Direct renin inhibitors mechanism of action. Why are renin inhibitors prescribed? Where to buy cheap medicine for hypertension
LECTURE 2 CLINICAL PHARMACOLOGY OF ARTERIAL HYPERTENSION TREATMENTSLECTURE 2 CLINICAL PHARMACOLOGY OF ARTERIAL HYPERTENSION TREATMENTS
Arterial hypertension is a pathological condition characterized by a long-term steady increase in blood pressure. The cause of a persistent increase in blood pressure in about 90% of patients remains unclear. In this case, we speak of essential hypertension or hypertension. In 2003, the experts of the European Society for Arterial Hypertension (EOAH) and the European Society of Cardiology (ESC) proposed a classification of blood pressure levels in adults (over 18 years of age), which has not undergone fundamental changes to date (Table 2.1).
Table 2.1.Definition and classification of blood pressure levels (EOAS-ESC Guidelines 2003 and 2007, National guidelines for the prevention, diagnosis and treatment of arterial hypertension, second revision, 2004)
It follows from the classification of blood pressure that there is no discrete “threshold” blood pressure that separates hypertension from normotension, and the indications for treatment and the degree of planned blood pressure reduction are determined by the total risk of cardiovascular diseases and complications in a particular patient. Thus, the decision on pharmacotherapy in patients with hypertension should be made not only on the basis of the level of blood pressure, but also taking into account the identified risk factors, pathological conditions or concomitant diseases (Table 2.2).
2.1. MAIN FACTORS INFLUENCING THE PROGNOSIS OF A PATIENT WITH ARTERIAL HYPERTENSION (RECOMMENDATIONS OF THE EOAS-ESC, 2007)
I.Risk factors
Levels of systolic blood pressure (BPs) and diastolic blood pressure (ADd) I-III degree.
The level of pulse blood pressure (in the elderly).
Age: men >55 years; women >65 years old.
Smoking.
Dyslipidemia:
Total cholesterol >5.0 mmol/l, or
LDL cholesterol >3.0 mmol/l, or
HDL cholesterol: in men<1,0 ммоль/л; у женщин <1,2 ммоль/л, или
Triglycerides >1.7 mmol/L.
Plasma glucose on an empty stomach - 5.6-6.9 mmol / l.
Abdominal obesity: waist circumference in men > 102 cm; in women > 88 cm.
Cases of early manifestations of cardiovascular pathology in a family history (stroke or heart attack in men - under the age of 55 years, in women - up to 65 years).
II.Subclinical organ damage
Signs of LV hypertrophy.
ECG (Sokolov-Lyon criterion > 38 mm; Cornell criterion > 2440 mm-ms) or EchoCG (LVMI in men > 125 g / m 2; in women > 110 g / m 2). *
Thickening of the media-intimal layer > 0.9 mm or atherosclerotic plaque in the carotid artery.
The speed of propagation of the pulse wave (carotid arteries - femoral arteries)> 12 m/s.
Ankle-brachial BP index<0,9.
Mild increase in plasma creatinine:
Men - 115-133 µmol/l;
* - the greatest risk in concentric hypertrophy of the left ventricle (if the ratio of the thickness of the LV wall to its radius in diastole> 0.42);
Women - 107-124 µmol / l.
Decreased glomerular filtration rate (<60 мл/мин на 1,73 м 2)** или клиренса креатинина (<60 мл/мин).***
Microalbuminuria (30–300 mg in 24 hours) or albumin/creatinine ratio: men >22 mg/g; in women >31 mg/g creatinine.
III.Diabetes
Fasting plasma glucose ≥7.0 mmol/l on repeated measurements.
Plasma glucose after exercise> 11 mmol / l.
IV.Diseases of the cardiovascular system or kidneys
Cerebrovascular diseases: ischemic stroke, hemorrhagic stroke, transient ischemic attack.
Heart disease: myocardial infarction, angina pectoris, coronary revascularization, heart failure.
Kidney disease: diabetic nephropathy, renal failure (plasma creatinine in men> 133 µmol/l; in women> 124 µmol/l).
Diseases of the peripheral arteries.
Severe retinopathy: hemorrhages or exudates, swelling of the optic nerve papilla.
The combined effect of multiple risk factors and conditions on prognosis can be assessed semi-quantitatively by risk stratification into four categories (low additional risk, moderate additional risk, high and very high additional risk), with the term "additional" meaning risk above average ( see table 2.2).
The degree of risk of cardiovascular diseases and complications determines the nature and urgency of therapeutic measures, among which pharmacotherapy occupies a central place (Table 2.3). Thus, the definition of hypertension may vary depending on the severity of the overall cardiovascular risk.
An important postulate of the treatment of hypertension: not limited to drug therapy. For many patients, the most important conditions for effective treatment are: diet (limiting the intake of salt, alcohol, saturated fat and cholesterol, increasing the intake of fruits and vegetables), avoiding
** - according to the Cockroft-Gault formula; *** - according to the MDRD formula.
Table 2.2.Stratification of the risk of cardiovascular diseases and complications (Recommendations of the EOAS-EOC, 2007)
Note:FR - risk factors; SPO - subclinical lesions of organs; MS - metabolic syndrome (the presence of at least 3 out of 5 possible risk factors: abdominal obesity, increased fasting glucose, blood pressure ≥ 130/85 mm Hg; low HDL cholesterol, increased triglycerides); DM - diabetes mellitus; CCC - cardiovascular system; BPs - systolic blood pressure; ADd - diastolic blood pressure.
Table 2.3.Initiation and nature of antihypertensive treatment depending on risk stratification (Recommendations of the EOAS-ESC, 2007)
Note:FR - risk factors; SPO - subclinical lesions of organs; MS - metabolic syndrome (the presence of at least 3 out of 5 possible risk factors: abdominal obesity, increased fasting glucose, blood pressure ≥130/85 mm Hg; low HDL cholesterol, increased triglycerides); DM - diabetes mellitus; CCC - cardiovascular system; BPs - systolic blood pressure; ADd - diastolic blood pressure; MOJ - modification of a way of life.
smoking, weight loss, regular exercise. Non-pharmacological intervention should be available to the patient with hypertension and be carried out constantly, subject to regular monitoring and every kind of encouragement from the doctor.
2.2. GENERAL PRINCIPLES OF TREATMENT OF ARTERIAL HYPERTENSION
The goal of treatment is to reduce the risk of cardiovascular diseases and complications, therefore, the aggressiveness of hypertension treatment and target blood pressure levels are determined by the severity of concomitant risk factors, the severity of subclinical organ damage and overt diseases of the cardiovascular system.
The object for pharmacotherapy in patients with hypertension is not only BP, but also other reversible risk factors, as well as conditions that determine the patient's prognosis within the cardiovascular continuum.
Along with antihypertensive pharmacotherapy, the most important place in the treatment of hypertensive patients is occupied by lifestyle interventions, which begin treatment in patients belonging to the low-risk group.
The task of antihypertensive therapy is to achieve a stable decrease in blood pressure to a level<140/90 мм рт. ст. и максимально близкого к оптимальному АД (см. классификацию АД) в зависимости от переноси- мости лечения.
The decrease in blood pressure should be gradual; in order to avoid unwanted side effects associated with hypotension and deterioration of regional blood circulation, one should strive to achieve and maintain the target level of blood pressure with the minimum necessary means, which implies: a) a rational choice of the drug (drugs); b) adequate combination of antihypertensive agents; c) rational dosing of drugs.
It is recommended to use long-acting or prolonged-acting antihypertensive drugs that provide a 24-hour effect in a single dose. This allows to achieve a stable hypotensive effect, round-the-clock protection of target organs and increase the patient's adherence to the prescribed treatment.
The best way to treat hypertension in acute situations (cerebrovascular accident, acute left ventricular failure, arterial embolism, acute pain, hypercatecholaminemia of various
origin) - the impact on the cause underlying the pathological condition.
Pharmacological drugs that are used to treat hypertension should affect one or more links in the pathogenesis of hypertension:
1) reduce the total peripheral vascular resistance (OPVR);
2) lower the minute volume of blood flow (MOV);
3) reduce the volume of circulating blood (BCC);
4) to prevent remodeling of the vascular wall and the development of left ventricular myocardial hypertrophy.
In addition, they must have the following properties for an "ideal" antihypertensive drug (Muston A. L., 2006, as amended):
Possess high efficiency when used as monotherapy;
It is good to combine with other drugs;
Quickly achieve target BP values;
To be prescribed once (per day) to maintain high adherence of the patient to treatment;
Have an effective duration of action over 24 hours;
Give a direct dose-dependent effect;
Have an optimal tolerability profile.
Although none of the currently used drugs fully possess all these properties, the rapid progress of pharmacological science allows us to hope that such a remedy will be found in the foreseeable future.
For a comparative assessment of the effectiveness of antihypertensive drugs, it is recommended to use the so-called T/P ratio (tough/peak ratio or dip/peak ratio), which is the ratio of the magnitude of the reduction in blood pressure at the end of the interdose interval (before the next dose of the drug) to the magnitude of the reduction in blood pressure during the period of maximum activity. The use of the T / P ratio allows you to get an idea of the duration and uniformity of the action of the antihypertensive drug. Antihypertensive drugs prescribed once a day should have a T / P of at least 50% with a pronounced hypotensive effect and at least 67% with a slight peak effect. The value of T/P, close to 100%, indicates a uniform decrease in blood pressure during the day and the absence of a negative effect of the drug on vari-
blood pressure stability, confirming the validity of the dose and single dose of the drug. Drugs with a large T/P also have a maximum aftereffect, so they can control blood pressure when a dose is missed. The value of T/P less than 50% indicates an insufficient hypotensive effect at the end of the interdose interval or excessive hypotension at the peak of the drug, which requires correction of the frequency of administration and/or dose of the drug. In addition, low T/P may indicate high BP variability.
2.3. ANTIHYPERTENSIVE DRUGS
Means that reduce the tone of sympathetic innervation in various links
1. Adrenoblockers.
1.1. β-blockers.
1.2. α-blockers.
1.3. Mixed blockers.
2. Means affecting the vasomotor center.
2.1. Agonists of α 2 -adrenergic receptors.
2.2. Imidazoline receptor agonists.
Ca 2+ channel blockers.
Drugs affecting the renin-angiotensin and endothelin systems.
1. Angiotensin-converting enzyme inhibitors.
2. Angiotensin II receptor blockers.
3. Renin synthesis inhibitors.
4. Blockers of endothelin receptors.
Diuretics.
1. Thiazide and thiazide-like diuretics.
2. Loop diuretics.
3. Potassium-sparing diuretics.
Currently, there are five main groups of antihypertensive drugs - the so-called drugs of the first line. These include:
1) thiazide diuretics (TD);
2) calcium channel blockers (CCBs);
3) angiotensin-converting enzyme inhibitors (ACE inhibitors);
4) angiotensin II receptor blockers (ARs);
5) β-blockers.
Based on the severity of the antihypertensive effect, monotherapy with first-line drugs gives approximately the same effect. They are effective in 55-45% of cases of mild to moderate hypertension.
Angiotensin-converting enzyme inhibitors
ACE inhibitors are divided into three classes (Table 2.4). Class I includes lipophilic ACE inhibitors such as captopril; class II ACE inhibitors are prodrugs that become active after biotransformation in the liver; The prototype of these drugs is enalapril. Class II drugs are divided into three subclasses. Subclass IIa includes drugs whose active metabolites are excreted primarily (more than 60%) through the kidneys. Active metabolites of subclass IIb drugs have two main elimination routes (liver and kidneys), while subclass IIc metabolites are characterized by predominantly hepatic (more than 60%) elimination. Class III ACE inhibitors are hydrophilic drugs such as lisinopril that are not metabolized in the body, do not bind to proteins, and are excreted by the kidneys.
Table 2.4.Classification of angiotensin-converting enzyme inhibitors
Angiotensin-converting enzyme is involved in the conversion of angiotensin I to angiotensin II (AT-II) and, due to additional kininase activity, inactivates bradykinin. The physiological effects of AT-II are realized mainly through two types of angiotensin receptors - AT 1 and AT 2. As a result of activation of AT 1 receptors, vasoconstriction occurs, which leads to an increase in peripheral vascular resistance and blood pressure, stimulates the synthesis and secretion of aldosterone, respectively, increases the reabsorption of Na + and water, increases BCC and blood pressure, increases hypertrophy and proliferation of cardiomyocytes and smooth muscle cells of the vascular wall. Via activation of AT 2 receptors, vasodilation is mediated, release of nitric oxide (endothelial relaxing factor) and vasodilating prostaglandins (PG), in particular PGI 2 .
ACE inhibitors, while suppressing ACE activity, simultaneously affect the renin-angiotensin-aldosterone (RAAS) and kallikrein-kinin systems (Scheme 2.1). At the same time, due to a decrease in the formation of AT-II, the cardiovascular and renal effects of RAAS activation are weakened, and due to the accumulation of bradykinin, the vasodilating effect of ACE inhibitors is potentiated. In addition, quinapril is characterized by the restoration of the function of extrasynaptic M 1 -cholinergic receptors located in the vascular endothelium and involved in vasodilation.
Thus, ACE inhibitors give the following hemodynamic effects:
Expansion of arteries, decrease in OPSS, decrease in blood pressure, decrease in afterload;
Expansion of veins, reduction of preload;
Secondary decrease in cardiac output by reducing pre- and afterload;
Increased natriuresis, diuresis, decreased BCC;
Reverse development of left ventricular hypertrophy;
Suppression of the development of smooth muscle hypertrophy and fibrous changes in the arterial wall, which contributes to vascular dilatation.
ACE inhibitors are characterized by non-linear pharmacokinetics, in which the effectiveness of the drug and the duration of its action can increase abruptly with increasing dose. Doses of ACE inhibitors are selected empirically, starting with the lowest recommended, under the control of blood pressure. BP needed
Scheme 2.1.The mechanism of action of ACE inhibitors at the cellular and systemic level
measured at the maximum effect of the drug and at the end of the interdose interval (usually 24 hours after taking a long-acting ACE inhibitor). The degree of blood pressure reduction at the peak of ACE inhibitor action should not exceed the degree of blood pressure reduction at the end of the interdose interval by more than 1.5-2 times.
The main indications for the use of ACE inhibitors in hypertension
Heart failure.
Left ventricular dysfunction.
Transferred MI.
diabetic nephropathy.
Nephropathy.
LV hypertrophy.
Atrial fibrillation.
metabolic syndrome.
Absolute contraindications to the use of ACE inhibitors in hypertension
Pregnancy.
Angioedema.
Hyperkalemia.
Tolerability of ACE inhibitors can be assessed on the 3-5th day, and clinical efficacy - not earlier than after 10-14 days. The recommended doses of drugs are presented in table. 2.5.
Side effects of ACE inhibitors
1. Arterial hypotension, which most often develops after taking the first dose in patients with severe left ventricular dysfunction or renal artery stenosis. In addition, a decrease in blood pressure is possible in elderly patients, as well as in patients receiving nitrates, diuretics, or other drugs that reduce blood pressure. To reduce the risk of developing hypotension in these categories of patients, it is recommended:
Start treatment with small doses of drugs;
24-48 hours before the appointment of an ACE inhibitor, stop diuretic drugs;
After taking the first dose, the patient should be in bed for several hours.
The end of the table. 2.5
Note:* - in elderly patients, the dose is reduced by 2 times.
2. Proteinuria and increased serum creatinine. Impaired renal function usually occurs in patients with a history of kidney disease, as well as in unilateral or bilateral stenosis of the renal arteries. To prevent this side effect, you must:
Start ACE inhibitor therapy at low doses;
Adjust the dose of the drug depending on glomerular filtration;
Give preference to drugs with a dual route of elimination (groups IIb and IIc);
Control the level of creatinine in the first 3-5 days of treatment, and then once every 3-6 months.
3. Hyperkalemia (>5.5 mmol/l). The likelihood of development increases with the simultaneous appointment of potassium-sparing diuretics, potassium preparations, NSAIDs, in patients with diabetes mellitus, urinary tract obstruction, interstitial nephritis.
4. Neutropenia. This complication often occurs in patients with renal insufficiency, while the appointment of immunosuppressants, procainamide (novocainamide), pyrazolones.
5. Dry painful cough - a consequence of interstitial edema of the tissues of the upper respiratory tract (due to an increase in the content of bradykinin), often limits the use of ACE inhibitors in patients with bronchopulmonary pathology. It is more common in women, people of the Negroid and Mongoloid race and in smokers. Cough usually occurs during the first days of ACE inhibitor treatment, but sometimes - several months or even years after the start of the drug. Disappears 1-2 weeks after the abolition of ACE inhibitors.
6. Quincke's edema. Occurs mainly in women in the first week of treatment and disappears within a few hours after discontinuation of the drug. The probability of occurrence does not depend on the chemical structure
ACE inhibitors.
Simultaneous administration of non-steroidal anti-inflammatory drugs (NSAIDs) to patients receiving ACE inhibitors, β-blockers and diuretics should be avoided, since the latter block the synthesis of prostaglandins and can cause fluid retention in the body with an exacerbation of the disease (Scheme 2.2). The most dangerous are indomethacin and rofecoxib, the safest is acetylsalicylic acid.
Angiotensin II receptor blockers
Losartan (Cozaar).
Valsartan (Diovan).
Olmesartan (Olmetek).
Irbesartan (Aprovel).
Kandesartan (Atakand).
Telmisartan (Pritor).
Eprosartan (Teveten).
Tasosartan.
Angiotensin-converting enzyme is far from the only enzyme that provides the formation of AT-II in the body (it accounts for no more than 20% of AT-II), while the remaining 80% is synthesized under the action of other enzymes (chymases, etc.). Therefore, one of the effective approaches to inhibition of excessive activity of the RAAS is the blockade of angiotensin receptors. Currently, there is a fairly large group of drugs that block type 1 receptors for angiotensin II. Their mechanism of hypotensive action is associated with a weakening of the effects of angiotensin II, which are realized through AT 1 receptors (see Scheme 2.1). Blockade of AT 1 receptors leads to the expansion of peripheral vessels, a decrease in peripheral vascular resistance and blood pressure; in addition, the secretion of aldosterone decreases, resulting in a decrease in the reabsorption of Na + and water, bcc and blood pressure. The proliferative effects of angiotensin II in relation to cardiomyocytes and smooth muscle cells of the vascular wall are weakened.
Blockers of AT 1 receptors (BARs) disrupt the negative feedback mechanism that regulates the synthesis and release of angiotensinogen and renin into the blood. Therefore, with long-term administration of drugs of this group, the content of angiotensinogen, renin, angiotensin I and II increases in the blood. Under conditions of blockade of AT 1 receptors by drugs, the resulting angiotensin II cannot interact with them, which causes additional stimulation of AT 2 receptors, leading to an increase in the synthesis and release of endothelial relaxing factor (ERF), PGI 2, and increased arterial vasodilation (see Scheme 2.1).
Scheme 2.2.Proposed mechanisms for weakening the effects of antihypertensive drugs under the influence of NSAIDs (Preobrazhensky D.V. et al., 2002)
End of table
In terms of their antihypertensive activity, BARs are comparable to other first-line antihypertensive drugs and are better tolerated. In addition, in patients with hypertension treated with biologics (particularly valsartan), the likelihood of developing new cases of atrial fibrillation is 17% lower, and the risk of persistent atrial fibrillation is 32% lower than in patients receiving calcium channel blockers (particularly amlodipine). ).
The maximum antihypertensive effect of BAP develops by the 3rd-4th week of treatment, and according to some reports even later. It is important to note that BARs do not disturb the physiological course of the diurnal (day-night) pressure curve; they are not characterized by either hypotension of the first dose or a sharp increase in blood pressure after a sudden withdrawal of the drug. Established the same antihypertensive efficacy and tolerability of BAD in patients of different ages (including those over 65), gender and race.
Indications for the use of BAR in hypertension
Heart failure.
diabetic nephropathy.
Proteinuria/microalbuminuria.
Atrial fibrillation.
metabolic syndrome.
ACE intolerance.
Absolute contraindications to the use of BAR in hypertension
Pregnancy.
Bilateral stenosis of the renal arteries.
Hyperkalemia.
The number of side effects that can develop with the use of BAR is small - occasionally there may be headache, dizziness, general weakness, nausea. By their organoprotective properties, BARs are probably not inferior to ACE inhibitors, and today they are the first-line drugs in the treatment of arterial hypertension, although the final place of these drugs in the treatment of hypertension may still be clarified.
Endothelin receptor blockers
Darusentan.
One of the most powerful vasoactive substances are the endothelial peptides endothelin (ET). Three representatives of this se-
Meistva - ET-1, ET-2, ET-3 - are produced by various tissues in which they are present as modulators of vascular tone, cell proliferation and hormone synthesis. The cardiovascular effects of endothelin are mediated through specific type A (vasoconstriction) and type B (vasodilation) receptors, with the former predominating. The strength of the vasoconstrictor effect of ET is 30 times greater than that of AT-II.
Among the blockers of endothelin receptors (bosentan, sitaxentan, tezosentan, ambrisentan, darusentan) for the treatment of arterial hypertension (primarily resistant), only darusentan has been proposed so far, however, a final judgment on its efficacy and safety can only be made after extensive clinical trials. Other drugs in this group have found use in the treatment of heart failure and pulmonary hypertension.
renin synthesis blockers
Aliskiren (Rasilez).
One of the approaches to the blockade of the RAAS is its inhibition at the earliest stage of activation (renin formation) with the help of specific inhibitors of renin synthesis. The drugs of this group have the ability to selectively block the conversion of angiotensinogen to AG-I, which determines their specificity. Due to this, there is a decrease in the levels of angiotensin I and angiotensin II in the blood and a concomitant decrease in blood pressure. The maximum decrease in plasma renin activity is observed already 1 hour after taking the drug (300 mg) and lasts 24 hours. With a course administration, the severity of this effect does not decrease.
The effectiveness of aliskiren in monotherapy (according to preliminary data) is comparable to the effectiveness of a combination of two traditionally prescribed antihypertensive drugs. In addition, it can be combined with diuretics, calcium channel blockers and ACE inhibitors.
In terms of the incidence of adverse events (diarrhea, headache, rhinitis), aliskiren is comparable to losartan. The final judgment on the efficacy and safety of the drug can be made at the end of large clinical trials.
β - adrenoblockers and mixed adrenoblockers
Another group of drugs with a pronounced hypotensive effect is β-blockers. The classification of β-blockers is presented in the lecture "Clinical pharmacology of agents for the treatment of coronary heart disease".
The mechanism of the hypotensive action of β-blockers is primarily associated with the blockade of β 1 -adrenergic receptors of the heart, which leads to a decrease in the strength and frequency of heart contractions and, accordingly, cardiac output. By blocking β 1 -adrenergic receptors of the juxtaglomerular apparatus of the kidneys, the drugs reduce the release of renin, and consequently, the formation of angiotensin II and aldosterone. In addition, non-selective BBs, blocking presynaptic β 2 -adrenergic receptors, reduce the release of catecholamines into the synaptic cleft. By reducing the activity of the SAS, β-blockers lead to regression of myocardial hypertrophy. β 1 -adrenergic blockers with additional vasodilating properties are able to reduce peripheral vascular resistance by dilating peripheral vessels (see the lecture "Clinical pharmacology of coronary heart disease treatments"). Basic information on the use of β-blockers in hypertension is presented in Table. 2.7.
More side effects of β-blockers are presented in the lecture "Clinical pharmacology of agents for the treatment of coronary heart disease".
The drugs of this group are the means of choice:
For the treatment of hypertension with severe activation of the SAS and RAAS;
With a combination of hypertension with coronary artery disease, tachyarrhythmias, heart failure;
In pregnant women (selective BAB);
In case of intolerance or in the presence of contraindications to the appointment of ACE inhibitors and BARs.
Indications for use β -adrenergic blockers in hypertension
Angina.
Postponed myocardial infarction.
Heart failure (bisoprolol, metoprolol succinate, carvedilol, nebivolol - for patients over 70 years of age).
Tachyarrhythmias.
Pregnancy (in trimesters, the use of atenolol, propranolol, metoprolol tartrate, labetalol is acceptable).
Glaucoma.
End of table 2.7
Absolute contraindications for use β -adrenergic blockers in hypertension
Bronchial asthma.
AV block II-III degrees (in the absence of a permanent pacemaker).
β -adrenergic blockers in hypertension
Peripheral vascular disease, Raynaud's syndrome.
metabolic syndrome.
Impaired glucose tolerance.
Athletes and physically active patients.
Chronic obstructive pulmonary disease.
It should be noted that β-blockers (primarily atenolol) have the lowest efficacy in relation to the prevention of strokes compared to other classes of antihypertensive drugs (ACE inhibitors, BARs, diuretics, calcium channel blockers). In addition, there is evidence that β-blockers, especially in combination with thiazide diuretics, should not be used in patients with metabolic syndrome or at a high risk of developing diabetes mellitus. Meanwhile, in patients with diabetes mellitus, β-blockers are as effective in reducing the risk of cardiovascular complications as in patients without diabetes mellitus.
Of the group of mixed blockers for the treatment of hypertension, carvedilol is most commonly used. The drug blocks β 1 - and α 1 -adrenergic receptors, additionally has antioxidant and antiproliferative activity (in relation to smooth muscle cells). Begin treatment with a dose of 12.5 mg, the average therapeutic dose is 25-50 mg / day once. Another mixed blocker - labetalol - can be used for arterial hypertension in pregnant women.
Calcium channel blockers
The classification of calcium channel blockers is presented in the lecture “Clinical pharmacology of drugs for the treatment of coronary heart disease”.
Depending on the belonging to the chemical class, calcium channel blockers can affect the leading pathophysio-
the logical mechanisms of hypertension are an increase in TPVR (for example, dihydropyridines) or an increase in the IOC (mainly phenylalkylamines). In addition, these drugs dilate the renal vessels, improve renal blood flow, and have an antiplatelet effect. CCBs do not adversely affect the metabolism of carbohydrates and lipids, do not cause bronchospasm and orthostatic hypotension.
CCBs are one of the drugs of choice for the treatment of hypertension in combination with paroxysmal tachycardia (phenylalkylamine derivatives), bronchial asthma.
Mechanisms of hypotensive action of calcium channel blockers
Blockade of slow calcium channels of the myocardium and the conduction system leads to a decrease in the strength and frequency of heart contractions, which is accompanied by a decrease in cardiac output (decrease in stroke volume and IOC). This mechanism of action is more characteristic of phenylalkylamine derivatives.
Blockade of calcium channels in vascular smooth muscle cells causes dilation of arterioles, a decrease in peripheral vascular resistance and blood pressure. This mechanism of action underlies the hypotensive effect of dihydropyridine derivatives.
Along with the actual antihypertensive effect, CCB slow down the development of left ventricular hypertrophy, and, very importantly, the progression of atherosclerosis of the carotid and coronary arteries.
Indications for the use of CCB in hypertension
Dihydropyridine CCBs (long-acting and long-acting dihydropyridines: nifedipine, amlodipine, lacidipine, etc.)
Angina.
Left ventricular hypertrophy.
Atherosclerosis of the carotid, coronary arteries.
Pregnancy.
AH in blacks.
Non-dihydropyridine CCBs (verapamil, diltiazem)
Angina.
Atherosclerosis of the carotid arteries.
Supraventricular tachyarrhythmias.
Absolute contraindications to the use of CCB in hypertension
AV block II-III degrees (non-dihydropyridine calcium channel blockers).
Heart failure (non-dihydropyridine calcium channel blockers).
Relative contraindications to the use of CCB in hypertension
Tachyarrhythmias (long-acting and long-acting dihydropyridines).
Heart failure (long-acting and long-acting dihydropyridines).
CCBs have some peculiarities of influencing various “endpoints”. So, against the background of therapy with drugs of this group, the risk of developing heart failure and myocardial infarction is slightly higher than against the background of therapy with other antihypertensive drugs. At the same time, CCBs, to a somewhat greater extent than other antihypertensive drugs, reduce the risk of cerebral stroke.
Additional indications for the appointment of dihydropyridine CCBs are: the elderly age of the patient, isolated systolic arterial hypertension, the presence of concomitant exertional angina, peripheral arterial disease, signs of atherosclerotic changes in the carotid arteries, pregnancy. For non-dihydropyridine calcium channel blockers, additional indications for prescribing are concomitant exertional angina, signs of atherosclerotic changes in the carotid arteries, and supraventricular arrhythmias.
Some information on the use of calcium channel blockers in hypertension is given in Table. 2.8.
Short-acting nifedipine (unlike its long-acting forms) with long-term use worsens the prognosis of patients with hypertension, coronary heart disease, therefore, it is not used for the systematic treatment of hypertension.
Side effects of CCB
Blockade of calcium channels in the heart can lead to bradycardia, atrioventricular blockade, cardiodepression. These side effects are typical for phenylalkylamines.
The result of the blockade of calcium channels of peripheral vessels are orthostatic hypotension, reflex tachycardia. In addition, patients may experience: reddening of the face, swelling of the ankles of non-cardiac origin due to vasodilation, gingivitis, constipation.
Diuretics
The widespread use of diuretic drugs for antihypertensive therapy is due to the fact that their treatment is cost-effective and does not cause an excessive decrease in blood pressure, and therefore there is no need for frequent medical supervision; in addition, the drugs do not cause the phenomenon of kickback. Diuretics are the drugs of choice in the treatment of hypertension in the elderly, including those with heart failure.
Classification of diuretics
1. Acting on the thick ascending part of the loop of Henle (loop diuretics):
Furosemide (Lasix).
Bumetanide (Bufenox).
Piretanide (Arelix).
Ethacrynic acid (Uregit).
Torasemide (Diuver).
2. Acting on the initial part of the distal tubule:
2.1. Thiazide diuretics (benzothiadiazine derivatives):
Dichlothiazide (Hypothiazide).
Metolazone (Zaroxolin).
Cyclomethiazide (Cyclopenthiazide).
Polithiazide (Renese).
2.2. Non-thiazide (thiazide-like) diuretics:
Clopamid (Brinaldix).
Chlorthalidone (Oxodoline).
Indapamide (Arifon).
Xipamide (Aquaphor).
3. Acting on the final part of the distal tubule and collecting ducts (potassium-sparing diuretics):
3.1. Competitive aldosterone antagonists:
Spironolactone (Veroshpiron).
Eplerenone (Inspra).
End of table 2.8
Note:* - for forms of prolonged action.
3.2. Sodium channel blockers:
Triamterene (Dyteq).
Amiloride (Modamid).
4. Acting on the proximal tubule (carbonic anhydrase inhibitors):
Acetazolamide (Diacarb).
5. Combined drugs:
Triampur (triamterene + dichlothiazide).
Moduretic (amiloride + dichlothiazide).
Furesis (furosemide + triamterene).
Spiro-D (furosemide + spironolactone).
Most often, thiazide and thiazide-like diuretics are used to treat hypertension. In the mechanism of their hypotensive action, two components can be conditionally distinguished. The first is associated with the actual diuretic effect and is realized at the cellular level by suppressing the electrically neutral transport of Na + and Cl - through the luminal membrane of the distal convoluted tubules, which leads to an increase in the excretion of sodium and, consequently, water. This is accompanied by a decrease in BCC and, accordingly, a decrease in blood return to the heart and cardiac output. This mechanism underlies the positive effect of thiazide diuretics in the first weeks of AH treatment and is dose-dependent (manifested in diuretic doses).
The second component manifests itself even when prescribed in non-diuretic doses and is due to a decrease in OPSS due to:
Strengthening the excretion of Na + and water from the vascular wall, leading to a decrease in its thickness and response to pressor effects;
Decreased sensitivity of adrenergic receptors to catecholamines;
Stimulation of the synthesis of vasodilating prostaglandins;
Disorders of Ca 2+ and Na + metabolism in vascular smooth muscle cells.
Comparative studies have shown that there is no significant difference in the antihypertensive activity of low (less than 25 mg hydrochlorothiazide per day or equivalent doses of other drugs) and high doses (more than 25 mg) thiazide diuretics. At the same time, low doses of diuretics are much better tolerated by patients and are not accompanied by significant electrolyte and metabolic disorders.
Unlike β-blockers, diuretics are equally effective in preventing cardiovascular complications in both middle-aged and elderly patients with hypertension and are able to improve the long-term prognosis in these patients with arterial hypertension. Diuretics are more effective than β-blockers in preventing the development of coronary artery disease and death, which makes them one of the first-line drugs in the initial treatment of hypertension.
Indications for the use of diuretics in hypertension
Thiazide and thiazide-like diuretics (low doses):
Isolated systolic hypertension in the elderly.
Heart failure.
AH in blacks. Aldosterone antagonists:
Heart failure.
Postponed myocardial infarction. Loop diuretics:
Heart failure.
End stages of kidney disease.
Absolute contraindications to the use of diuretics in hypertension
Gout (thiazide diuretics).
Renal failure (aldosterone antagonists).
Hyperkalemia (aldosterone antagonists).
Relative contraindications to the use of diuretics in hypertension
Pregnancy.
Metabolic syndrome (high doses and combination with β-blockers).
Side effects of thiazide diuretics
1. Renal (hypokalemia, hyponatremia, hypomagnesemia, hypercalcemia, metabolic alkalosis).
2. Extrarenal (hyperglycemia associated with inhibition of insulin secretion by β-cells of the islets of Langerhans; hyperuricemia with the onset of gouty syndrome; increased levels of cholesterol and triglycerides in the blood; secondary hyperaldosteronism with prolonged use).
Unlike thiazide diuretics, the natriuretic effect of loop diuretics is more pronounced, but the antihypertensive effect is weaker.
Note:* - possible long-term treatment with non-diuretic doses of thiazides as part of combined antihypertensive therapy.
The mechanism of action of loop diuretics is associated with blockade in the thick section of the ascending knee of the nephron loop (loop of Henle) of Na +, K + and two C1 - ions. The result is an increase in diuresis, a decrease in BCC, blood return to the heart and cardiac output. In addition, due to an increase in the synthesis of vasodilating prostaglandins in the vascular wall, arterioles and veins expand, which leads at the system level to a decrease in peripheral vascular resistance, a decrease in post- and preload, cardiac output, and in the kidneys to an increase in renal blood flow and, consequently, filtration and natriuresis.
Side effects of loop diuretics are similar to those of thiazide diuretics (with the exception of the effect on calcium levels (hypocalcemia). Additionally, gastrointestinal dysfunction may occur, manifested by nausea, loss of appetite, abdominal pain, and dyspeptic symptoms.
In addition, with long-term diuretic therapy, their diuretic effect may decrease due to the development of secondary hyperaldosteronism.
The mechanism of action of aldosterone antagonists is based on the blockade of aldosterone receptors, followed by a violation of the implementation of the main effects of mineralocorticoids. In the nuclear apparatus of renal epithelial cells, this leads to a violation of the expression of certain genes, which results in a decrease in the synthesis of permeases, and, as a result, an increase in natriuresis and diuresis, and a decrease in potassium secretion into the urine. At the systemic level, this is manifested by a decrease in RAAS activity, a slight increase in diuresis (up to 200 ml / day) and a decrease in BCC. The antihypertensive effect of spironolactone is especially pronounced in conditions of primary and secondary hyperaldosteronism.
Most often, aldosterone antagonists are used in combination with thiazide or loop diuretics (if necessary, their long-term use) to prevent secondary hyperaldosteronism and hypokalemia. The effect when using drugs develops after about 3 days, and it may take up to 3-4 weeks to achieve a detailed clinical effect. Side effects include hyperkalemia, hormonal disorders (gynecomastia, decreased libido, impotence in men, menstrual irregularities, deepening of the voice in women).
A more selective aldosterone receptor blocker than spironolactone is the new drug eplerenone (Inspra). Its high selectivity avoids most endocrine side effects. The actual diuretic effect of the drug is negligible.
The mechanism of action of another potassium-sparing diuretic, triamterene, is associated with the blockade of sodium channels in the luminal membrane of the collecting duct epithelium. As a result, the release of Na + from the lumen of the tubules into the cells decreases. This leads to a decrease in the flow of K + through the basement membrane and a decrease in its secretion into the urine. The antihypertensive effect of triamterene is associated with a decrease in circulating blood volume and cardiac output. Side effects: crystalluria, cylindouria, urolithiasis.
Agonistsα 2-adrenergic receptors
Clonidine (Clonidine).
Guanfacine (Estulik).
Methyldopa (Dopegyt).
In recent years, the frequency of use for the treatment of AH agonists α 2 -adrenergic receptors - clonidine and guanfacine, the mechanism of hypotensive action of which is associated with the activation of inhibitory α 2 -adrenergic and imidazoline I 1 receptors in the CNS, has significantly decreased. Clonidine is currently not recommended for the systematic treatment of hypertension and is used mainly for the relief of hypertensive crises. Side effects of the drug are a consequence of the activation of α 2 -adrenergic receptors and include dry mouth, lethargy, depression, bradycardia, recoil syndrome, development of tolerance.
Methyldopa (Dopegyt) in the process of metabolism turns into methylnorepinephrine, which activates inhibitory α 2 -adrenergic receptors of the vasomotor center, which leads to a decrease in sympathetic impulses and blood pressure. In addition, it is a "false" mediator that disrupts synaptic transmission due to competition with norepinephrine in the synaptic cleft. Begin treatment with 250 mg 2-3 times a day, subsequently the daily dose can be increased to 1 g in 2-3 doses. Methyldopa is a traditional drug for the treatment of arterial hypertension in pregnant women.
Side effects include lethargy, drowsiness, night terrors, depression, and parkinsonism. With prolonged use, autoimmune myocarditis, hemolytic anemia, and hepatitis may occur.
Imidazoline receptor agonists
Moxonidine (Physiotens).
Rilmenidine (Albarel).
A new class of antihypertensive drugs are imidazoline receptor agonists, whose place in the treatment of hypertension is currently being specified. The mechanism of action of drugs is associated primarily with the activation of central imidazoline I 1 receptors, which leads to suppression of the activity of the sympathetic nervous system and a decrease in blood pressure. In addition, they interact with imidazoline receptors in the epithelium of the renal tubules, increasing natriuresis. They can also activate inhibitory a 2 -adrenergic receptors, but the affinity of drugs for them is much less than for imidazoline receptors. Compared to clonidine, drugs have fewer side effects, tolerance develops somewhat less often, and they practically do not cause a recoil syndrome.
Indications for the use of imidazoline receptor agonists in hypertension
metabolic syndrome
Absolute contraindications to the use of imidazoline receptor agonists in hypertension
AV block.
Severe heart failure.
Severe depression.
Moxonidine is prescribed at 0.1 mg orally once a day. After 5-7 days, the dose can be increased to 0.2 mg / day once (under the control of blood pressure), after 2-3 weeks the dose is increased to 0.4 mg / day once (or 0.2 mg 2 times a day) . The maximum daily dose is 0.6-0.8 mg.
Rilmenidine is prescribed 1 mg 1 time per day. With insufficient effect after one month of treatment, the dose may be increased to 2 mg / day in two divided doses.
Sympatholytics
Central sympatholytics (rauwolfia alkaloids) are currently not recommended for the systematic treatment of hypertension, due to their low efficacy and a large number of side effects. Reserpine in synaptic endings selectively and persistently disrupts the active transport of catecholamines from the cytosol to the granules, as a result of which neurotransmitters are destroyed by monoamine oxidase. This leads to the depletion of catecholamine stores, disruption of synaptic transmission and a decrease in blood pressure. Reserpine is characterized by a slowly developing moderate hypotensive effect and a pronounced psychosedative effect.
Side effects: depression, increased suicidal behavior, fear, drowsiness, nightmares. In addition, due to the activation of the parasympathetic division of the autonomic nervous system, bradycardia, atrioventricular blockade, an increase in the acid-forming function of the stomach, bronchospasm, and nasal congestion are possible.
a - adrenoblockers
Prazosin (Adverzuten).
Terazosin (Haytrin).
Doxazosin (Tonocardin).
For the treatment of hypertension, α 1 -blockers are sometimes used - prazosin, doxazosin, terazosin. These drugs block α 1 -adrenergic receptors of peripheral vessels, which leads to the expansion of arterioles, a decrease in peripheral vascular resistance and blood pressure. In addition, afterload decreases and cardiac output decreases secondarily.
Indications for use a -adrenergic blockers in hypertension
Benign prostatic hyperplasia.
Impaired glucose tolerance.
Dyslipidemia.
Relative contraindications for use α -adrenergic blockers in hypertension
orthostatic hypotension.
Heart failure.
Treatment with α 1 -adrenergic blockers begins with the minimum dose that the patient must take at bedtime, preliminarily
changing diuretic drugs (to avoid the “first dose” phenomenon manifested by orthostatic hypotension). The main advantage of this group of drugs is their beneficial effect on metabolic parameters (unlike β-blockers and diuretics). However, this is offset by their side effects: orthostatic hypotension, non-cardiac edema, tachycardia, and rapidly developing tolerance. In addition, at low doses, relatively well tolerated by patients, the hypotensive effect of α 1 -blockers is usually insufficient, and at high doses the number of side effects sharply increases. The recommended doses of drugs are presented in table. 2.10.
Table 2.10.Recommended doses and individual pharmacokinetic parameters of α 1 -blockers used to treat arterial hypertension
2.4. PHARMACOTHERAPY OF ARTERIAL HYPERTENSION
Target blood pressure values
It is necessary to strive to reduce blood pressure to the level< 140/90 мм рт. ст. и ниже (при хорошей переносимости) у всех больных АГ. У больных сахарным диабетом и у пациентов с высоким и очень
high cardiovascular risk (comorbidities of the cardiovascular system and kidneys - stroke, myocardial infarction, renal dysfunction, proteinuria) the target level of blood pressure should be<130/80 мм рт. ст. К сожалению, достичь этого уровня АД непросто, даже при комбинированной антигипертензивной терапии, особенно у пожилых пациентов, у больных сахарным диабетом и в целом у пациентов с сопутствующими повреждениями сердечнососудистой системы. Таким образом, для скорейшего и простейшего достижения целевого АД следует начинать антигипертензивную терапию еще до появления значимых кардиоваскулярных повреждений.
Antihypertensive therapy
Previously, a staged scheme for the treatment of hypertension was widely used, involving the initial prescription of a single antihypertensive drug in low or medium doses, followed by dose escalation and (or) combination with other (s) drugs with insufficient effectiveness at the previous stage of treatment. Currently, the need for initial combination therapy in a significant number of patients with hypertension has been postulated.
Choice of antihypertensive drug
The main benefits of antihypertensive treatment are due to the reduction in blood pressure per se. According to the European guidelines for hypertension (2007), members of the five main classes of antihypertensive agents (thiazide diuretics, calcium channel blockers, ACE inhibitors, angiotensin receptor antagonists and β-blockers) are suitable for both initial and maintenance antihypertensive treatment in monotherapy or in combination with each other. At the same time, β-blockers, especially in combination with thiazide diuretics, should not be used in patients with metabolic syndrome or at a high risk of developing diabetes mellitus. Since many patients require a combination of antihypertensive drugs, too much attention to the choice of the first drug is often not justified. Nevertheless, there are many pathological conditions in which the priorities of some drugs over others have been proven.
Drugs of choice when prescribing antihypertensive treatment depending on concomitant diseases or conditions (Recommendations of the EOAS-ESC, 2007)
Note:ACE inhibitors - angiotensin-converting enzyme inhibitors; CCB - calcium channel blockers; BAR - angiotensin II receptor blockers; BAB - β - adrenoblockers; AA are aldosterone antagonists.
* - non-dihydropyridine CCBs.
Ultimately, the choice of a specific drug or combination of drugs depends on the following factors:
Previous experience with the drug (drug class) in the individual patient;
Predominant efficacy and safety of the drug in a given profile of cardiovascular risk;
The presence and nature of concomitant (non-cardiac) pathology, which may limit the use of certain classes of antihypertensive drugs (Table 2.11);
Possibilities of interaction with other antihypertensive drugs and with drugs prescribed for other conditions;
The age and race of the patient;
Features of hemodynamics;
Treatment costs.
Table 2.11.The main contraindications to the appointment of antihypertensive drugs, depending on concomitant diseases and conditions
Note:PEKS - implanted pacemaker; AAB -α- blockers; CCB dgp - dihydropyridine calcium channel blockers; CCB n / dgp - non-dihydropyridine calcium channel blockers; AIR are imidazoline receptor agonists.
Criteria for choosing monotherapy or a combination of antihypertensive agents
Clinical experience suggests that hypertension monotherapy achieves target BP in only a minority of patients, while the vast majority of patients require a combination of two or more antihypertensive drugs.
Treatment of hypertension can be started with monotherapy or with a combination of two antihypertensive drugs in low doses. In the future, if necessary, you can increase the dose or amount of drugs used.
With monotherapy, it is advisable to start treatment of patients with AH of the first degree with low or moderate cardiovascular risk (Scheme 2.3). Initially, one drug is prescribed at a low dose; if it is not effective enough, the dose is increased to full; if ineffective or poorly tolerated, a drug of another class is prescribed at a low, and then at a full dose. The criterion for a "positive response" to treatment: a decrease in blood pressure ≥20 mm Hg. Art. for systolic and ≥10 mmHg. Art. for diastolic blood pressure. This tactic is called sequential monotherapy. Its disadvantages are that the target values of blood pressure against the background of monotherapy can only be achieved in 20-30% of patients, and frequent changes in drugs and doses increase the complexity of treatment, reduce the degree of trust in the doctor and patient adherence to treatment, and unnecessarily delay needed to normalize blood pressure. With the ineffectiveness of monotherapy, they switch to combined treatment.
The combination of antihypertensive drugs is initially required in patients with II-III degree hypertension or with high and very high cardiovascular risk (see Figure 2.3). Treatment can be initiated with a "low dose" combination that causes fewer side effects and complications than full dose monotherapy. If the low-dose combination is partially effective, the dose of one or both components may be increased, or a third drug may be prescribed at a low dose. Some patients may require three or more full-dose drugs to achieve target BP. Most often, patients with diabetes mellitus, kidney pathology and severe concomitant diseases of the cardiovascular system require combination therapy. The disadvantages of the tactics of initial (initial) combined antihypertensive therapy should be considered: the risk of unreasonable prescribing of an “extra” drug, difficulties in determining
Scheme 2.3.Tactics for the treatment of arterial hypertension: the choice between monotherapy and combination therapy (Recommendations of the EOAS-ESC, 2007)
the division of the drug that is the culprit of the allergy or poor tolerance to treatment. Benefits of combined treatment:
Faster than with effective monotherapy, achievement of target blood pressure;
Greater efficiency in the control of hypertension in general;
Better tolerance with less pronounced side effects;
Reducing the time and number of attempts required to select effective therapy, which helps to increase the doctor's confidence and the patient's trust in him;
The possibility of prescribing fixed combinations of drugs in one tablet, which simplifies treatment and increases patient adherence to therapy.
Meanwhile, not all antihypertensive agents can be effectively and safely combined. A rational combination of drugs should have the following properties:
Summation or potentiation of the hypotensive effects of the constituting a combination of drugs;
Compensation of counter-regulatory mechanisms that are triggered by the use of each of the drugs that make up the combination;
Absence of side effects caused by the interaction of the combined drugs;
The ability to effectively prevent subclinical target organ damage and reduce the risk of cardiovascular complications according to controlled studies.
The effectiveness of various combinations from most classes of antihypertensive agents is presented in table. 2.12.
Table 2.12.Various combinations of antihypertensive drugs (Chazova I. E., Ratova L. G., 2006, with changes)
In 2007, European experts recommended only six rational combinations of five main classes of antihypertensive drugs for the treatment of hypertension:
1) thiazide diuretic + ACE inhibitor (TD + ACE inhibitor);
2) thiazide diuretic + angiotensin II receptor blocker (TD +
BAR);
3) calcium channel blocker + ACE inhibitor (CCB + ACE inhibitor);
4) calcium channel blocker + angiotensin II receptor blocker (CCB + BAR);
5) calcium channel blocker + thiazide diuretic (CCB + TD);
6) β-blocker + calcium channel blocker (dihydropi-
ridin) (BAB + BPC).
The combination of thiazide diuretics and potassium-sparing agents (triamterene, amiloride, spironolactone) is also recognized as expedient, the rationality of the combination of ACE inhibitors and BARs, renin blockers and thiazide diuretics is being studied. The undoubtedly effective combination of thiazide diuretics with β-blockers, recommended and successfully used previously, is now recognized as undesirable due to increased negative metabolic effects. It should not be used in patients at risk of diabetes mellitus and metabolic syndrome.
The most effective drug combinations
1. Currently, the combination of an ACE inhibitor and a diuretic is one of the most widely prescribed. Its use allows reaching the target level of blood pressure in more than 80% of patients. In this case:
There is a potentiation of the antihypertensive effects of drugs;
ACE inhibitors reduce the activity of the RAAS, which increases with long-term administration of diuretics;
The diuretic increases the effectiveness of ACE inhibitors in patients with normo- and hyporenin forms of hypertension;
ACE inhibitors prevent the development of hypokalemia against the background of diuretics;
ACE inhibitors do not affect lipid metabolism and reduce hyperuricemia and hyperglycemia that occurs while taking diuretics.
This combination is recommended primarily for patients with heart failure, left ventricular hypertrophy, diabetic nephropathy. It is also effective in patients with severe hypertension, in elderly patients with monotherapy failure.
ACE inhibitors.
2. According to antihypertensive effects, BARs are similar to ACE inhibitors, so their combination with diuretics has almost the same advantages as the combination of ACE inhibitors with diuretics.
The combined use of a BAR and a diuretic leads to a marked decrease in blood pressure in patients with both high and low renin activity.
3. The combination of ACE inhibitors + CCBs (as well as BAR + CCBs) is effective in both high- and low-renin forms of hypertension. The use of these drugs allows:
Potentiate the hypotensive effect;
Enhance the natriuretic effect;
To increase the effectiveness of ACE inhibitors in patients with normo- and hyporenin forms of hypertension;
Increase the effectiveness of dihydropyridine CCBs by suppressing ACE inhibitors of SAS activity;
Reduce the severity of edema of the legs while taking CCB (most typical for dihydropyridine CCB);
Reduce dry cough while taking ACE inhibitors;
Achieve organoprotective action (including nephroprotective due to the expansion of afferent arterioles in the kidneys under the influence of ACE inhibitors and afferent and efferent arterioles under the influence of non-dihydropyridine CCBs);
Eliminate the possibility of a negative impact on lipid, carbohydrate and purine metabolism.
4. The combination of β-blockers and CCBs (dihydropyridine derivatives) allows:
Achieve additivity in the hypotensive effect;
Reduce, with the help of β-blockers, the activation of the SAS, which develops at the initial stage of the use of dihydropyridine
BPC;
Reduce the severity of edema of the legs on the background of taking
BKK.
The combination is indicated for patients with hypertension with coronary artery disease, as well as patients with severe hypertension refractory to monotherapy.
5. The combination of CCBs and diuretics does not seem obvious, as it allows for an increase in adverse orthostatic reactions and a compensatory increase in the activity of the renin-angiotensin system. In the same time:
The antihypertensive effect of both drugs is markedly potentiated;
The effectiveness of treatment of isolated systolic hypertension in elderly patients increases;
The severity of organoprotective effects increases.
6. The combination of β-blockers and diuretics is still very often used. In this case:
Hypotensive effects of drugs are potentiated;
- β-blockers prevent the development of hypokalemia against the background of diuretics;
- β-blockers prevent the activation of the SAS and RAAS against the background of the appointment of diuretics.
This combination is not only highly effective, but also low cost. At the same time, with the simultaneous appointment of β-blockers and diuretics, their negative effect on carbohydrate and lipid metabolism is potentiated, potency decreases. This combination is not used in patients with metabolic syndrome and a high risk of diabetes, and to reduce the adverse effects on lipid and glucose metabolism, small doses of diuretics (equivalent to no more than 6.25-12.5 mg of hydrochlorothiazide) are used.
7. With the combined use of a β-blocker with an α 1 -blocker, the following occurs:
Potentiation of the hypotensive effect;
Reduction by β-blockers of SAS activation, which develops at the initial stage of the use of α 1 -blockers;
Decrease in a 1 -blockers of vasospasm caused by non-selective β-blockers;
Reduction of a 1 -blockers of the adverse effects of β-blockers on lipid and carbohydrate metabolism.
Meanwhile, the long-term effects of such a combination of antihypertensive agents have been little studied.
8. Modern drugs of central action (imidazoline receptor agonists) are well combined with all other classes of antihypertensive drugs. However, when combined with β-blockers, care must be taken due to the risk of developing bradycardia. The effect of this combination on long-term prognosis has not been studied.
There are both low-dose and full-dose combined drugs with a fixed composition of the main antihypertensive drugs (Table 2.13). The advantages of fixed rational combinations include:
Ease of prescribing and dose titration process, increasing patient adherence to treatment;
Mutual increase in the antihypertensive effect of drugs included in the combined dosage form;
An increase in the number of patients with a stable decrease in blood pressure due to the multidirectional antihypertensive effect of its constituent components;
Reducing the incidence of side effects, both due to lower doses of combined antihypertensive agents, and due to the mutual neutralization of these effects;
Reducing the cost of treatment;
Exclusion of the possibility of using irrational combinations;
The most effective organoprotection and reduction of the risk and number of cardiovascular complications.
Fixed combinations have two main disadvantages:
The fixedness of doses limits the ability to vary doses of drugs. However, this is overcome by issuing combinations containing different doses of the same components;
Certain difficulties in identifying and correlating adverse events with the influence of one or another component of the drug.
Less effective drug combinations
Currently, there are no convincing data in favor of the use of combinations of β-blocker + ACE inhibitor and β-blocker + BAR. It is believed that both drugs act in the same direction - they reduce the activity of the RAAS, therefore, potentiation of the antihypertensive effect does not occur when they are administered together. Nevertheless, there are some features of the action of drugs that may cause synergism of their antihypertensive effect. Thus, it is assumed that hyperreninemia resulting from ACE inhibition can be significantly reduced with the help of β-blockers, which suppress the secretion of renin by the juxtaglomerular apparatus of the kidneys. In turn, vasoconstriction that occurs when prescribing BAB can be significantly reduced when using ACE inhibitors that have vasodilatory properties. Sometimes such a combination can be recommended when severe tachycardia persists with low RAAS activity. In patients with chronic heart failure, the need for an ACE inhibitor in combination with a β-blocker is beyond doubt, but in patients with hypertension, this combination cannot be considered optimal.
Table 2.13. Composition of some combined antihypertensive drugs
Continuation of table 2.13
The end of the table. 2.13
End of table 2.13
Note:* - in the form of succinate.
The combination of ACE inhibitors and BARs is rarely used in clinical practice, since it is believed that both drugs act on different levels of the same system - the RAAS - and potentiation of the antihypertensive effect does not occur when they are administered together, since BARs cause a complete decrease in RAAS activity. At the same time, ACE inhibitors suppress the reactive increase in AT-II synthesis caused by BAR, and therefore weaken the indirect stimulation of type II angiotensin receptors, which is considered one of the important mechanisms of the antihypertensive effect of BAR. However, this particular combination may be useful and even indispensable in the treatment of high-renin forms of hypertension and to nephroprotection in patients with arterial hypertension.
Irrational drug combinations
Irrational combinations include such combinations of drugs, the use of which either does not potentiate the antihypertensive effect, or increases side effects. These include combinations: β-blocker + CCB of the phenylalkylamine series, β-blocker + centrally acting drug, CCB of the dihydropyridine series + α 1 -blocker.
To ensure maximum effectiveness of the treatment of hypertension, the doctor should follow several rules:
It is advisable to prescribe a fixed combination of drugs (in one tablet), which simplifies the regimen and improves patient compliance;
It is necessary to give preference to drugs of prolonged action to ensure a 24-hour effect with a single dose. This allows to achieve a stable hypotensive effect and permanent protection of target organs, in addition - to increase the patient's adherence to treatment;
The effectiveness of round-the-clock control of blood pressure can be assessed by measuring blood pressure before taking the next dose of the drug or during outpatient monitoring;
Increased attention should be paid to the side effects of drugs, as they are the most important reason for refusal of treatment (lack of adherence to treatment);
In uncomplicated hypertension and in elderly patients, the volume of therapy is increased gradually, until the target blood pressure is reached;
At high CV risk, target BP should
be achieved as soon as possible, by the method of combination therapy with a relatively rapid increase in dose, along with the actual antihypertensive treatment, correctable risk factors (hyperglycemia, hypercholesterolemia, etc.) are corrected according to generally accepted standards; - taking care of maintaining the patient's high adherence to treatment is a fundamentally important component of hypertension therapy, it includes: planning regular patient visits, medical education of the patient (including hypertension schools); explanation of the essence of the action of drugs and discussion of possible side effects; regular encouragement in relation to achieved patient lifestyle changes; encouraging self-monitoring of blood pressure; involvement of relatives in the process of implementing medical recommendations, a simple and understandable regimen for taking drugs, tied to the daily routine.
Criteria for the effectiveness of antihypertensive therapy
The results of the therapy can be divided into short-term (immediate), medium-term (intermediate) and long-term (long-term). The immediate results are determined after a few weeks or months of treatment and include a decrease in blood pressure to an acceptable level, the absence of side effects, improvement in laboratory parameters, adequate compliance with doctor's prescriptions, and a favorable effect on quality of life. Intermediate results, sometimes called surrogate end points of treatment, are an indicator of the effectiveness of ongoing antihypertensive and organoprotective therapy. They include the effect on the state of the function of the heart and kidneys, left ventricular hypertrophy, the progression of atherosclerosis, angina pectoris, the effect on the state of carbohydrate and lipid metabolism. Long-term outcomes represent the endpoints of treatment and include measures such as cardiac, cerebrovascular, and renal complications, aortic and peripheral arterial disease, and mortality (from cardiac and non-cardiac causes).
Short-term criteria for the effectiveness of antihypertensive therapy (1-6 months from the start of treatment)
Reducing blood pressure and / or blood pressure by 10% or more or achieving the target level of blood pressure.
Absence of hypertensive crises.
Maintaining or improving the quality of life.
Influence on modifiable risk factors.
Medium-term criteria for the effectiveness of antihypertensive therapy (more than 6 months from the start of treatment)
Achieving target values of blood pressure.
Absence of target organ damage or reversible dynamics of existing complications.
Elimination of modifiable risk factors.
Long-term criteria for the effectiveness of antihypertensive therapy
Stable maintenance of blood pressure at the target level.
No progression of target organ damage.
Compensation for existing cardiovascular complications.
2.5. TREATMENT OF HYPERTENSION CRISES
Hypertensive crises (HCr) are usually understood as conditions with a sudden increase in blood pressure, which are heterogeneous in clinical manifestations and prognosis and may pose a threat to life or health. HCr can complicate all stages of hypertension, but most often they occur in stage II-III. A sudden increase in blood pressure can be provoked by neuropsychic trauma, alcohol consumption, sharp fluctuations in atmospheric pressure, the abolition of antihypertensive therapy, etc. In the pathogenesis of HCR, there are:
Vascular mechanism - an increase in total peripheral resistance as a result of an increase in vasomotor (neurohumoral influences) and basal (with sodium retention) arteriolar tone;
Cardiac mechanism - an increase in cardiac output, myocardial contractility and ejection fraction in response to an increase in heart rate, circulating blood volume.
MS Kushakovsky (2004) distinguishes three types of hypertensive crises.
Neurovegetative. This type of hypertensive crisis is the most common. Blood pressure rises at night or during awakening, accompanied by agitation, severe headaches, tachycardia. Blood pressure rises rapidly: systolic to 230-250 mm Hg. Art., diastolic up to 120-125 mm Hg. Art.
At edematous form the patient is inhibited, obese, lethargic, his face is puffy, diuresis is sharply reduced.
Convulsive form is rare, observed in the most severe course of hypertension and is manifested by loss of consciousness, tonic and clonic convulsions.
Among hypertensive crises, emergency and urgent conditions are distinguished. Emergency hypertensive crises (type I HCR) are hypertensive conditions characterized by a pronounced increase in blood pressure (>180/120 mm Hg), complicated by signs of onset or progressive dysfunction of target organs (unstable angina pectoris, acute left ventricular failure, aortic aneurysm dissection, eclampsia, stroke, papilledema, etc.). However, even if the increase in blood pressure does not exceed 180/120 mm Hg. Art., but leads to the appearance or aggravation of symptoms of target organ damage, such a condition should be considered as type I HCr.
To prevent or limit damage to target organs in this case, an immediate decrease in blood pressure is required during the first minutes and hours (not necessarily to normal) using parenteral drugs.
Emergency conditions in hypertensive crises
Hypertensive encephalopathy.
AH with signs of left ventricular failure.
hypertension in myocardial infarction.
hypertension in unstable angina.
AH in aortic dissection.
Severe hypertension associated with subarachnoid hemorrhage or cerebrovascular accident.
Crisis in pheochromocytoma.
Hypertension in amphetamines, LSD, cocaine or ecstasy poisoning.
AG during surgery.
Severe preeclampsia or eclampsia.
The initial goal of treating emergency hypertensive conditions is to reduce mean arterial blood pressure by no more than 25% in the range from several minutes to one hour with the help of parenteral antihypertensive drugs. Subsequently, if BP is stable, it
reduce over the next 2-6 hours to 160 mm Hg. (systolic) and 100-110 mm Hg. Art. (diastolic) (transition to oral dosage forms is possible). At the same time, an excessive decrease in blood pressure, which can cause renal, cerebral or coronary ischemia, should be avoided. If this level of blood pressure is well tolerated and the patient's condition is clinically stable, then over the next 24-48 hours, a further gradual decrease in blood pressure to a normal level can be carried out.
Patients with ischemic stroke for whom clinical studies have not shown benefit from urgent antihypertensive treatment;
Patients with aortic dissection in whom systolic BP should be reduced to< 100 мм рт. ст., если они это переносят.
Hypertensive emergencies (type II HC) are understood as situations associated with a sharp increase in blood pressure without progressive dysfunction of target organs. This also includes cases of asymptomatic increase in blood pressure ≥220 mm Hg. Art. and/or BPd ≥120 mm Hg. Art.
In these situations, a gradual decrease in blood pressure by 15-25% of the original or ≤160/110 mm Hg is necessary. Art. within 12-24 hours (using oral antihypertensive drugs). Evaluation of the effectiveness and correction of emergency therapy is carried out after the time necessary for the onset of the onset of the hypotensive effect of the drug (15-30 minutes).
To stop the convulsive form of a hypertensive crisis, diazepam (Seduxen, Relium, Sibazon) is additionally prescribed at a dose of 10-20 mg (2-4 ml of a 0.5% solution). The drug is administered intravenously slowly until the seizures are eliminated. You can also prescribe magnesium sulfate 2.5 g intravenously bolus slowly (10 ml of a 25% solution in 10 ml of a 0.9% sodium chloride solution). In this case, the main danger is respiratory arrest. Less dangerous is intravenous drip of magnesium sulfate (10 ml of a 25% solution in 250 ml of a 0.9% sodium chloride solution). With respiratory depression, intravenous administration of calcium chloride is necessary.
For the treatment of hypertensive crises, the doctor must have a relatively small, but complete, and most importantly, well-known set of antihypertensive drugs (Table 2.14).
Table 2.14. The main drugs used to relieve hypertensive crisis
Continuation of the table. 2.14
Continuation of table 2.14
Continuation of the table. 2.14
Continuation of table 2.14
The end of the table. 2.14
End of table 2.14
Note:* - with intravenous administration of clonidine, a short-term increase in blood pressure is possible due to the activation of peripheral α 1 - and α 2 -adrenergic receptors of the vessels; ** - introduction through a special system; *** - you can repeat the bolus after 5 minutes or increase the infusion to 300 mcg / min.
Requirements for a parenteral drug for the treatment of hypertensive crises
The short time of the onset of the hypotensive effect and its preservation is 3-4 hours after the cessation of administration.
Dose-dependent predictable effect.
Minimal effect on cerebral and renal blood flow, myocardial contractility.
Efficacy in most patients.
No contraindications for use in most patients.
Minimal range of side effects.
Requirements for an oral preparation for the treatment of hypertensive crises
Rapid (20-30 min) onset of hypotensive action when taken orally, lasting 4-6 hours.
Dose-dependent, predictable hypotensive effect.
Can be used in most patients (no side effects).
Availability.
After the start of antihypertensive therapy, medical observation for at least 6 hours is desirable for the timely detection of possible complications of HCC (primarily cerebrovascular accident and myocardial infarction) and side effects of drug therapy (for example, orthostatic hypotension). With the development of orthostatic hypotension, bed rest with blood pressure monitoring is recommended. With an excessive decrease in blood pressure, intravenous drip of fluids (for example, isotonic sodium chloride solution) is possible; with persistent hypotension, vasopressors (for example, dopamine) can be added to therapy.
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The history of the study of the renin-angiotensin-aldosterone system (RAAS), which turned out to be the most successful in terms of developing approaches to the pharmacological modulation of its activity, allowing to prolong the life of patients with cardiovascular and renal diseases, began 110 years ago. When was renin identified - the first component. Later, in experimental and clinical studies, it was possible to clarify the physiological role of renin and its significance in the regulation of RAAS activity in various pathological conditions, which became the basis for the development of a highly effective therapeutic strategy - direct renin inhibitors.
Currently, the first direct renin inhibitor Rasilez (aliskiren) is justified even in situations where other RAAS blockers - ACE inhibitors and ARBs are not indicated or their use is difficult due to the development of adverse events.
Another circumstance that makes it possible to count on the additional possibilities of direct renin inhibitors in protecting the target organs of hypertension compared to other RAAS blockers is that when using drugs that block the RAAS at other levels, according to the law of negative feedback, there is an increase in the concentration of prorenin, and an increase in plasma renin activity. It is this circumstance that cancels the often noted decrease in the effectiveness of ACE inhibitors, including from the point of view of their ability to reduce elevated blood pressure. Back in the early 1990s, when many organoprotective effects of ACE inhibitors were not established as reliably as they are today, it was shown that as their dose increases, plasma renin activity and plasma angiotensin concentration significantly increase. Along with ACE inhibitors and ARBs, thiazide and loop diuretics can also provoke an increase in plasma renin activity.
Aliskiren was the first direct renin inhibitor, the effectiveness of which was confirmed in controlled phase III clinical trials, which has a sufficient duration of action and reduces elevated blood pressure even in monotherapy, and its prescription can now be considered as an innovative approach to the treatment of hypertension. Comparisons were made of its effect on plasma concentration and activity of individual components of the RAAS with ACE inhibitors and ARBs. It turned out that aliskiren and enalapril almost equally reduce the plasma concentration of angiotensin II, but unlike aliskiren, enalapril administration led to a more than 15-fold increase in plasma renin activity. The ability of aliskiren to prevent negative changes in the balance of activity of RAAS components was also demonstrated when compared with ARBs.
A pooled analysis of a clinical study that included a total of 8481 patients who received aliskiren monotherapy or placebo showed that a single dose of aliskiren at a dose of 150 mg / day. or 300 mg/day. caused a decrease in SBP by 12.5 and 15.2 mm Hg. respectively, compared with a 5.9 mmHg reduction, placebo (R<0,0001). Диастолическое АД снижалось на 10,1 и 11,8 мм рт.ст. соответственно (в группе, принимавшей плацебо – на 6,2 мм рт.ст.; Р < 0,0001). Различий в антигипертензивном эффекте алискирена у мужчин и женщин, а также у лиц старше и моложе 65 лет не выявлено.
In 2009, the results of a multicenter controlled clinical trial were published, in which the effectiveness of aliskiren and hydrochlorothiazide was compared in 1124 hypertensive patients. If necessary, amlodipine was added to these drugs. By the end of the monotherapy period, it became clear that aliskiren leads to a more pronounced decrease in blood pressure than hydrochlorothiazide (-17.4/-12.2 mm Hg vs. -14.7/-10.3 mm Hg; R< 0,001)
Direct renin inhibitor (aliskiren)
Stimulates the secretion of renin by the kidneys, reducing the volume of circulating blood and perfusion of the kidney. Renin, in turn, converts angiotensinogen to angiotensin I, a precursor of angiotensin II, and the latter triggers a cascade of reactions leading to an increase in blood pressure. Thus, suppression of renin secretion can reduce the production of angiotensin II. While taking thiazide diuretics, ACE inhibitors and ARBs, plasma renin activity increases. Therefore, suppression of renin activity may be a potentially effective strategy for suppressing the entire renin-angiotensin system. Aliskiren is the first drug of a new class - a direct renin inhibitor, for which hypotensive activity has been proven. The improved bioavailability of the oral formulation of aliskiren compared to previously offered drugs of this kind and the long half-life allows this drug to be taken once a day.
Aliskiren effectively reduces blood pressure both in monotherapy and in combination with thiazide diuretics (hydrochlorothiazide), ACE inhibitors (ramipril, lisinopril). ARBs (valsartan) or CCBs (amlodipine). When aliskiren is taken with these antihypertensive agents, plasma renin activity does not increase, but remains at or even below the basal level. Alixiren has placebo-like safety and tolerability and does not interact with a wide range of drugs, with the exception of furosemide. There are currently limited data on the long-term efficacy and tolerability of aliskiren in diabetic patients with hypertension. As a result, the exact role of this drug in the treatment of hypertension in diabetic patients has not been fully established.
ALISKIREN (Rasilez drug) - tablets 150 mg and 300 mg, initial dose 150 mg / 1 time per day, with insufficient control of blood pressure after 2 weeks, the dose can be increased to 300 mg / 1 time per day
Mechanism of action. Antihypertensive agent, selective renin inhibitor of non-peptide structure. When using aliskiren as a monotherapy and in combination with other antihypertensive agents, the suppression of negative feedback is neutralized, resulting in a decrease in plasma renin activity (in patients with arterial hypertension by an average of 50-80%), as well as levels of antitensin I and II. After the first dose, there is no hypotensive reaction (the effect of the first dose) and a reflex increase in heart rate in response to vasodilation.
Pharmacokinetics. After oral administration, the time to reach the maximum plasma concentration of aliskiren is 1-3 hours, the absolute bioavailability is 2.6%. Simultaneous food intake does not have a significant effect on the pharmacodynamics of the drug. Therefore, aliskiren can be taken with or without food. Aliskiren is moderately bound to plasma proteins (47-51%), regardless of concentration. The elimination half-life of aliskiren is 40 hours (varies from 34 to 41 hours). It is excreted mainly unchanged through the intestines (91%). About 1.4% of the ingested dose is metabolized with the participation of the CYP3A4 isoenzyme. After oral administration, about 0.6% of aliskiren is excreted by the kidneys. When using aliskiren in patients over 65 years of age, dose adjustment of the drug is not required. The pharmacokinetics of aliskiren does not change significantly in patients with mild to moderate hepatic impairment (Child-Pugh score 5-9).
drug interaction. The probability of interaction of aliskiren with other drugs is low. When using aliskiren with one of the following drugs, its C max or AUC may change: valsartan (decrease by 28%), metformin (decrease by 28%), amlodipine (increase by 29%), cimetidine (19% increase). Since in experimental studies it was found that P-glycoprotein (a membrane carrier of molecules) plays an important role in the regulation of absorption and distribution of aliskiren, it is possible to change the pharmacokinetics of the latter when used simultaneously with substances that inhibit P-glycoprotein (depending on the degree of inhibition). There was no significant interaction of aliskiren with weakly or moderately active inhibitors of P-glycoprotein, such as atenolol, digoxin, amlodipine and cimetidine. With simultaneous use with an active inhibitor of P-glycoprotein atorvastatin (at a dose of 80 mg / day) in an equilibrium state, an increase in AUC and C max of aliskiren (dose of 300 mg / day) by 50% is noted. With the simultaneous administration of an active inhibitor of P-glycoprotein ketoconazole (200 mg) and aliskiren (300 mg), an increase in Cmax of the latter by 80% is observed. In experimental studies, the simultaneous administration of aliskiren with ketoconazole led to an increase in the absorption of the latter from the gastrointestinal tract and a decrease in its excretion with bile. Changes in the plasma concentration of aliskiren in plasma when used simultaneously with ketoconazole or atorvastatin are expected in the range of concentrations determined by increasing the dose of aliskiren by 2 times. In controlled clinical trials, the safety of aliskiren at a dose of 600 mg and an increase in the maximum recommended therapeutic dose by 2 times has been demonstrated. When using aliskiren together with ketoconazole or atorvastatin, dose adjustment of aliskiren is not required. When used with such a highly active P-glycoprotein inhibitor as cyclosporine (200 and 600 mg), healthy individuals showed an increase in C max and AUC of aliskiren (75 mg) by 2.5 and 5 times, respectively (it is not recommended to use aliskiren simultaneously with cyclosporine). With the simultaneous use of aliskiren with furosemide, there is a decrease in AUC and C max of furosemide by 28% and 49%, respectively. To prevent possible fluid retention when prescribing aliskiren together with furosemide at the beginning and during treatment, it is necessary to adjust the dose of furosemide depending on the clinical effect. Caution should be exercised when aliskiren is used concomitantly with potassium salts, potassium-sparing diuretics, potassium-containing table salt substitutes, or any other medicinal products that can increase the concentration of potassium in the blood.
Side effect. From the digestive system: often - diarrhea. Dermatological reactions: sometimes - skin rash. From the side of laboratory parameters: rarely - a slight decrease in the concentration of hemoglobin and hematocrit (on average by 0.05 mmol / l and 0.16%, respectively), which did not require discontinuation of treatment, a slight increase in the concentration of potassium in the blood serum (0.9% compared to 0.6% with placebo). Allergic reactions: in some cases - angioedema.
Contraindications and restrictions. Contraindications: children and adolescents under 18 years of age, pregnancy, lactation (breastfeeding), hypersensitivity to aliskiren. Use during pregnancy and lactation (breastfeeding) is contraindicated.
The efficacy and safety of aliskiren have not been established in patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale).
The efficacy and safety of aliskiren has not been established: in patients with severely impaired renal function (serum creatinine >150 µmol/l for women and >177 µmol/l for men and/or glomerular filtration rate less than 30 ml/min), with nephrotic syndrome, renovascular hypertension and during a regular hemodialysis procedure.
With caution, alisikiren should be used in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney, diabetes mellitus, reduced BCC, hyponatremia, hyperkalemia, or patients after kidney transplantation.
The efficacy and safety of aliskiren has not been established: in patients with severely impaired renal function (serum creatinine >150 µmol/l for women and >177 µmol/l for men and/or glomerular filtration rate less than 30 ml/min), with nephrotic syndrome, renovascular hypertension and during a regular hemodialysis procedure, as well as in patients with severe liver dysfunction (more than 9 points on the Child-Pugh scale), in patients with unilateral or bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney.
In patients with diabetes during therapy with aliskiren in combination with an ACE inhibitor, there was an increase in the frequency of hyperkalemia (5.5%). When using aliskiren and other drugs that affect the RAAS in patients with diabetes, it is necessary to regularly monitor the electrolyte composition of the blood plasma and kidney function.
Against the background of aliskiren therapy, an increase in the concentration of potassium, creatinine, and blood urea nitrogen is possible, which is characteristic of drugs that affect the RAAS. At the beginning of treatment with aliskiren in patients with reduced BCC and / or hyponatremia (including against the background of high doses of diuretics), symptomatic arterial hypotension is possible. Before use, correction of violations of the water-salt balance should be carried out. In patients with reduced BCC and / or hyponatremia, treatment should be carried out under close medical supervision.
Candidate of Chemical Sciences O. BELOKONEVA.
Perhaps today there is no more common chronic disease than hypertension (high blood pressure). Even its slow and seemingly imperceptible course eventually leads to fatal consequences - heart attacks, strokes, heart failure, kidney damage. Back in the century before last, scientists found that the kidneys produce a protein - renin, which causes an increase in blood pressure in the vessels. But only 110 years later, through the joint efforts of biochemists and pharmacologists, it was possible to find an effective remedy that could withstand the dangerous action of a long-known substance.
Science and life // Illustrations
Rice. 1. Liver cells constantly release a long peptide angiotensinogen into the bloodstream.
Rice. 2. Cardiovascular continuum: the path from hypertension to damage to the heart, blood vessels, kidneys and other organs.
Rice. 3. A direct renin inhibitor (DRI) is built into the active center of renin and prevents it from splitting angiotensinogen.
In the early 1990s, the number of cardiovascular patients began to grow in Russia. And so far in our country, the mortality rate among the working population exceeds European indicators. Representatives of the male half of the population turned out to be especially unstable to social cataclysms. According to the World Health Organization, the life expectancy of men in our country is only 59 years. Women turned out to be more resilient - they live an average of 72 years. Every second citizen of our country dies from cardiovascular diseases and their consequences - heart attacks, strokes, heart failure, etc.
One of the main causes of cardiovascular disease is atherosclerotic vascular disease. With atherosclerosis, the inner shell of the vessel thickens, so-called plaques are formed, which narrow or completely clog the lumen of the artery, which disrupts the blood supply to vital organs. The main cause of atherosclerotic vascular lesions is a violation of fat metabolism, mainly an increase in cholesterol.
Another equally important and most common cause of cardiovascular disease is hypertension, which is manifested by a steady increase in blood pressure. An increase in blood pressure also leads to vascular damage. Namely, the lumen of the vessel narrows, its wall thickens (hypertrophy of the muscle layer develops), the integrity of the inner lining of the vessel, the endothelium, is violated. Such changes are called vascular remodeling. All this leads to the fact that the vessel affected by atherosclerosis loses elasticity, ceases to pulsate under the influence of blood flow. If healthy vessels can be compared with flexible rubber tubes that transmit a pulse wave and dampen blood flow turbulence, then pathological vessels are similar to a metal pipeline. Vascular remodeling contributes to the progression of atherosclerosis.
Hypertension as a cause of heart attacks and strokes
Hypertension often goes unnoticed. Patients do not know that they are sick, do not change their lifestyle, do not go to the doctor and do not take medication. Meanwhile, due to its destructive effect on the body, hypertension can be called a “silent killer”. If the disease develops quickly, then it leads to the progression of atherosclerosis and, ultimately, to a heart attack, stroke, gangrene of the lower extremities. If the disease proceeds for a long time and the body has time to adapt to blockage of blood vessels, damage to the heart muscle develops (first hypertrophy, and then myocardial atrophy, which leads to chronic heart failure), kidneys (albuminuria - loss of protein in the urine, impaired renal function and, as a result, - renal failure) and metabolic disorders (glucose intolerance, and then diabetes mellitus).
The causes of hypertension are not fully understood, although research in this direction has been going on for more than a century. How does hypertension occur and why does it cause such deadly complications? The answer to these questions is given by biochemistry.
Molecules that increase blood pressure
The role of biochemical disorders in the development of hypertension has been known for a long time. In 1897, Robert Tigerstedt, professor of physiology at Karolinska University in Stockholm, a Finn by birth, announced his discovery at an international conference in Moscow. Together with his assistant, Per Gustav Bergman, he discovered that intravenous administration of kidney extract caused an increase in blood pressure in rabbits. The substance that increases blood pressure is called renin. Tigerstedt's report did not cause a sensation, moreover, the study was considered small, insignificant, made for the sake of another publication. The disillusioned professor stopped his research and returned to Helsinki in 1900. Bergman took up medical practice, and the scientific world forgot about the pioneering work of Scandinavian physiologists for 40 years.
In 1934, a Canadian scientist working in California, Harry Goldblatt, caused the symptoms of arterial hypertension in dogs by clamping the renal artery and proceeded to release the protein substance - renin from the kidney tissue. This was the beginning of discoveries in the field of the mechanism of regulation of blood pressure. True, Goldblatt managed to obtain a preparation of pure renin only after 30 years.
Literally a year after the first publication of Goldblatt, in 1935, two research groups at once - from Buenos Aires under the leadership of Eduardo Mendez and the American under the leadership of Irving Page - independently of each other, also using the technique of clamping the renal artery, isolated another substance that increases arterial pressure. Unlike the large protein molecule renin, it was a small peptide consisting of only eight amino acids. American researchers called it hypertensin, and Argentine researchers called it angiotonin. In 1958, during an informal meeting over a glass of martini, scientists compared the results of their studies, realized that they were dealing with the same compound, and came to a compromise agreement on the chimeric name of the peptide they had discovered - angiotensin.
So, the main compounds that increase pressure were discovered, only the connecting links in the mechanism of the development of hypertension were missing. And they appeared. In the late 1950s, the concept of the functioning of the renin-angiotensin system (RAS) was formed.
The classic idea of how the RAS functions is shown in Fig. one.
It is angiotensin II, acting on certain receptors, that leads to an increase in blood pressure, and with prolonged activation of the RAS, to dramatic consequences in the form of damage to the heart, blood vessels, kidneys, and ultimately to death (Fig. 2).
Several types of angiotensin II receptors have been found, the most studied of which are type 1 and type 2 receptors. When angiotensin II interacts with type 1 receptors, the body responds with vasospasm and increased production of aldosterone. Aldosterone is a hormone of the adrenal cortex that is responsible for fluid retention in the body, which also contributes to an increase in blood pressure. So type 1 receptors are responsible for the "harmful" action of angiotensin II, that is, for an increase in blood pressure. The interaction of angiotensin II with type 2 receptors, on the contrary, leads to a beneficial effect in the form of vasodilation.
As it turned out, the destructive effect of angiotensin II is not limited to an increase in pressure. Recent studies show that the binding of angiotensin II to type 1 receptors contributes to the development of atherosclerosis. It turned out that angiotensin II causes inflammation in the walls of blood vessels, promotes the formation of reactive oxygen species and, as a result, disrupts the structure and function of the endothelium - the cells lining the walls of blood vessels. Dysfunction of the endothelium leads to the development of atherosclerosis and remodeling of the vessel walls.
So, the renin-angiotensin system (RAS) plays a key role both in increasing pressure and in the development of atherosclerosis. Scientists have found that the genes responsible for the functioning of proteins involved in the ASD determine a person's predisposition to hypertension and cardiovascular disease. If certain genes are active, then the RAS is also hyperactivated, and the likelihood of developing hypertension and cardiovascular disease increases several times.
Search for drugs for hypertension. Three targets in a molecular chain
As soon as the concept of the renin-angiotensin system (RAS) was formed, three molecular targets were immediately identified in it, with the help of which it was possible to prevent the development of hypertension. Therefore, the strategy for the search for new drugs has developed along three main lines (see Fig. 1): the search for renin inhibitors; search for angiotensin-converting enzyme (ACE) inhibitors; search for type 1 angiotensin II receptor blockers (ARBs).
The enzyme renin has been and remains the most attractive target for pharmacologists, since it is the key molecule of the RAS. If there is no renin, angiotensin II is not produced either. However, the first inhibitors (substances that block activity) of renin, developed back in the 60s of the last century, could not be put into practice due to unsatisfactory pharmacological properties and the high cost of synthesis. They were poorly absorbed from the gastrointestinal tract and had to be administered intravenously.
After the failure of renin, pharmacologists began looking for another molecular target. The poisonous snake Bothrops gararaca helped scientists find it, the bite of which leads to a long and sometimes fatal drop in blood pressure. In 1960, the Brazilian Sergio Ferreiro began searching for the substance contained in the poison and causing "vascular paralysis." In 1968, they found that the substance was found to be an inhibitor of an enzyme that converts angiotensin I to angiotensin II. This is how the angiotensin-converting enzyme (ACE) was discovered. In 1975, captopril appeared, the first synthetic ACE inhibitor that could be taken in tablet form and whose effectiveness other ACE inhibitors could not surpass. It was a breakthrough and a real success in the treatment of hypertension. Now the number of ACE inhibitors is very large, there are more than 30 of them.
Along with the successes, data appeared on the side effects of captopril and other ACE inhibitors, in particular, the appearance of a rash, itching, and a painful dry cough. In addition, even at maximum doses, ACE inhibitors cannot completely neutralize the harmful effects of angiotensin II. In addition, the formation of angiotensin II during treatment with ACE inhibitors is very quickly restored due to alternative mechanisms. This is the so-called escape effect, which causes doctors to increase the dose or change the drug.
In Europe and the United States, over the past 10 years, ACE inhibitors have given way to a new class of drugs - angiotensin receptor blockers (ARBs). Modern ARBs completely turn off the "bad" type 1 receptors without affecting the "beneficial" type 2 receptors. These drugs, the first of which was losartan, have practically no side effects characteristic of ACE inhibitors, in particular, they do not cause a dry cough. ARBs are as good as ACE inhibitors in lowering blood pressure and more. Recent studies show that ACE inhibitors and angiotensin receptor blockers (ARBs) prevent damage to the heart and blood vessels and even improve the condition of blood vessels and myocardium affected by hypertension.
Curiously, if captopril is still as effective as newer ACE inhibitors, ARBs are constantly being improved. The newer ARBs are more specific for type 1 receptors and remain active in the body longer.
Last Assault
Despite the success of ACE inhibitors and ARBs, pharmacologists have not given up hope of "overcoming" the substance that plays a key role in hypertension, renin. The goal is very attractive - to turn off the molecule that "triggers" the biochemical cascade of the RAS.
A more complete blockade of the angiotensin II synthesis system was expected from renin inhibitors. The renin enzyme catalyses the process of angiotensinogen conversion, that is, it interacts with only one molecule in the biochemical cascade (Fig. 3). This means that renin inhibitors should not have significant side effects, unlike ACE inhibitors, which affect not only ACE, but also other regulatory systems.
A long-term search for renin inhibitors resulted in the synthesis of several molecules, one of which, aliskiren, already appeared in the arsenal of American doctors in 2007. Direct renin inhibitors (RDIs) have many advantages. They are easily tolerated by patients, are slowly excreted from the body, well (better than ACE inhibitors) reduce pressure, do not cause a withdrawal effect upon discontinuation.
So, our story began with renin, and it will end with it. The development of science has finally given scientists the opportunity to "approach" the protein, discovered 110 years ago, at a completely new molecular level. But perhaps the new drug is just the beginning. It turned out that renin is not only an enzyme, but also a hormone that interacts with special receptors discovered in 2002. It is likely that inhibitors of renin can not only block its enzymatic activity, but also prevent the binding of renin to renin receptors. This possibility is being actively explored. The next step in the search for new drugs for the treatment of hypertension may be the synthesis of renin receptor blockers or even therapy at the gene level. The development of inhibitors of enzymes for the synthesis of aldosterone and other enzymes - endopeptidases is also promising. But that's a topic for another article.
In any case, in the near future, patients will have access to drugs that are far superior to all known today and that can reverse the horrendous statistics of mortality from cardiovascular diseases. All this is due to scientific research and the introduction of the developments of scientists into medical practice.
By the non-commercial name of the drug for hypertension, one can conclude about the mechanism of its action. Angiotensin-converting enzyme (ACE) inhibitors have the ending -pril in their name (enalapril, lisinopril, ramipril). Angiotensin receptor blockers (ARBs) - ending sartan (valsartan, irbesartan, telmisartan). Direct renin inhibitors (DRIs) can be distinguished by the ending kiren (aliskiren, remikiren, enalkiren).
A non-commercial name should not be confused with a trademark. There are usually no rules and patterns in the names of brand names of original drugs.
Glossary for the article
Blockers are substances that block the interaction of physiologically active substances with receptors.
Inhibitors are substances that block the activity of enzymes.
Receptors are protein molecules on the surface of the cell membrane. The interaction of other molecules with them leads to the launch of a chain of reactions inside the cell.
Enzymes are protein molecules that catalyze processes in a living cell.
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Received 10.03.2014
Vasiliev Alexander Petrovich, Dr. honey. Sci., Chief Researcher, Department of Arterial Hypertension and Coronary Insufficiency, Scientific Department of Clinical Cardiology, Branch of the Federal State Budgetary Institution "Research Institute of Cardiology" of the Siberian Branch of the Russian Academy of Medical Sciences "Tyumen Cardiology Center".
Address: 625026, Tyumen, st. Melnikaite, 111. E-mail: [email protected] Streltsova Nina Nikolaevna, Researcher, Department of Arterial Hypertension and Coronary Insufficiency, Scientific Department of Clinical Cardiology, Branch of the Federal State Budgetary Institution "Research Institute of Cardiology" of the Siberian Branch of the Russian Academy of Medical Sciences "Tyumen Cardiology Center". Address: 625026, Tyumen, st. Melnikaite, 111. E-mail: [email protected]
UDC 616-08-035+616-08-031.81
ON THE POSSIBILITIES OF APPLICATION OF THE DIRECT RENIN INHIBITOR ALISKIRENE FOR THE TREATMENT OF SOCIALLY SIGNIFICANT DISEASES
A.F. Kolpakova
FSBI "Design and Technology Institute of Computer Engineering" SB RAS, Novosibirsk
Email: [email protected]
PROSPECTS FOR THE USE OF DIRECT RENIN INHIBITOR ALISKIREN FOR THE TREATMENT OF SOCIALLY SIGNIFICANT DISEASES
Design Technological Institute of Digital Techniques SB RAS, Novosibirsk
The review analyzes the results of randomized trials of the efficacy and safety of the direct renin inhibitor aliskiren in the treatment of patients with arterial hypertension in combination with obesity, diabetes mellitus, menopause and kidney damage; chronic kidney disease, metabolic syndrome. It has been established that aliskiren has not only hypotensive, but also cardio- and renoprotective effects, which can expand the indications for its use.
Key words: direct renin inhibitor, efficacy and safety of treatment, organoprotective effect.
This review analyzes the results of randomized studies of the efficacy and safety of direct renin inhibitor aliskiren in the treatment of patients with arterial hypertension associated with obesity, diabetes, menopause, kidney failure, chronic kidney disease, and metabolic syndrome. The authors conclude that, along with the hypotensive action, aliskiren exerts cardioprotective and renoprotective effects that can expand the indications for the use of this drug. Key words: direct renin inhibitor, efficacy and safety of treatment, organoprotective effect.
Introduction
According to the World Health Organization, socially significant non-communicable diseases account for 63% of all deaths, or approximately 36 million deaths annually, causing enormous damage to the socio-economic development of most countries of the world. In the economically developed countries of the world, the leading place in the structure of morbidity and mortality is occupied by cardiovascular diseases (CVD), including arterial hypertension (AH). About 40% of the adult population of the Russian Federation has an elevated level of blood pressure (BP). It is known that hypertension is the most important risk factor for myocardial infarction and cerebral stroke, mainly determining high mortality in our country. Despite progress in the effectiveness of CVD treatment, the number of people with uncontrolled or resistant hypertension is growing. There is also the problem of low adherence of patients to treatment.
Studies of recent decades have proven the role of the sympathetic-adrenal and renin-angiotensin-aldosterone (RAAS) systems in the formation and progression of hypertension, heart failure, chronic kidney disease and systemic atherosclerosis. In addition, RAAS is involved in the processes of tissue growth and development, modulation of inflammation and apoptosis, as well as in potentiation of the synthesis and secretion of a number of neurohumoral substances. The key link in the RAAS is the enzyme renin, which causes the transformation of angiotensinogen into angiotensin I (AT1). AT1 is further converted with the help of angiotensin-converting enzyme (ACE) into the most active angiotensin II (AT11) in humans. Thus, the tone of the RAAS as a whole and, consequently, the severity of the associated positive and negative effects of its components on target tissues (myocardium, vascular wall, renal tissue), which are realized through interaction with receptors for AT1 and AT11, and as well as aldosterone receptors. If the subsequent stages of RAAS activation can be carried out with the participation of different enzymes, then the formation of AT1 from angiotensinogen is impossible without the participation of renin. Focusing on the results of clinical studies, it can be argued that plasma renin activity is one of the most reliable markers of poor CVD prognosis. So, L. Sechi et al. (2008) in a study of 247 patients with AH demonstrated that an increase in plasma renin activity predisposes to the activation of endothelium-dependent and plasma hemostasis and, accordingly, increases the likelihood of thrombosis, including at the level of microcirculation, which naturally exacerbates the severity of target organ damage. A direct correlation was found between plasma renin activity, serum fibrinogen concentration, plasma levels of D-dimer and plasminogen activator inhibitor type 1, as well as signs of hypertensive heart and kidney damage. In addition, there are many circumstances in which plasma renin activity may be persistently elevated in a patient:
Hypertension, metabolic syndrome, type 2 diabetes mellitus, abdominal obesity, chronic kidney disease. Drugs that block subsequent levels of RAAS, primarily angiotensin-converting enzyme (ACE) inhibitors, as well as increasing sodium excretion, in particular thiazide diuretics, also predispose to an increase in plasma renin activity.
In recent years, pharmacological control over the activity of the RAAS has been carried out in the direction of limiting the production of AT11 due to ACE inhibition, blockade of AT11 and aldosterone receptors, as well as limiting renin secretion, mainly through the use of p-blockers. An analysis of the mechanism of action of modern antihypertensive drugs recommended as first-line drugs that affect the RAAS showed that all of them, with the exception of β-blockers, lead to an increase in the level of renin, prorenin and ACE. Thus, the use of diuretics is accompanied by an increase in the level of prorenin, renin, aPf, AT1, AT11 in plasma and AT11 in tissues. The use of ACE inhibitors is associated with a more pronounced increase in the content of prorenin, renin, ACE and AT1. It has been established that the use of AT1 receptor blockers (ARBs) is accompanied by stimulation of all RAAS mediators: a significant increase in prorenin, renin, aPf, AT1, AT11 in plasma and AT11 in tissues.
Numerous studies have shown that an adequate reduction in RAAS activity with ACE inhibitors, ARBs, or aldosterone is postulated rather than actually achieved, as the "escape" phenomenon develops. To overcome this phenomenon, combinations of ACE inhibitor + ARB + β-blocker, ACE inhibitor + spironolactone are used. Thus, renin has been and remains the most attractive target for pharmacologists, since it is a key link in the RAAS.
Purpose of the study: to analyze the literature data on the efficacy and safety of monotherapy and combination therapy with a direct renin inhibitor (RIR) for such socially significant diseases as cardiovascular diseases, chronic kidney disease, metabolic syndrome, and diabetes mellitus.
Efficacy and safety of aliskiren monotherapy
The emergence of PIR can be seen as a way to achieve more complete control of RAAS activity and overcome the "escape" phenomenon. A direct renin inhibitor, aliskiren (Novartis, Switzerland), acts by binding to the active site of the renin molecule, prevents the binding of renin to angiotensinogen, and thereby blocks the formation of AT1, a precursor of ATP. Aliskiren has undergone clinical trials, is registered in many countries of the world, including Russia, and is recommended for the treatment of arterial hypertension as monotherapy or in combination with other antihypertensive drugs.
As a result of the analysis of controlled clinical trials (RCTs), the efficacy and safety of aliskiren as an antihypertensive pre-
parata for monotherapy. Thus, in an 8-week placebo-controlled study, the efficacy and safety of A were evaluated in 672 patients with AH of I-II degrees, a dose-dependent decrease in SBP and DBP was revealed. The antihypertensive effect of PIR persisted for two weeks after its withdrawal. Aliskiren was well tolerated and the incidence of adverse events did not differ from placebo. A pooled analysis of clinical studies including 8481 patients who received PIR monotherapy or placebo showed that a single dose of PIR at a dose of 150 or 300 mg per day caused a decrease in SBP by 12.5 and 15.2 mm Hg. Art. respectively compared with a decrease of 5.9 mm Hg. Art. in patients receiving placebo (p<0,0001). ДАД снижалось на 10,1 (на дозе 150 мг) и 11,8 мм рт. ст. (на дозе 300 мг) соответственно (в группе плацебо - на 6,2 мм рт. ст., р<0,0001). Различий в антигипер-тензивном эффекте пИр у мужчин и женщин, а также у лиц старше и моложе 65 лет не выявлено.
A study of the antihypertensive effect of PIR compared with ACE inhibitors in patients with mild to moderate hypertension found the following: PIR reduces SBP and DBP significantly more than ramipril. After 12 weeks of treatment, SBP and DBP return to baseline faster after discontinuation of ramipril than after discontinuation of aliskiren. Comparison of the antihypertensive efficacy of aliskiren, irbesartan, and ramipril after a missed dose showed that in this case, the achieved reduction in blood pressure was significantly greater in the PIR group than in the ramipril group.
When comparing the therapeutic potential of PIR with that of other antihypertensive drugs, it turned out that PIR at ranged doses of 75, 150, and 300 mg/day is as effective as hydrochlorothiazide (HCT) at doses of 6.25, 12.5, and 25 mg/day. day . At the same time, in patients with mild and moderate hypertension, the frequency of achieving the target level of blood pressure when using PIR at a dose of 75 mg / day was 51.9%, and when the daily dose was increased to 300 mg - 63.9%. According to L.A Sica et al. (2006), in order to achieve adequate control of blood pressure in almost 45% of patients with mild to moderate hypertension who received aliskiren at a daily dose of 150-300 mg, it became necessary to additionally prescribe a diuretic. It was found that the severity of the antihypertensive effect of aliskiren in the dose range of 75-300 mg/day was equivalent to 100 mg/day of losartan.
According to a study by A.H. Gradman et al. (2005), aliskiren at a dose of 150 mg/day had similar efficacy and comparable safety to irbesartan at the same dose. In an 8-week RCT involving 1123 patients with mild to moderate hypertension, PIR monotherapy at ranged doses of 75, 150, and 300 mg/day was shown to be as effective as valsartan monotherapy at doses of 80, 160, and 320 mg/day. day . M. Weir et al. (2006) in a meta-analysis of eight RCTs, which involved 8570 patients, found that in mild and moderate hypertension, monotherapy with aliskiren (75-600 mg / day) leads to a dose-dependent decrease in blood pressure, regardless of age and gender of patients . In general, it must be concluded that
PIR effectively reduces office and daily BP, as well as equivalent doses of other antihypertensive drugs; it may be somewhat more effective than routinely used doses of ACE inhibitors and ARBs. The latter circumstance, apparently, is associated with a long time during which the concentration of PIR decreases by 50%, due to which adequate control of blood pressure is achieved in the early morning hours. This fact is likely to have a serious clinical significance in preventing negative cardio- and cerebrovascular events.
The high safety of aliskiren was established both in healthy volunteers during the first phase trials and in patients with hypertension. The frequency of adverse reactions that led patients to refuse to continue the study was comparable to that in the placebo group. The most commonly reported side effects were fatigue, headache, hypotension, dizziness, and diarrhea. It should be noted that the incidence of side effects depends on the dose of the drug. It is important that PIR does not affect the metabolism of endogenous bradykinin and substance P, therefore, it does not lead to the manifestation of cough and angioedema as often as ACE inhibitors. In general, the tolerability of PIR is comparable to that of angiotensin receptor antagonists and placebo. Aliskiren is not only well tolerated by patients with hepatic impairment, but also has a pharmacokinetic profile independent of the severity of hepatic insufficiency. The latter circumstance allows us to consider PIR as the drug of choice in patients with hypertension with concomitant mild and moderate hepatocellular insufficiency. Moreover, there are data on the safety of aliskiren in patients with renal insufficiency (with a glomerular filtration rate of more than 35 ml / min / 1.73 m2), diabetes mellitus, obesity, metabolic syndrome and heart failure, as well as in older age groups. At the same time, there is a potential risk of deterioration of renal function against the background of the use of PIR in monotherapy or when combined with ARBs in patients with clinically significant renal artery stenosis, during parenteral anesthesia, as well as in patients receiving long-term high doses of cyclooxygenase-2 inhibitors .
Combination therapy, including aliskiren. In most cases, patients with hypertension require combination therapy with two or three antihypertensive drugs to achieve the target blood pressure. Clinical studies have shown that the antihypertensive efficacy of PIR is increased when combined with other antihypertensive drugs. Thus, it was found that the combined use of aliskiren and valsartan has a synergistic effect on the degree of blood pressure reduction and exceeds the effectiveness of each of these components in the form of monotherapy. The effect of aliskiren, valsartan and a combination of these drugs on blood pressure was studied in a large study in 312 clinical centers (USA, Spain).
niya, Germany) with the participation of 1797 patients with hypertension. By the end of the 8th week of treatment, it was noted that under the action of a combination of aliskiren and valsartan, blood pressure decreased significantly to a greater extent than with the use of only aliskiren or valsartan. In 2009, the results of a multicenter controlled clinical trial were published, in which the effectiveness of PIR and HCT (initial antihypertensive therapy) was compared in 1124 hypertensive patients; if necessary, amlodipine was added to these drugs. By the end of the monotherapy period (week 12), it became clear that PIR leads to a more pronounced decrease in blood pressure than HCT (-17.4/-12.2 vs. 4.7/-10.3 mm Hg, p<0,001). У пациентов с мягкой и умеренной АГ с ожирением и без ПИР+ГХТ обеспечивают достоверное снижение ДАД и САД. . Доказана и эффективность комбинированной терапии, включающей алискирен у пациентов с плохо контролируемой (резистентной) АГ .
W.B. White et al. (2010) analyzed the safety and tolerability of PIR in combination with ARBs and thiazide diuretics in the treatment of hypertension in 13 RCTs, including 9 short-term (8 weeks) and 4 long-term (2652 weeks) for the period up to August 31, 2009. In these The study included 12,942 patients with stage 1 and stage 2 hypertension. Short-term studies have shown that the combination of PIR with an ARB (valsartan or losartan) or a thiazide diuretic is tolerated by patients similarly to monotherapy with these drugs. These data have also been confirmed in long-term studies. At the same time, in short-term studies in patients treated with a combination of aliskiren + valsartan or aliskiren + losartan, adverse reactions were detected in 32.2-39.6%, and with monotherapy - in 30.0-39.6% of patients. In long-term studies, adverse reactions were observed in 55.5% of patients receiving the combination of aliskiren + losartan, in 45% - aliskiren + diuretic, and did not differ significantly from those with losartan monotherapy (53%) and diuretic (48.9). %). In other words, the safety and tolerability of combination therapy with aliskiren with the ARB valsartan or losartan was similar to monotherapy with these drugs.
Y. Liu et al. (2014) as a result of the analysis of 19 RCTs, including 13614 hypertensive patients receiving combination therapy of aliskiren + amlodipine and aliskiren + hydrocloptiazid, concluded that the combination therapy led to significantly (p<0,00001) большему снижению АД по сравнению с монотерапией. При этом не было установлено достоверных различий между комбинированной терапией и монотерапией в отношении побочных эффектов, кроме периферических отеков и гиперкалиемии при лечении только амлодипином. Подобный гипотензивный эффект комбинированной терапии получен у больных с ожирением и без него. Кроме того, выявлено, что лечение комбинацией алискирен+ амлодипин достоверно более эффективно, чем алиски-рен+гидрохлоптиазид, число побочных эффектов и отказов от лечения, обусловленных нежелательными реакциями, существенно не различалось .
Organoprotective action of aliskiren. In exp-
Animal studies have proven the ability of aliskiren to induce vasodilation of the renal arteries and increase minute diuresis, lead to reversal of albuminuria, reduce the formation of superoxide radicals, have anti-inflammatory and antiatherosclerotic effects, and also contribute to the reduction of left ventricular hypertrophy. At the same time, the reno- and cardioprotective qualities of aliskiren were comparable to those of valsartan.
The cardioprotective and nephroprotective effects of PIR have been confirmed in the treatment of patients with hypertension and chronic kidney disease in many clinical studies. S.C. Tang. et al. (2012) found that in patients with non-diabetic nephropathy, the addition of PIR to losartan significantly reduced proteinuria. The authors attribute the nephroprotective effect of PIR to the decrease in circulating levels of interleukin-6 and transforming growth factor beta (TGF-b) that they found.
The AVOID - Aliskiren in the evaluation of proteinuria in Diabetes study (part of the ASPIRE HIGHER program), which also involved Russian clinical centers, was designed to evaluate the potential of aliskiren in protecting target organs in various situations characterized by a very high risk of potentially fatal complications. In 599 patients with diabetic nephropathy with hypertension, we studied the effect of a combination of maximum doses of losartan and aliskiren on urinary albumin excretion, assessed by the ratio of urine albumin/creatinine. The addition of aliskiren (300 mg/day) to losartan (100 mg/day) was accompanied by a significant decrease in the urine albumin/creatinine ratio by 20%, including a decrease in this ratio by 50% or more in 24.7% of patients. At the same time, when losartan was combined with placebo, a decrease in the urine albumin / creatinine ratio by 50% or more was achieved only in 12.5%. The renoprotective effect of aliskiren did not depend on blood pressure. In the study by M. Ohsawa et al. (2013) showed that the addition of aliskiren to ARB therapy in patients with chronic kidney disease with hypertension leads to a more significant decrease in blood pressure and improvement in heart and kidney function compared with the addition of benazepril.
According to the results of the ALOFT (Aliskiren Observation of Heart Failure Treatment) study, the addition of aliskiren to the standard regimen for the treatment of chronic heart failure (CHF) with signs of an unfavorable prognosis (persistent increase in plasma natriuretic peptide) and AH made it possible to improve the clinical condition, reduce the ratio of the magnitude of mitral regurgitation to the area of the mitral orifice and transmitral blood flow. Thanks to aliskiren, the concentration of markers of maladaptive neurohumoral activation (plasma levels of brain natriuretic peptide (BNUP) and its precursor, urinary aldosterone concentration, and plasma renin activity) decreased. At the same time, the level of BNP during therapy with the addition of 150 mg of aliskiren decreased 5 times more than with standard therapy.
In the randomized study ALLAY (The
Aliskiren Left Ventricular Assessment of Hypertrophy) involved 465 hypertensive patients who received aliskiren at a dose of 300 mg, losartan - 100 mg per day, or a combination of both. Against the background of taking PIR, renin activity and plasma aldosterone concentration decreased, but these indicators increased during treatment with losartan. Aliskiren also caused a decrease in the mass index of the left ventricular myocardium, which reflected the regression of hypertrophy in patients with hypertension and overweight. The combination of aliskiren and losartan resulted in a further decrease in left ventricular hypertrophy.
Clinical studies of I.M. Fustei et al. (2013) showed that antihypertensive therapy with PIR in patients with hypertensive nephropathy and metabolic syndrome for 3 months. significantly reduced the levels of cholesterol, triglycerides, indicators of insulin resistance and improved kidney function (decrease in microalbuminuria and increase in glomerular filtration) and the functional state of the vascular endothelium.
The results of completed studies of the ASPIRE HIGHER program (AVOID, ALOFT, ALLAY, AGELESS) and a number of other short-term RCTs have shown high clinical efficacy and organoprotective effect of aliskiren both in monotherapy and in combination therapy. However, the ASPIRE and AVANTGARDE studies have had conflicting results. The ASPIRE study showed that the addition of aliskiren to the optimal treatment regimen for patients with myocardial infarction does not prevent the development of left ventricular remodeling, but leads to more pronounced adverse reactions in the form of renal dysfunction, hypotension and hyperkalemia.
Some hope was associated with dual blockade of the RAAS using a combination of aliskiren and standard therapy (ACE inhibitors or ARBs) in patients with type 2 diabetes mellitus with a high risk of cardiovascular and renal complications. The ALTITUDE - Aliskiren Trial I Type 2 Diabetes Using Cardio-renal Diseases Endpoints study (part of the ASPIRE HIGHER program) included 8561 patients. The primary objective of this study was to evaluate the efficacy of adding aliskiren to standard therapy in terms of the effect on the combined end point (cardiovascular death and complications: successful resuscitation, non-fatal myocardial infarction, non-fatal stroke, unplanned hospitalization due to CHF; development of end-stage chronic renal failure , doubling of serum creatinine, death from causes associated with kidney damage). This study was prematurely terminated due to the lack of efficacy of adding aliskiren to standard therapy and adverse reactions in the form of non-fatal stroke, impaired renal function, hyperkalemia and hypotension. Based on the findings, combination therapy with aliskiren and an ACE inhibitor or ARB is not recommended in patients with AD and diabetes or renal insufficiency. Then the Committee on Medical Products of the European Medicines Agency and the US Food and Drug Administration reported that antihypertensive drugs,
The report by G. Mihai et al. does not contradict the results of ALTITUDE. (2013), who found in an RCT an accelerated progression of aortic atherosclerosis compared with placebo when taking aliskiren at a dose of 300 mg per day for 36 weeks when analyzing the results of three-dimensional magnetic resonance imaging in patients with cardiovascular disease. Due to this fact, the study was prematurely terminated.
Another disappointment was the announcement of the results of the ASTRONAUT study. The addition of aliskiren to conventional heart failure therapy with ACE inhibitors, aldosterone antagonists, and angiotensin receptor blockers was expected to have an additional effect on mortality and readmission risk. However, the results showed a significant lack of difference between the control group and the group of patients treated with a combination of drugs with the addition of aliskiren in the primary endpoints - the number of hospitalizations and deaths from CVD. At the same time, the risk of side effects in the form of hyperkalemia, hypotension and renal failure increased compared with placebo.
Thus, there are conflicting data in the literature on the results of treatment with aliskiren in combination with an ACE inhibitor or ARB. This controversy may be related to the fact that in the ALTITUDE study, treatment was with a high dose (330 mg/day) of aliskiren in combination with high doses of an ACE inhibitor or an ARB. Recent studies by W.P. Wu et al. (2012) found that the addition of 150 mg of aliskiren to ACE inhibitor or ARB therapy in 103 Chinese patients with chronic kidney disease for 6 months. contributed to the control of blood pressure and a decrease in proteinuria both in the group with concomitant type 2 diabetes and without it. At the same time, no significant changes in glomerular filtration rate and potassium concentration were noted, in addition, aliskiren not only reduces plasma renin activity, but also affects the expression of prorenin receptors, which play an important role in potassium metabolism.
In Canada, 903,346 patients aged 66 years and older who were hospitalized for various conditions (hyperkalemia, acute renal ischemia, cerebral stroke) were treated with aliskiren in combination with an ACE inhibitor or ARB for 28 months. As a result of multivariate analysis, it was found that aliskiren therapy was not associated with a significant increase in the risk of hospitalization for hyperkalemia, stroke, or acute renal failure. Treatment of PIR in combination with an ACE inhibitor or ARB in patients with chronic kidney disease, diabetes, CHF for 28 months. also not accompanied by an increase in side effects. Researcher R.M. came to similar conclusions. Touyz (2013) from Canada.
Conclusion
Thus, based on the analysis of the above
According to the research results, it can be concluded that the direct renin inhibitor aliskiren has a high antihypertensive potential, a favorable therapeutic profile, high safety, good tolerability, and has a pronounced organoprotective effect. Multicenter randomized trials have proven the efficacy and safety of combination therapy of aliskiren + amlodipine, aliskiren + amlodipine + hydrochlorothiazide in hypertension of various origins. Therefore, aliskiren is indicated for the majority of patients with hypertension as an additional class of antihypertensive drugs for combination therapy, and this is reflected in the Russian guidelines for the diagnosis and treatment of arterial hypertension (2010). This group can also include patients with established excessive activation of the RAAS, with hypertension of various origins, metabolic syndrome, obesity, chronic renal failure, chronic kidney disease, as well as hypertension in menopausal and postmenopausal women.
However, a number of unresolved issues remain, in particular combination therapy with aliskiren and ACE inhibitors or ARBs, which require further research.
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Received 03/12/2014
Kolpakova Alla Fedorovna, Dr. honey. Sciences, Professor, Leading Researcher, Laboratory of Bio-
Informatics FGBU "Design and Technological Institute of Computer Science" SB RAS. Address: 630090, Novosibirsk, st. acad. Rzhanova, 6. E-mail: [email protected]
UDC 616.24-008.331.1-085
ENDOTHELIN RECEPTOR ANTAGONISTS IN THE TREATMENT OF PULMONARY ARTERIAL HYPERTENSION (LITERATURE REVIEW)
S.N. Ivanov1, T.G. Volkova1, R.V. Volkov2, Yu.A. Khrustaleva1, V.G. Efimenko1
1FGBU "Novosibirsk Research Institute of Circulatory Pathology named after Academician E.N. Meshalkin" of the Ministry of Health of Russia 2Novosibirsk State Regional Clinical Hospital E-mail: [email protected]
ENDOTHELIN RECEPTOR ANTAGONIST IN THE TREATMENT OF PULMONARY ARTERIAL HYPERTENSION (LITERATURE REVIEW)
S.N. Ivanov1, T.G. Volkova1, R.V. Volkov2, Yu.A. Khrustaleva1, V.G. Efimenko1
federal State Institution "Novosibirsk Research Institute of Circulation Pathology n.a. acac1. E.N. Meshalkin" of the Ministry of Healthcare of the Russian Federation Novosibirsk State Regional Hospital
This analytical article provides a review of the literature on the use of endothelin receptor antagonists in the treatment of pulmonary arterial hypertension (PAH). The main drugs widely used in practice are discussed: bosentan (Traklir) and ambrisentan. Currently, both drugs of this group are registered in Russia. The article presents the main clinical studies on the use of endothelin receptor antagonists.
Keywords: pulmonary arterial hypertension, bosentan (traclear), ambrisentan.
This analytical article provides a review of the literature for using the endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. The authors discuss the use of two main drugs widely used in clinical practice: bosentan (Tracleer) and ambrisentan. Both of these drugs have been registered in the Russian Federation. The article presents findings of the main clinical trials of endothelin receptor antagonists. Key words: pulmonary arterial hypertension, bosentan (Tracleer), ambrisentan.
Pulmonary arterial hypertension (PAH) is a disease characterized by vascular obstruction and varying degrees of vasoconstriction leading to increased pulmonary vascular resistance and right ventricular heart failure (RHF). Without treatment, PAH eventually leads to the development of RVF and death. The median survival of untreated patients is 2.8 years. Epidemiological data vary, but the prevalence of the disease in Europe is estimated at 15 cases per million people.
The pathophysiological mechanisms underlying the development of PAH include pulmonary vascular dysfunction, which leads to an imbalance of vasoactive substances and proliferation factors, leading to the development of vascular remodeling and pulmonary vasoconstriction. Endothelin (ET) is considered as an important mediator of PAH development. It has been established that in PAH, the level of ET-1 increases, which contributes to the progression of the disease. Significant correlation found
between serum endothelin 1 levels and disease severity as measured by pulmonary vascular resistance (PVR), mean pulmonary artery pressure (MPAP), and right atrial pressure. Detailed, evidence-based recommendations for the treatment of PAH have previously been published.
There are two pharmacological approaches to the treatment of the disease: the use of drugs of the supportive or symptomatic therapy group (aimed at reducing the degree of vasoconstriction, dyspnea and thromboembolic complications) and the use of drugs that affect the pathophysiological mechanisms of the development of the disease. ET-1 receptor antagonists are drugs that can limit both the vasoconstrictor and proliferative effects of endothelin and thus improve the clinical course of the disease.
Tracleer (bosentan) is the first and currently
