Treatment of arterial hypertension

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

• following a diet with limited salt and cholesterol-increasing foods;
• discontinuation of medications that cause the development of arterial hypertension;
• reduction of excess body weight;
• reducing alcohol consumption;
• increasing physical activity;
• quitting smoking.

Strict sodium restriction is of particular importance for nephrological patients. Daily consumption of table salt in renal arterial hypertension should be limited to 5 g/day. Given the high sodium content in ready-made food products (bread, sausages, canned goods, etc.), this virtually eliminates the additional use of table salt in cooking. Some expansion of the salt regime is allowed only with the constant use of thiazide and loop diuretics.

Treatment of arterial hypertension, or antihypertensive therapy, involves achieving "target pressure". In this regard, the issues of the rate of reduction of arterial pressure, tactics of antihypertensive treatment carried out against the background of pathogenetic therapy of the main renal disease, the choice of the optimal drug, the use of combinations of antihypertensive drugs are discussed.

It is currently considered proven that a single maximum reduction in high blood pressure should not exceed 25% of the initial level in order not to impair kidney function.

Treatment of arterial hypertension in chronic kidney diseases involves the need to combine antihypertensive therapy and pathogenetic treatment of the underlying disease. Pathogenetic therapy agents for kidney diseases: glucocorticoids, cyclosporine, heparin, dipyridamole, epoetin alpha (e.g., erythropoietin) - can themselves affect blood pressure, which should be taken into account when they are prescribed in combination with antihypertensive drugs.

In patients with stage 1 and 2 renal arterial hypertension, glucocorticoids may increase it if their administration does not result in a pronounced diuretic and natriuretic effect, which is usually observed in patients with initially pronounced sodium retention and hypervolemia. Increased blood pressure is a contraindication for the administration of high doses of glucocorticoids, except in cases of rapidly progressing glomerulonephritis.

The use of NSAIDs simultaneously with antihypertensive drugs may neutralize the effect of the latter or significantly reduce their effectiveness.

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

The choice of antihypertensive drugs and the selection of the most preferable ones for the treatment of renal arterial hypertension is based on several principles. The drug should have:

• high efficiency (blockade of key mechanisms of arterial hypertension development; 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 (lack of addiction, preservation of basic properties over a long period);
• the possibility of combining with other antihypertensive drugs and potentiating their action.

Antihypertensive drugs

Currently, arterial hypertension is treated using the following groups of antihypertensive drugs:

• ACE inhibitors;
• angiotensin II receptor blockers;
• calcium channel blockers;
• beta blockers;
• diuretics;
• alpha-blockers.

Centrally acting drugs (methyldopa, clonidine) have an auxiliary role and are currently rarely used.

Of the listed groups of drugs, the first-choice drugs include those capable of blocking 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 simultaneously have nephroprotective properties.

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

Angiotensin-converting enzyme inhibitors

The drugs of this group block ACE, which, on the one hand, converts inactive angiotensin I into a powerful vasoconstrictor - angiotensin II, and on the other hand, destroys kinins - tissue vasodilator hormones. As a result, 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 pronounced decrease in arterial pressure, which is based on the normalization of general and local-renal peripheral resistance; correction of intraglomerular hemodynamics, which is based on the expansion of the efferent renal arteriole, 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	Trade name	Dosage and frequency of administration
Captopril	Capoten	75-100 mg in 3 doses
Enalapril	Renitek	5-10-20 mg in 1-2 doses
Ramipril	Tritace	2.5-5 mg once
Perindopril	Prestarium	4-8 mg once
Cilazapril	Inhibase	5 mg once
Fosinopril	Monopril	10-20 mg once
Quinapril	Accupro	20-40 mg once
Trandolapril	Hopten	2-4 mg once
Lisinopril	Diroton	10-40-80 mg once
Benazepril	Lotensin	10-20-40 mg once

Depending on the time of elimination from the body, first-generation ACE inhibitors are distinguished (captopril with a half-life of less than 2 hours and a duration of hemodynamic effect of 4-5 hours). The half-life of second-generation ACE inhibitors is 11-14 hours; the duration of the hemodynamic effect is more than 24 hours. To maintain an optimal concentration of the drug in the blood during the day, captopril must be taken 4 times a day and other ACE inhibitors must be taken once (sometimes twice a day).

The effect of all ACE inhibitors on the kidneys is almost the same. With initially preserved renal function, with long-term use (months, years), they increase renal blood flow, do not change or slightly reduce the level of serum creatinine, increasing the SCF. In patients with initial and moderate renal failure, long-term therapy with drugs adjusted to the degree of renal failure has a beneficial effect on renal function (the level of serum creatinine decreases, the SCF increases, the onset of terminal renal failure is delayed).

In severe renal failure (SCF <30 ml/min), their use requires caution and constant monitoring. An increase in serum creatinine levels by 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 arterial hypertension with ACE inhibitors, which do not resolve in response to a dose reduction, require discontinuation of the drug.

ACE inhibitors have the property of correcting intrarenal hemodynamics, reducing intrarenal hypertension and hyperfiltration, and decreasing the severity of proteinuria.

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

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

Complications and side effects may occur when prescribing ACE inhibitors. In kidney diseases, dangerous complications when taking drugs include an increase in the level of serum creatinine, accompanied by a drop in SCF, and hyperkalemia. The basis of the dynamic disorder of the nitrogen-excreting function of the kidneys when they are prescribed is the expansion of the efferent arterioles of the renal glomeruli, leading to a decrease in intraglomerular pressure and filtration. As a rule, the violation of intrarenal hemodynamics is restored on its own during the first week of drug use. An increase in the creatinine level within 2-3 months from the start of treatment, which reaches 25-30% of the initial level, requires discontinuation of the drug.

Cough and hypotension often occur when using ACE inhibitors. Cough can occur both in the earliest stages of treatment and 20-24 months after its onset. The mechanism of cough is associated with the activation of kinins and prostaglandins. The basis for discontinuing medications when cough occurs is a significant deterioration in the patient's quality of life. After discontinuing the drugs, the cough goes away within a few days. A more severe complication is hypotension. The risk of its occurrence is higher in patients with congestive heart failure, especially in the elderly.

Relatively common complications of treatment with ACE inhibitors include headache and dizziness. These complications, as a rule, do not require discontinuing the drug.

In nephrological practice, the use of ACE inhibitors is contraindicated in the following cases:

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

The use of ACE inhibitors for the listed kidney diseases may be complicated by an increase in blood creatinine, a decrease in glomerular filtration, and even the development of acute renal failure.

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

Angiotensin II receptor blockers

The effect of angiotensin II on target cells is achieved through the interaction of the hormone with receptors, the most important of which are angiotensin II receptors of types 1 and 2. The functions of these receptors are directly opposite: stimulation of type 1 receptors increases blood pressure and progresses renal failure, while stimulation of type 2 receptors has the opposite effect. Accordingly, pharmacological blockade of ATI receptors predetermines a decrease in blood pressure and limits the impact of factors that contribute to the progression of renal failure.

Selective angiotensin II receptor blockers type 1 approved for clinical use

International Nonproprietary Name	Trade name	Dosage and frequency of administration
Irbesartan	Aprovel	75-300 mg once
Valsartan	Diovan	80-160 mg once
Losartan	Kozaar	25-100 mg once
Candesartan	Atacand	4-16 mg once
Eprosartan	Teventen	300-800 mg once
Telmisartan	Mikardis, Prytor	20-80 mg once

All clinical and nephroprotective properties of angiotensin II receptor blockers (ARBs) are similar to those of ACE inhibitors. The drugs effectively reduce blood pressure, correct intraglomerular hemodynamics, improve renal blood supply, reduce proteinuria and slow the rate of progression of renal failure. To achieve the effects of ARBs, a low-salt balance is also necessary, which determined the release of the drug Gizaar, containing losartan, in a dose of 50 mg in combination with hydrochlorothiazide in a dose of 12.5 mg.

In contrast to ACE inhibitors, when using ARBs, kinins do not accumulate in the blood, which excludes the development of cough from the side effects of the drug. At the same time, an increase in the level of creatinine and potassium in the blood serum can develop due to the same reasons as when using ACE inhibitors, so the doctor's tactics in the development of these complications should not differ from the tactics when using ACE inhibitors. Risk groups for decreased renal function and contraindications for prescribing the two groups of drugs also do not differ.

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

Calcium channel blockers

The mechanism of the antihypertensive action of calcium channel blockers is associated with the expansion of arterioles and a decrease in elevated TPR due to the inhibition of the entry of Ca ²⁺ ions into the cell and with the blockade of the vasoconstrictor effect of endothelin.

According to the modern classification, there are three groups of calcium channel blockers:

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

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

In the 1980s, second-generation calcium channel blockers appeared. Their main advantages are long-lasting action, good tolerability, and tissue specificity.

Trade names and doses of calcium channel blockers

International Nonproprietary Name	Trade name	Dosage and frequency of administration
Nifedipine	Corinfar, cordafen, adalat	30-40 mg in 3-4 doses
Nifedipine-retard	Adalat-S	20-40 mg once
Felodipine	Plendil	5-10 mg once
Amlodipine	Norvask	5-10 mg once
Verapamil	Isoptin SR	240-480 mg once
Diltiazem	Altiazem RR	180 mg twice daily

In terms of antihypertensive activity, calcium channel blockers are a group of highly effective drugs. Their advantages over other antihypertensive drugs include their pronounced antisclerotic (the drugs do not affect the lipoprotein spectrum of blood serum) and antiaggregatory properties. These qualities make them the drugs of choice for treating the elderly.

Calcium channel blockers have a beneficial effect on renal function: they increase renal blood flow and cause natriuresis. Verapamil and diltiazem reduce intraglomerular hypertension, while nifedipine either does not affect it or promotes an increase in intraglomerular pressure. In this regard, verapamil, diltiazem and their derivatives are preferred among drugs in this group for the treatment of renal arterial hypertension. All calcium channel blockers have a nephroprotective effect due to a decrease in renal hypertrophy, inhibition of metabolism and mesangial proliferation, which slows the rate of progression of renal failure.

Side effects are usually associated with the use of short-acting dihydropyridine calcium channel blockers. This group of drugs has a period of action limited to 4-6 hours, and a half-life of 1.5 to 4-5 hours. Over a short period of time, the concentration of nifedipine in the blood serum varies widely - 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 (release of catecholamines, activation of the RAAS and other "stress hormones"). These characteristics determine the presence of the main side effects when taking drugs: tachycardia, arrhythmia, "steal" syndrome with exacerbation of angina, facial flushing and other symptoms of hypercatecholaminemia, which are unfavorable for the function of both the heart and kidneys. The safety of using the drugs in early pregnancy has not yet been established.

Extended-release drugs provide a constant concentration of the drug in the blood over a long period of time, so they are free of the above-mentioned side effects and can be recommended for the treatment of nephrogenic arterial hypertension.

Verapamil may cause bradycardia, atrioventricular block and, in rare cases (when using large doses), atrioventricular dissociation. Constipation may also develop. Calcium channel blockers are contraindicated in hypotension. Verapamil should not be prescribed for atrioventricular conduction disorders, sick sinus syndrome, or severe heart failure.

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

Beta-blockers

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

Trade names and doses of beta blockers

International Nonproprietary Name	Trade name	Dose and frequency of administration
Propranolol Nadolol Oxprenolol Pindolol Atenolol	Anaprilin, Inderal, Obzidan Corgard Trazicor Visken Tenormin, atenol, prinorm	80-640 mg in 2-4 doses 80-320 mg in 2-4 doses 120-400 mg in 2-4 doses 10-60 mg in 3-4 doses 100-200 mg in 1-2 doses
Metoprolol Betaxolol Talinolol Carvedilol Bisoprolol	Betaloc, egiloc Locren Cordanum Dilatrend Concor	100-200 mg in 2-3 doses 5-20 mg in 1-2 doses 150-600 mg in 1-3 doses 25-100 mg in 1-2 doses 2.5-10 mg once a day

A distinction is made between non-selective beta-blockers (blocking both beta1- and beta2-adrenoreceptors) and cardioselective ones, blocking mainly beta1-adrenoreceptors. Some of the beta-blockers (oxprenolol, pindolol, acebutolol, talinolol) have sympathomimetic activity, which makes it possible to use them in heart failure, bradycardia, and in patients with bronchial asthma.

According to the duration of action, beta-blockers are classified as short-acting (propranolol, oxprenolol, metoprolol, acebutolol), medium-acting (pindolol), and long-acting (atenolol, betaxolol, bisoprolol).

Significant advantages of this group of drugs are their antianginal activity, the ability to prevent the development of myocardial infarction, and the reduction or slowing of the development of myocardial hypertrophy.

The drugs of this group do not inhibit renal blood supply and do not cause a decrease in renal function. With long-term treatment with SCF, diuresis and sodium excretion remain within the initial values. With treatment with high doses of drugs, RAAS is blocked and hyperkalemia may develop.

Side effects of beta-blocker treatment:

• sinus bradycardia (heart rate less than 50 beats per minute);
• arterial hypotension;
• worsening left ventricular failure;
• atrioventricular block of varying degrees;
• exacerbation of bronchial asthma or other chronic obstructive pulmonary diseases;
• development of hypoglycemia, especially in patients with labile diabetes mellitus;
• exacerbation of intermittent claudication and Raynaud's syndrome;
• development of hyperlipidemia;
• In rare cases, sexual dysfunction is observed.

Beta-blockers are contraindicated in:

• acute heart failure;
• pronounced sinus bradycardia;
• sick sinus syndrome;
• atrioventricular block II and III degree;
• bronchial asthma and severe broncho-obstructive diseases.

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

Diuretics

The drugs in this group are designed to remove sodium and water from the body. The essence of the action of all diuretics is to block the reabsorption of sodium and consistently reduce the reabsorption of water when 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 a portion of exchangeable sodium and a decrease in the OPS due to a change in the electrolyte composition of the arteriole walls (sodium output) and a decrease in their sensitivity to pressor vasoactive hormones. In addition, when conducting combined therapy with antihypertensive drugs, diuretics can block the sodium-retaining effect of the main antihypertensive drug, potentiate the antihypertensive effect and simultaneously allow a somewhat expanded salt regime, making the diet more acceptable for patients.

For the treatment of renal arterial hypertension in patients with intact renal function, the most widely used diuretics are those acting in the distal tubules: a group of thiazide diuretics - hydrochlorothiazide (hypothiazide, adelfan-ezidrex) and thiazide-like diuretics - indapamide (arifon).

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

Due to its lipophilic properties, indapamide selectively accumulates in the vessel wall and has a long half-life (18 hours). 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 vasodilatory effect, as well as with the ability to reduce the content of free intracellular calcium, which ensures lower sensitivity of the vascular wall to the action of pressor amines. The diuretic effect of the drug develops when taking large therapeutic doses (up to 40 mg of indapamide per day).

For the treatment of renal arterial hypertension in patients with impaired renal function and diabetes mellitus, diuretics acting in the area of the loop of Henle, or loop diuretics, are used. Of the loop diuretics, furosemide (lasix), ethacrynic acid (uregit), and bumetanide (burinex) are the most common in clinical practice.

Furosemide has a strong natriuretic effect. In parallel with the loss of sodium, when using 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 SCF, so it is indicated for the treatment of patients with renal failure. Furosemide is prescribed at 40-120 mg / day orally, intramuscularly or intravenously up to 250 mg / day.

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

[ 34 ], [ 35 ], [ 36 ], [ 37 ], [ 38 ], [ 39 ], [ 40 ], [ 41 ]

Alpha blockers

Of this group of antihypertensive drugs, the most widely used are prazosin and, most recently, a new drug, doxazosin (for example, cardura).

Prazosin is a selective antagonist of postsynaptic alpha1-adrenoreceptors. The antihypertensive effect of the drug is associated with a direct decrease in OPS. Prazosin expands the venous bed, reduces preload, which justifies its use in combination therapy in patients with heart failure.

The antihypertensive effect of prazosin when taken orally occurs after 0.5-3 hours and lasts for 6-8 hours. The half-life of the drug is 3 hours, it is excreted through the gastrointestinal tract, so no dose adjustment is required in case of renal failure. The initial therapeutic dose of prazosin is 0.5-1 mg per day, within 1-2 weeks the dose is increased to 3-20 mg per day (in 2-3 doses). The maintenance dose of the drug is 5-7.5 mg / day. Prazosin has a beneficial effect on kidney function: it 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 appointment of the drug in chronic renal failure. Side effects include postural hypotension, dizziness, drowsiness, dry mouth, impotence.

Doxazosin (for example, cardura) is structurally close to prazosin, but has a long-term effect. The drug significantly reduces TPS, has pronounced antiatherogenic properties (reduces the level of total cholesterol, LDL and VLDL cholesterol, increases the level of HDL cholesterol). The drug has no negative effect on carbohydrate metabolism. These properties make doxazosin the drug of choice for the treatment of arterial 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, the peak concentration in the blood occurs after 2-4 hours; the half-life is within 16-22 hours. Therapeutic doses of the drug are 1-16 mg 1 time per day. Side effects include dizziness, nausea, headache.

The above modern antihypertensive drugs are the most effective in treating renal arterial hypertension. However, each of the presented drugs in monotherapy provides normalization of arterial pressure only in half of nephrological patients. This situation is explained primarily by 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 using a combination of antihypertensive drugs with different mechanisms of action. It is possible to use several combinations of drugs: for example, an ACE inhibitor, or an AT1 receptor antagonist, or a beta-blocker with a diuretic; a dihydropyridine calcium channel blocker in combination with a beta-blocker, etc.

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 enhanced by introducing a third drug. With a decrease in renal function, real success is achieved by using a combination of three, sometimes four antihypertensive drugs. These combinations must necessarily include a diuretic in order to create a low-salt regimen for optimal "work" of antihypertensive drugs.

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

[ 42 ], [ 43 ]