on which the treatment of essential hypertension is based, retain their significance:

• Compliance with a diet with a restriction of salt and products that increase cholesterol;
• abolition of drugs that cause the development of hypertension;
• Reduction of excess body weight;
• reduction of alcohol consumption;
• increased physical activity;
• to give up smoking.

Especially important for nephrological patients is the strict limitation of sodium. Daily intake of table salt with renal arterial hypertension should be limited to 5 g / day. Taking into account the high sodium content in the finished food products (bread, sausages, canned food, etc.), this practically eliminates the additional use of table salt in cooking. Some expansion of the salt regime is allowed only with the constant intake of thiazide and loop diuretics.

Treatment of hypertension, or antihypertensive therapy, involves achieving "target pressure". In this regard, discuss the pace of lowering blood pressure, the tactics of antihypertensive treatment, conducted against the background of pathogenetic therapy of the underlying kidney disease, the choice of the optimal drug, the use of combinations of antihypertensive drugs.

It is now considered proven that a one-stage maximum reduction in elevated blood pressure should not exceed 25% of the baseline, so as not to disrupt kidney function.

Treatment of arterial hypertension in chronic kidney disease is the need to combine antihypertensive therapy and pathogenetic treatment of the underlying disease. The agents of pathogenetic therapy of kidney diseases: glucocorticoids, cyclosporine, heparin, dipyridamole, epoetin alfa (for example, erythropoietin), can themselves affect blood pressure, which should be taken into account in their combined use with antihypertensive drugs.

In patients with renal arterial hypertension of the 1 st and 2 nd stages glucocorticoids can enhance it, if they do not develop a pronounced diuretic and natriuretic effect, which, as a rule, is observed in patients with initially expressed sodium retention and hypervolemia. Increased blood pressure is a contraindication for the appointment of high doses of glucocorticoids, with the exception of cases of rapidly progressive glomerulonephritis.

The administration of NSAIDs simultaneously with antihypertensive agents can neutralize the effect of the latter or significantly reduce their effectiveness.

In the presence of severe renal failure (GFR less than 35 ml / min), heparin in combination with antihypertensive drugs should be used with great care because of the risk of developing hypotension.

The choice of antihypertensive drugs and the selection of the most preferred for the treatment of renal arterial hypertension is based on several principles. The preparation must possess:

• high efficiency (blockade of key mechanisms of development of arterial hypertension, normalization of cardiac output and OPS, protective effect on target organs);
• safety (absence of serious side effects, duration of the main effect, absence of "withdrawal syndrome");
• reliability (absence of addiction, preservation of basic properties for a long period);
• the possibility of combining with other antihypertensive drugs and potentiating their action.

Antihypertensive drugs

Currently, the treatment of hypertension is carried out using the following groups of antihypertensive drugs:

• ACE inhibitors;
• angiotensin II receptor blockers;
• blockers of slow calcium channels;
• beta-blockers;
• diuretics;
• alpha-adrenoblockers.

Central action drugs (methyldopa, clonidine) have an auxiliary value, and now they are rarely used.

Of the listed groups of drugs, the drugs of first choice include drugs that can block the formation and effects of angiotensin II (ACE inhibitors and angiotensin II receptor blockers, respectively). These groups of drugs meet all the requirements for antihypertensive drugs and possess nephroprotective properties simultaneously.

[1], [2], [3], [4], [5], [6], [7]

Angiotensin converting enzyme inhibitors

Drugs of this group block ACE, which, on the one hand, turns inactive angiotensin I into a powerful vasoconstrictor - angiotensin II, and on the other, destroys kinin - tissue vasodilator hormones. As a result, the pharmacological inhibition of this enzyme blocks the systemic and organ synthesis of angiotensin II and promotes the accumulation of kinins in the circulation and tissues. Clinically, these effects are manifested by a marked decrease in blood pressure, which is based on the normalization of general and local-renal peripheral resistance; correction of intralubular hemodynamics, which is based on the extension of the renal arteriolus, the main site of application of local renal angiotensin II.

In recent years, the nephroprotective role of ACE inhibitors has been proven by reducing the production of cellular factors that contribute to the processes of sclerosis and fibrosis.

Angiotensin converting enzyme inhibitors

International Nonproprietary Name	Tradename	Dose and frequency of admission
Captopril	Kapoten	75-100 mg in 3 doses
Enalapril	Renitek	5-10-20 mg in 1-2 administration
Ramipril	Tritace	2.5-5 mg once
Perindopril	Prestarium	4-8 mg once
Cilazapril	Inhibais	5 mg once
Fosinopril	Monopril	10-20 mg once
Quinapril	Akkupro	20-40 mg once
Trandolapril	Gopten	2-4 mg once
Lisinopril	Diroton	10-40-80 mg once
Benazepril	Lotenzin	10-20-40 mg once

Depending on the time of removal from the body, ACE inhibitors of the first generation (captopril with a half-life of less than 2 hours and a duration of hemodynamic effect of 4-5 hours) are isolated. The half-life of ACE inhibitors of the second generation is 11-14 hours; the duration of the hemodynamic effect is more than 24 hours. To maintain the optimal concentration of the drug in the blood during the day, 4-fold administration of captopril and a single (sometimes two-fold) intake of other ACE inhibitors are necessary.

The effect of all ACE inhibitors on the kidneys is almost identical. With initially preserved renal function with long-term administration (months, years), they increase renal blood flow, do not change or slightly reduce serum creatinine level, increasing GFR. In patients with initial and moderate renal insufficiency, long-term therapy with drugs corrected for the degree of renal insufficiency has a beneficial effect on renal function (serum creatinine level decreases, GFR increases, and the period of onset of terminal renal failure slows down).

With severe renal failure (GFR <30 mL / min), their use requires caution and constant monitoring. Increasing the level of serum creatinine more than 30% of the initial level and the development of hyperkalemia (more than 5.5-6.0 mmol / l) in response to the treatment of hypertension with ACE inhibitors that do not go in response to a dose reduction require withdrawal of the drug.

ACE inhibitors have the ability to correct intrarenal hemodynamics, reducing intrarenal hypertension and hyperfiltration, and reducing the intensity of proteinuria.

An essential condition for the manifestation of antihypertensive and antiproteinuric properties of ACE inhibitors is a sharp restriction of sodium in the diet. Increased consumption of table salt leads to a loss of antihypertensive and antiproteinuric properties of drugs.

There are several risk factors for stable decrease in renal function against the background of ACE inhibitors: elderly and senile age of patients (the dose of ACE inhibitors must be reduced), severe systemic atherosclerosis, diabetes mellitus, severe heart failure.

With the appointment of ACE inhibitors, complications and side effects may occur. In kidney diseases, serious complications when taking medications are considered to be an increase in the serum creatinine level, accompanied by a fall in GFR, and hyperkalemia. The dynamic violation of the nitrogen excretory function of the kidneys during their appointment is based on the expansion of the renal glomeruli that carry out arterioles, leading to a decrease in intraluminal pressure and filtration. As a rule, the violation of the intrarenal hemodynamics is restored independently during the first week of application of the drugs. Increasing the level of creatinine within 2-3 months from the start of treatment, which reaches 25-30% of the baseline, requires withdrawal of the drug.

Often when using ACE inhibitors, cough and hypotension occur. Cough can occur both in the earliest periods of treatment, and after 20-24 months from its onset. The mechanism of coughing is associated with the activation of kinins and prostaglandins. The basis for the abolition of drugs when a cough occurs is a significant deterioration in the quality of life of the patient. After cessation of the drugs, the cough lasts for several days. A more severe complication is hypotension. The risk of its occurrence is higher in patients with congestive heart failure, especially in old age.

Relatively frequent complications of treatment with ACE inhibitors include headache, dizziness. These complications, as a rule, do not require the withdrawal of the medicine.

In nephrological practice, the use of ACE inhibitors is contraindicated when:

• the presence of stenosis of the renal arteries of both kidneys;
• presence of stenosis of the renal artery of a single kidney (including transplanted);
• combination of renal pathology with severe heart failure;
• severe chronic renal failure against long-term treatment with diuretics;
• pregnancy, since their use in the II and III trimesters can lead to fetal hypotension, malformations and malnutrition.

The appointment of ACE inhibitors in these renal diseases can be complicated by the growth of blood creatinine, the drop of glomerular filtration, up to the development of acute renal failure.

[8], [9], [10], [11], [12]

Angiotensin II receptor blockers

The effect of angiotensin II on target cells is carried out by the interaction of the hormone with receptors, the most important of which are the receptors for angiotensin II of the 1 st and 2 nd type. The functions of these receptors are directly opposite: when stimulating type 1 receptors, blood pressure rises and renal failure progresses, while stimulation of Type 2 receptors has the opposite effect. Accordingly, the pharmacological blockade of ATI receptors determines the reduction in blood pressure and limits the effect of factors contributing to the progression of renal failure.

Selective blockers of receptors for angiotensin II of the 1 st type, allowed for clinical use

International Nonproprietary Name	Tradename	Dose and frequency of admission
Irbesartan	Aprovel	75-300 mg once
Valsartan	Diovan	80-160 mg once
Losartan	Cosaar	25-100 mg once
Candesartan	Atacand	4-16 mg once
Eprosartan	Twente	300-800 mg once
Telmisartan	Mykardis, praitor	20-80 mg once

All clinical and nephroprotective properties of angiotensin II receptor blockers (ARB) are similar to those of ACE inhibitors. Drugs effectively reduce arterial pressure, correct intramedular hemodynamics, improve renal blood supply, reduce proteinuria and slow the rate of progression of renal failure. To achieve the effects of ARB, a low salt balance is also needed, which determined the release of a preparation of gisaar containing losartan in a dose of 50 mg in combination with hydrochlorothiazide at a dose of 12.5 mg.

In contrast to ACE inhibitors, the use of ARB in the blood does not accumulate kinins, which excludes the development of cough from the side effects of the drug. At the same time, an increase in serum creatinine and potassium levels may develop due to the same reasons as with ACE inhibitors, so the physician's tactics in developing these complications should not differ from the tactics with the use of ACE inhibitors. The risk groups for reducing kidney function and contraindications to the appointment of two groups of drugs also do not differ.

[13], [14], [15], [16], [17], [18], [19], [20], [21]

Blockers of slow calcium channels

The mechanism of antihypertensive action of blockers of slow calcium channels is associated with the expansion of arterioles and a decrease in elevated OPS due to inhibition of the entry of Ca ^{2+ ions} into the cell and with blockade of the vaso-constrictive effect of endothelin.

According to modern classification, three groups of drugs of slow calcium channel blockers are distinguished:

• phenylalkylamines (verapamil);
• dihydropyridines (nifedipine);
• benzothiazepines (diltiazem).

They are called prototype drugs, or blockers of slow calcium channels of the first generation. For antihypertensive activity, all three groups of prototype drugs are equivalent, i.e. The effect of nifedipine in a dose of 30-60 mg / day is comparable with the effects of verapamil in a dose of 240-480 mg / day and diltiazem in a dose of 240-360 mg / day.

In the 80 years of the XX century, blockers of slow calcium channels of the second generation appeared. Their main advantages are the duration of action, good tolerability and tissue specificity.

Trade names and doses of calcium channel blockers

International Nonproprietary Name	Tradename	Dose and frequency of admission
Nifedipine	Corinthar, Cordafen, Adalat	30-40 mg in 3-4 doses
Nifedipine retard	Adalat-S	20-40 mg once
Felodipine	Plandil	5-10 mg once
Amlodipine	Norvask	5-10 mg once
Verapamil	Isoptin SR	240-480 mg once
Diltiazem	Altiazem PP	180 mg twice daily

For antihypertensive activity, slow calcium channel blockers are a group of highly effective drugs. Advantages over other antihypertensive agents are considered to be their pronounced antisclerotic (preparations do not affect the lipoprotein spectrum of blood serum) and antiaggregatory properties. These qualities make them the drugs of choice for the treatment of the elderly.

Blockers of slow calcium channels favorably affect renal function: they increase the kidney blood flow and cause sodium nares. Verapamil and diltiazem reduce intra-cerebral hypertension, while nifedipine either does not affect it, or promotes an increase in intra-cell pressure. In this regard, for the treatment of renal arterial hypertension from the drugs of this group preference is given to verapamil, diltiazem and their derivatives. All slow calcium channel blockers have a nephroprotective effect due to a decrease in kidney hypertrophy, inhibition of metabolism and the proliferation of mesangium, which slows the rate of progression of renal failure.

Side effects are associated, as a rule, with the use of slow calcium channel blockers dihydropyridine series of short action. In this group of drugs, the period of action is limited to 4-6 hours, the half-life period ranges from 1.5 to 4-5 hours. Within a short time, the concentration of nifedipine in serum varies in a wide range - from 65-100 to 5-10 ng / ml . Such a pharmacokinetic profile with a "peak" increase in the concentration of the drug in the blood leads to a drop in blood pressure for a short time and a number of neurohumoral reactions (ejection of catecholamines, activation of RAAS and other "stress hormones"). These characteristics determine the presence of major adverse reactions when taking medications: tachycardia, arrhythmias, "stinging" syndrome with exacerbation of angina, redness of the face and other symptoms of hypercatecholamineemia, which are unfavorable for the function of both the heart and kidneys. The safety of the use of drugs in the early period of pregnancy has not yet been established.

Long-acting drugs provide for a long time a constant concentration of the drug in the blood, so they are deprived of the above-mentioned adverse reactions and can be recommended for the treatment of nephrogenic arterial hypertension.

Verapamil can cause bradycardia, atrioventricular blockade and in rare cases (with the use of large doses) - atrioventricular dissociation. It is also possible to develop constipation. Reception of slow calcium channel blockers is contraindicated in case of hypotension. Verapamil can not be prescribed for violations of atrioventricular conduction, syndrome of weakness of the sinus node, severe heart failure.

[22], [23], [24], [25], [26], [27], [28]

Beta-blockers

The mechanism of their antihypertensive action is associated with a decrease in cardiac output, inhibition of renin secretion by the kidneys, a decrease in OPS, and release of norepinephrine from the endings of post-ganglionic sympathetic nerve fibers, with a decrease in the venous influx to the heart and volume of circulating blood.

Trade names and doses of beta-blockers

International Nonproprietary Name	Tradename	Dose and frequency of admission
Propranolol Nadolol Oxprenolol Pindolol Atenolol	Anaprilin, inderal, obzidan Korgard Tracicore Vicin Tenormin, atenol, prinorm	80-640 mg in 2-4 administration 80-320 mg in 2-4 administration 120-400 mg in 2-4 administration 10-60 mg in 3-4 doses 100-200 mg in 1-2 doses
Metoprolol Betaxolol Talinolol Carvedilol Bisoprolol	Betalok, egilok Lokren Cordanum Dilatrend Concor	100-200 mg in 2-3 doses 5-20 mg in 1-2 administration 150-600 mg in 1-3 administration 25-100 mg in 1-2 administration 2,5-10 mg once a day

Distinguish between non-selective beta-blockers (blocking and beta1 and beta2-adrenoreceptors) and cardioselective, blocking predominantly beta1-adrenergic receptors. Some of the beta-blockers (oxprenolol, pindolol, acebutolol, talinolol) have sympathomimetic activity, which makes it possible to use them in heart failure, bradycardia, in patients with bronchial asthma.

By the duration of the action, short-acting beta-blockers (propranolol, oxprenolol, metoprolol, acebutalol), medium (pindolol) and long-acting (atenolol, betaxolol, bisoprolol) are discernible.

Essential advantages of this group of drugs are their anti-anginal activity, the possibility of preventing the development of myocardial infarction, a decrease or slowdown in the development of myocardial hypertrophy.

Preparations of this group do not suppress blood supply to the kidneys and do not cause a decrease in renal function. With long-term treatment of GFR diuresis and sodium excretion remain within the initial values. When treating high doses of drugs, RAAC is blocked and hyperkalaemia may develop.

Side effects in the treatment of beta-blockers:

• sinus bradycardia (heart rate less than 50 per minute);
• arterial hypotension;
• increased left ventricular failure;
• atrioventricular blockade of various degrees;
• exacerbation of bronchial asthma or other chronic obstructive pulmonary diseases;
• development of hypoglycemia, especially in patients with labile course of diabetes mellitus;
• exacerbation of intermittent claudication and Raynaud's syndrome;
• development of hyperlipidemia;
• in rare cases observe a violation of sexual function.

Preparations beta-blockers are contraindicated for:

• acute heart failure;
• pronounced sinus bradycardia;
• syndrome of weakness of the sinus node;
• atrioventricular blockade of II and III degree;
• bronchial asthma and severe bronchial obstructive diseases.

[29], [30], [31], [32], [33], [34]

Diuretics

Preparations of this group are designed to remove sodium and water from the body. The essence of the action of all diuretics is to blockade the reabsorption of sodium and the consequent decrease in the reabsorption of water as sodium passes through the nephron.

The antihypertensive effect of natriuretics is based on a decrease in the volume of circulating blood and cardiac output due to the loss of part of the exchangeable sodium and the reduction in OPS due to a change in the electrolyte composition of arteriolar walls (sodium release) and a decrease in their sensitivity to pressoric vasoactive hormones. In addition, when combined therapy with antihypertensive drugs is used, diuretics can block the sodium-blocking effect of the main antihypertensive drug, potentiate the antihypertensive effect and at the same time allow the salt regime to be somewhat extended, making the diet more acceptable for patients.

To treat renal arterial hypertension in patients with preserved renal function, diuretics acting in the area of the distal tubules were most widely used: a group of thiazide diuretics-hydrochlorothiazide (hypothiazide, adelfan-ezidrex) and thiazide-like diuretics-indapamide (arifone).

Treatment of hypertension is carried out using small doses of hydrochlorothiazide (12.5-25 mg once a day). The drug is released unchanged through the kidneys. It has the property of reducing GFR, so its use is contraindicated in renal failure (serum creatinine levels greater than 210 mmol / l, GFR less than 30 ml / min).

Indapamide due to lipophilic properties selectively accumulates in the vessel wall and has a long half-life (18 h). The antihypertensive dose of the drug is 2.5 mg once a day. The mechanism of its antihypertensive action is associated with the ability to stimulate the production of prostacyclin and thereby cause a vasodilating effect, and also with the property of reducing the content of free intracellular calcium, which provides less sensitivity of the vascular wall to the action of pressor amines. Diuretic effect of the drug develops when receiving large therapeutic doses (up to 40 mg of indapamide per day).

To treat renal arterial hypertension in patients with impaired renal function and in diabetes mellitus diuretics are used, acting in the loop area of Henle, loop diuretics. From loop diuretics, furosemide (Lasix), ethacrynic acid (uretite), bumetanide (burinex) are most common in clinical practice.

Furosemide has a powerful natriuretic effect. In parallel with the loss of sodium in the application of furosemide, the excretion of potassium, magnesium and calcium from the body increases. The period of action of the drug is short (6 hours), the diuretic effect is dose-dependent. The drug has the ability to increase GFR, so it is indicated for the treatment of patients with renal insufficiency. Furosemide is prescribed at 40-120 mg / day orally, intramuscularly or intravenously up to 250 mg / day.

Among the side effects of all diuretic drugs, hypokalemia, more pronounced with thiazide diuretics, is most important. Correction of hypokalemia is especially important in patients with arterial hypertension, as potassium itself helps to lower blood pressure. If the serum potassium level drops below 3.5 mmol / l, potassium-containing drugs should be added. Other side effects include hyperglycemia (thiazide diuretics, furosemide), hyperuricemia (more pronounced with thiazide diuretics), development of gastrointestinal dysfunction, erectile dysfunction.

[35], [36], [37], [38], [39], [40], [41], [42]

Alpha-blockers

Of this group of antihypertensive drugs, prazosin and, most recently, a new drug, doxazosin (for example, cardura), have become most common.

Prazosin is a selective antagonist of postsynaptic alpha 1-adrenergic receptors. The antihypertensive effect of the drug is associated with a direct decrease in OPS. Prazosin dilates the venous pathway, reduces preload, which makes it justified to use it in combination therapy in patients with heart failure.

The antihypertensive effect of prazosin upon ingestion comes in 0.5-3 hours and persists for 6-8 hours. The half-life of the drug is 3 hours, it is excreted through the gastrointestinal tract, so there is no need for correction of the dose in renal failure. The initial therapeutic dose of prazosin is 0.5-1 mg per day, for 1-2 weeks the dose is increased to 3-20 mg per day (2-3 times). The maintenance dose of the drug is 5-7.5 mg / day. Prazosin favorably affects the function of the kidneys: increases renal blood flow, the value of glomerular filtration. The drug has hypolipidemic properties, little effect on the electrolyte composition. The above properties contribute to the prescription of the drug in chronic renal failure. Side effects include postural hypotension, dizziness, drowsiness, dry mouth, impotence.

Doxazosin (for example, cardura) is structurally similar to prazosin, but has a prolonged effect. The drug significantly reduces OPS, has pronounced anti-atherogenic properties (reduces the level of total cholesterol, LDL cholesterol and VLDL, increases the level of HDL cholesterol). There is no negative effect of the drug on carbohydrate metabolism. These properties make doxazosin the drug of choice for the treatment of hypertension in patients with diabetes mellitus. Doxazosin, like prazosin, has a beneficial effect on kidney function, which determines its use in patients with renal arterial hypertension in the stage of renal failure. When taking the drug peak concentration in the blood comes in 2-4 hours; the half-life is within 16-22 hours. The therapeutic doses of the drug are 1-16 mg once a day. Side effects include dizziness, nausea, headache.

These modern antihypertensive drugs are most effective in the treatment of renal arterial hypertension. However, each of the presented drugs with monotherapy provides normalization of blood pressure in only a half of nephrologic patients. This situation is primarily due to the peculiarities of the pathogenesis of renal arterial hypertension, which includes a number of independent factors, which predetermines the possibility of its correction only when a combination of antihypertensive drugs with a different mechanism of action is used. It is possible to use several combinations of drugs: for example, an ACE inhibitor, or an antagonist of an ATI receptor, or a beta-blocker with a diuretic; dihydropyridine calcium channel blocker in combination with a beta-adrenoblocker and so on.

In renal arterial hypertension with preserved renal function, a combination of 2 antihypertensive drugs can be used, and if the correction of arterial pressure is ineffective, therapy can be strengthened by the introduction of a third drug. With a decrease in renal function, real success is achieved by using a combination of three, sometimes four antihypertensive drugs. In these combinations, it is necessary to include a diuretic with the goal of creating a low salt regime for optimal "work" of antihypertensive drugs.

In conclusion, it should be noted that the treatment of arterial hypertension in diseases of the kidneys, leading to inhibition of progression of renal failure and lengthening of the pre-dialysis period of life of patients, is confirmed by evidence of "evidence-based medicine".

[43], [44],