Combined antihypertensive therapy: state of the art. Antihypertensive drugs - classification, list of drugs of the latest generation
What
drugs should be prescribed when selecting antihypertensive therapy in
first line? Science is still developing different methods and approaches,
new groups of drugs are being tested. Different doctors may have their own scheme
treatment. However, there are general concepts based on statistics and research.
At the initial stage
In uncomplicated cases, drug antihypertensive therapy
often start with the use of proven "conventional" drugs: beta-blockers and
diuretics. In large-scale studies involving 48,000 patients,
it has been shown that the use of diuretics, beta-blockers reduces the risk of
cerebral circulation, sudden death, myocardial infarction.
Alternative
option - the use of captopril. According to new data, the frequency of occurrence
heart attacks, strokes, deaths with conventional treatment or
when using captopril, almost the same. Moreover, for a special group
patients who have not previously been treated with antihypertensive drugs, captopril
shows a clear advantage over conventional therapy, significantly reducing the relative
risk of cardiovascular events by 46%.
Long-term use of fosinopril in patients with diabetes, as well as arterial
hypertension is also associated with a significant reduction in the risk of death, myocardial infarction, stroke,
exacerbation of angina pectoris.
Therapy for hypertrophy of the left
ventricle
IN
as antihypertensive therapy, many doctors practice the use of
angiotensin-converting enzyme (ACE) inhibitors. These drugs have
cardioprotective properties and lead to a decrease in the mass of the LV myocardium (left ventricle). At
study of the degree of impact of various drugs on the LV myocardium
it was found that the reverse degree of development of its hypertrophy is most pronounced
it is in ACE inhibitors, since antiotensin-2 controls growth, hypertrophy
cardiomyocytes and their division. In addition to their cardioprotective effects, ACE inhibitors
have a nephroprotective effect. This is important, because despite all the successes
antihypertensive therapy, the number of patients who develop terminal
kidney failure, increasing (compared to the "eighties" in
4 times).
Therapy with calcium antagonists
Increasingly used
as first-line calcium antagonists. For example, when
isolated systemic arterial hypertension (AH) effective dihydropyridine
long-term blockers
action of calcium channels. A four-year study of 5,000 patients showed a significant effect
nitrendipine on the incidence of cerebral stroke. In another study, basic
The drug was a long-acting calcium antagonist, felodipine. 19 000
patients were followed up for four years. As BP decreases
(blood pressure) beneficial effects increased, there was
significant reduction in the risk of cardiovascular events and
increased frequency of sudden death. "SystEur" study, in
which involved 10 Russian centers, also showed a 42% reduction in the incidence of strokes
when using nisoldipine.
Antagonists
calcium are also effective in pulmonary arterial hypertension (this is a systemic
hypertension in patients with obstructive pulmonary disease).
Pulmonogenic hypertension develops several years after the onset of pulmonary
diseases, and there is a clear connection between the exacerbation of the pulmonary process and
rises in pressure. Benefits of calcium antagonists in pulmonary hypertension
is that they reduce calcium-mediated hypoxic
vasoconstriction. Increases oxygen delivery to tissues, decreases
hypoxia of the kidneys, vasomotor center, decreased blood pressure, as well as
afterload and myocardial oxygen demand. In addition, the antagonists
calcium reduce the synthesis of histamine, kinin, serotonin in tissues, mucosal edema
bronchi and bronchial obstruction. An additional benefit of calcium antagonists (particularly
isradipine) - their ability to change metabolic processes in patients with hypertension.
By normalizing or lowering blood pressure, these drugs can prevent the development
dyslipidemia, glucose and insulin tolerance.
At
calcium antagonists revealed a clear relationship between dose, plasma concentration
blood and pharmacological hypotensive effect. By increasing the dose of the drug,
it is possible, as it were, to control the hypotensive effect, increasing or decreasing it. For
long-term treatment of hypertension, prolonged drugs with low
absorption rate (amlodipine, prolonged gastrointestinal form
nifedipine, or osmoadolat, a long-acting form of felodipine). At
the use of these funds occurs smooth vasodilation without reflex
activation of the sympathetic-adrenal system, the release of catecholamines, reflex tachycardia
and increased myocardial oxygen demand.
Not recommended as first choice drugs based on tolerability
vasodilators of myotropic type of action, central alpha-2-adrenergic
agonists, peripheral adrenergic agonists.
For citation: Karpov Yu.A., Starostin I.V. Combined antihypertensive therapy: state of the art // BC. 2012. No. 25. S. 1283
An increase in blood pressure (BP) is the result of a complex interaction of genetic and environmental factors leading to the activation and/or suppression of BP regulation systems. The complexity of the mechanisms that provide BP control, which was first mentioned by Irvine Page, significantly affects differences in individual sensitivity to antihypertensive therapy. A huge number of options for arterial hypertension (AH) makes it almost impossible, with few exceptions, to determine a specific option for increasing blood pressure in the daily practice of a doctor who decides on the choice of treatment.
Hypertension is a hemodynamic disorder by definition, and increased peripheral vascular resistance is the hallmark hemodynamic feature of elevated BP. Understanding this fact led to the discovery and development of a special class of vasodilators with a targeted mechanism of action, although many of the previously used antihypertensive agents also had a vasodilatory effect, for example, by blocking the activity of the sympathetic nervous system. The first non-specific vasodilator was hydralazine, followed by vasodilators that block calcium channels of vascular smooth muscle cells (calcium antagonists - AA), postsynaptic α-adrenergic receptors of peripheral neurons of the sympathetic nervous system (α-blockers) and blockers of the renin-angiotensin-aldosterone system (RAAS) ( angiotensin converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), and finally direct renin inhibitors (RIRs).
The vasodilatory effect is also inherent in thiazide diuretics (TD), which, by reducing the sodium content in vascular smooth muscle cells, reduce their sensitivity to vasopressors - catecholamines, etc. When using antihypertensive drugs in a heterogeneous population of hypertensive patients, the selectivity of active substances and their other features lead to an unpredictable decrease in BP in each individual patient. For example, the administration of an ACE inhibitor to a patient with RAAS hyperactivation due to renal artery stenosis will lead to a significant decrease in blood pressure and impaired renal function. In turn, the appointment of ACE inhibitors to older people and people of the Negroid race (who in most cases have a reduced level of RAAS activity) will only lead to a slight decrease in blood pressure. Most often, the "phenotype" of hypertension in a particular patient remains unspecified.
A recent meta-analysis of 354 placebo-controlled trials of various antihypertensive monotherapy regimens in specially selected hypertensive patients (n=56,000) showed a mean placebo-adjusted decrease in systolic BP of 9.1 mmHg. and diastolic blood pressure - by 5.5 mm Hg. . These average values hide a wide range of individual reactions to antihypertensive therapy - from a decrease in SBP by 20-30 mm Hg. and until there is no effect, and sometimes even some increase in blood pressure.
The second factor that determines the individual response to antihypertensive monotherapy is the individual differences in BP counterregulation systems activated in response to a decrease in its level. In some cases, such a reaction can completely compensate for the decrease in blood pressure. Thus, the use of antihypertensive monotherapy does not always give a satisfactory result. What should be the next step in such a situation? Should I increase the dose, change the drug, or use a combination of antihypertensive agents?
Rationale for application
combined antihypertensive therapy
The rationale for using combination therapy for hypertension is clear enough. First, in contrast to blindly administered monotherapy, the combination of drugs acting on different systems of blood pressure regulation significantly increases the likelihood of its effective reduction. Secondly, the appointment of a combination of drugs can be regarded as an attempt to block the activation of counterregulatory systems that counteract the decrease in blood pressure during the use of monotherapy (Fig. 1).
Thirdly, a significant part of the population of patients with hypertension suffers from the so-called moderate or severe hypertension (stage 2), this group includes patients with systolic blood pressure over 160 mm Hg. and / or diastolic blood pressure more than 100 mm Hg, which is about 15-20% of all patients with hypertension. These patients are at the highest risk of cardiovascular events. Increase in blood pressure for every 20 mm Hg. doubles the risk of such events.
The risk of hypertension increases with age, and the proportion of patients with stage 2 hypertension also increases. An increase in the proportion of patients with isolated systolic AH, which is the cause of loss of vascular elasticity and an increase in vascular resistance, is also associated with age.
Despite some differences in recommendations, in some of them combination treatment is considered first-line therapy, however, only under certain conditions. Such a place of combination therapy is natural in view of the risks of severe hypertension, the recognition of the inevitability of using dual (and sometimes triple) therapy to achieve target blood pressure values of less than 140/90 mm Hg. and the need to quickly lower blood pressure to a more acceptable level to reduce the risks.
For systolic BP 20 mmHg above target and/or diastolic BP 10 mmHg above target, the US Joint National Committee on the Prevention, Diagnosis, and Treatment of High Blood Pressure (JNC-7) recommends start antihypertensive therapy with a combination of two drugs. Similar recommendations are contained in the latest Russian recommendations, with the recommendation for the use of first-line combination antihypertensive therapy extending to patients with lower BP levels, multiple risk factors, target organ damage, diabetes mellitus, kidney disease, or associated cardiovascular diseases.
There are concerns that the use of more than one antihypertensive drug at the start of treatment may, in some cases, provoke clinically significant hypotension and increase the risk of coronary events. An analysis of studies on the treatment of hypertension has provided some evidence for the existence of a J-shaped relationship between BP reduction and cardiovascular risk, however, apparently, this applies to high-risk patients, including those with known CAD, when a pronounced decrease in BP can lead to poor myocardial perfusion. Patients with uncomplicated hypertension tolerate low blood pressure satisfactorily, as, for example, in the Systolic hypertension in Elderly study (“Systolic hypertension in the elderly”), where in the active treatment group it was possible to reduce systolic blood pressure to 60 mmHg. . Ongoing studies designed to compare initiation of antihypertensive therapy with dual and sequential monotherapy will evaluate the safety of the new approach.
Fourth, compared with monotherapy, combination therapy can achieve a decrease in BP variability. Additional analysis of several randomized trials showed that visit-to-visit systolic BP variability is a strong and independent of mean BP predictor of myocardial infarction and stroke. It is noteworthy that AK and diuretics showed the greatest effectiveness in reducing such variability in blood pressure and the risk of stroke. β-blockers, on the contrary, increased systolic BP variability in a dose-dependent manner and showed the least effectiveness in preventing stroke. The addition of an AA or, to a lesser extent, a diuretic to a RAAS inhibitor reduces systolic BP variability, which is an additional argument in support of combination therapy.
Combinations of drugs
There are 7 classes of antihypertensive drugs, each of which includes several representatives, so there are a large number of combinations (Table 1). Below, combinations will be presented in accordance with their division into rational (preferred), possible (acceptable) and unacceptable or ineffective. The assignment of a combination to one group or another depends on data on outcomes, antihypertensive efficacy, safety and tolerability.
Rational (preferred) combinations
RAAS inhibitors and diuretics. Currently, this combination is most often used in clinical practice. A significant number of factorial design studies have shown additional BP reduction with the combination of TD and ACE inhibitors, ARBs, or PIRs. Diuretics reduce the volume of intravascular fluid, activate the RAAS, which inhibits the excretion of salt and water, and counteracts vasodilation. The addition of a RAAS inhibitor to a diuretic weakens the effect of this counterregulatory mechanism. In addition, the use of a diuretic can cause hypokalemia and impaired glucose tolerance, and RAAS blockers can reduce this undesirable effect. It has been shown that chlorthalidone reduces blood pressure more effectively than hydrochlorothiazide, because. has a longer duration of action, so chlorthalidone should be preferred as the second component in combination with a RAAS inhibitor. Most RAAS inhibitors are available in fixed combination with hydrochlorothiazide.
The Hypertension in the Very Elderly (HYVET) study, which evaluated the efficacy of the thiazide-like diuretic indapamide, was recently completed. ACE inhibitor perindopril was added to this diuretic to enhance the antihypertensive effect in 75% of patients. A 30% reduction in stroke and a 64% reduction in heart failure was shown with this combination compared with placebo.
With the use of a combination of an ACE inhibitor and a diuretic, the EPIGRAPH project was implemented under the auspices of the All-Russian Scientific Society of Cardiology. This project consisted of two multicenter studies - EPIGRAPH-1 and EPIGRAPH-2. This project is valuable in that it contributed to the creation of a non-fixed combination of Enzix (Stada) containing two drugs in one blister - enalapril (ACE inhibitor) and indapamide (diuretic), which allows, if necessary, to change their dosages and correlate the time of administration with the circadian rhythm of blood pressure , have 2 drugs in one package, rather than using two separate ones. The drug is available in three forms: Enziks - 10 mg of enalapril and 2.5 mg of indapamide; Enziks Duo - 10 mg of enalapril and 2.5 mg of indapamide + 10 mg of enalapril; Enziks Duo forte - 20 mg of enalapril and 2.5 mg of indapamide + 20 mg of enalapril. Various dosages make it possible to correct therapy depending on the severity and risk of hypertension, drug tolerance.
In a study conducted in Ukraine, we studied the effect of long-term therapy with a non-fixed combination of enalapril and indapamide in 1 blister (Enzix, Enziks Duo) on the daily blood pressure profile and LV remodeling parameters, its systolic and diastolic function, as well as the quality of life of patients with stable hypertension. The results of the study showed that in patients with hypertension, long-term use of a combination of enalapril and indapamide (Enziks, Enziks Duo) significantly improves the magnitude and speed of the morning rise in blood pressure and positively affects blood pressure variability. Also, the obtained data indicated that long-term use of a non-fixed combination of enalapril and indapamide in 1 blister (Enzix, Enzix Duo) has a distinct antihypertensive effect, leads to a reversal of LV remodeling and improvement of its diastolic function, an increase in the quality of life along with a good safety profile and portability.
RAAS inhibitors and calcium antagonists. Combining AK with an ACE inhibitor, ARB or PIR allows you to achieve an additional reduction in blood pressure. Peripheral edema is a common dose-dependent adverse event observed with monotherapy with dihydropyridine AKs. The severity of this undesirable phenomenon can be weakened by adding a RAAS inhibitor to AK. According to a recent meta-analysis, ACE inhibitors are more effective than ARBs in this regard. According to the results of the ACCOMPLISH study (The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension Trial, Study on the use of combination therapy to prevent cardiovascular events in patients with systolic hypertension), the fixed combination of ACE inhibitor benazepril with AK amlodipine is more effective in reducing morbidity and mortality than the fixed combination of an ACE inhibitor with hydrochlorothiazide. Overall, ACE inhibitors and ARBs showed similar reductions in endpoints, although it has been suggested that ACE inhibitors are slightly more cardioprotective and ARBs are better at protecting against strokes.
The international INVEST study compared two antihypertensive regimens: verapamil, to which trandolapril was added if necessary, and atenolol, to which hydrochlorothiazide was added, if necessary. The study included 22,576 patients with hypertension diagnosed with coronary artery disease, the observation was carried out for 2.7 years. The main composite endpoint, represented by cardiovascular events, was reached in both groups with the same frequency. Apparently, this can be explained by the fact that the disadvantages of the treatment regimen, which included a β-blocker in hypertension, were compensated by the advantages of β-blockers in CAD.
b-blockers and diuretics. Not all experts consider this combination to be rational. At the same time, it has been shown that the addition of diuretics to β-blockers causes an increase in the antihypertensive effect in populations with low-renin AH. Although both classes of drugs have similar side effects in terms of impaired glucose tolerance, development of diabetes mellitus and sexual dysfunction, however, the real clinical significance of "metabolic" side effects is greatly exaggerated, and endpoint studies have shown that the use of such a combination leads to a decrease in cardiovascular morbidity and mortality.
Possible (acceptable) combinations
Calcium channel blockers and diuretics. Most physicians do not always combine AKs with diuretics. However, in the VALUE (Valsartan Antihypertensive Long-term Use Evaluation Trial) study, hydrochlorothiazide was added to amlodipine, when it was not effective enough, and this combination was well tolerated by patients, although the risk of detecting diabetes mellitus and hyperkalemia increased compared with the valsartan group. However, in the amlodipine group, the reduction in morbidity and mortality was not less than in the valsartan group.
Calcium channel blockers and β-blockers. The combination of a β-blocker with dihydropyridine AK has an additional effect on lowering blood pressure and is generally well tolerated. Conversely, β-blockers should not be combined with non-dihydropyridine AKs such as verapamil and diltiazem. The combination of the negative chronotropic effect of both classes of drugs can lead to the development of bradycardia or heart block, up to complete transverse, and death of the patient.
Double blockade of calcium channels. A recent meta-analysis showed that the combination of dihydropyridine AK with verapamil or diltiazem leads to an additional decrease in blood pressure without a significant increase in the frequency of adverse events. Such combination therapy can be used in patients with documented angioedema while taking RAAS inhibitors, as well as in patients with severe renal insufficiency, accompanied by a risk of hyperkalemia. However, data on long-term safety and outcomes against the background of such therapy are currently not available.
Double blockade of the RAAS. The use of this combination is based on an increase in blood pressure-lowering effect, which has been proven in a number of studies. However, the importance of this combination has diminished due to the lack of evidence of safety in long-term studies. In the ONTARGET study, patients receiving combination therapy with telmisartan and ramipril had more adverse events, and the number of cardiovascular events, despite some additional reduction in blood pressure, did not decrease compared with monotherapy. Thus, in such a combination in patients with a high risk of adverse events, there is little point. However, due to the fact that blockade of the RAAS by ACE inhibitors or ARBs increases plasma renin activity, it has been suggested that the addition of a direct renin inhibitor is effective. In a double-blind study of the combination of aliskiren and an ARB conducted in 1797 patients, a small but statistically significant decrease in blood pressure was found. Notably, in an open prospective cross-sectional study of patients with resistant hypertension, the aldosterone antagonist spironolactone was more effective in lowering blood pressure than double RAAS blockade. Use of PIR plus an ACE inhibitor or ARB in the ALTITUDE (Aliskiren Trialin Type 2 Diabetes Using Cardiovascular and Renal Disease End points) study based on 2012 interim analysis proved to be inappropriate due to the increased risk of adverse events, and the study was prematurely terminated. Apparently, it is advisable to transfer combinations of ACE inhibitors with ARBs to the group of non-recommended combinations.
Unacceptable and ineffective combinations
RAAS blockers and β-blockers. The combination of these classes of drugs is often used in patients who have had a myocardial infarction, as well as in patients with heart failure, because. they have been shown to reduce recurrent heart attacks and improve survival. However, this combination does not provide any additional reduction in blood pressure in comparison with monotherapy with these drugs. Thus, it is not reasonable to use a combination of a RAAS inhibitor and a β-blocker for the treatment of hypertension as such.
β-blockers and drugs with a central antiadrenergic effect. Combining β-blockers with centrally acting antiadrenergics such as clonidine provides little or no additional BP reduction. Moreover, when using such a combination, reactions with an excessive increase in blood pressure were even observed.
Other drug classes in combination therapy: α-blockers and spironolactone
α-adrenergic antagonists are widely used as adjunctive therapy to achieve BP targets. The advent of extended-release formulations has improved the tolerability profile of these drugs. Data from an observational analysis from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) showed that doxazosin in the gastrointestinal therapeutic system dosage form, used as a third-line therapy, lowers blood pressure and causes a moderate decrease in serum lipids. In contrast to previous data from the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) study, doxazosin use in the ASCOT study did not show an association with an increase in heart failure.
Therapy consisting of 4 antihypertensive drugs is often required in patients with treatment-resistant drugs at maximum doses or triple antihypertensive therapy, including a RAAS blocker, AK and a thiazide diuretic, AH (failure to achieve target values<140/90 мм рт.ст.). Недавние сообщения свидетельствуют об эффективности добавления спиронолактона к тройной терапии, заключающейся в снижении АД в среднем на 22/9,5 мм рт.ст. Таким образом, спиронолактон может быть рекомендован в качестве компонента антигипертензивной терапии у больных с резистентной АГ.
Undesirable phenomena. There is evidence that the severity of edema associated with the use of dihydropyridine AKs can be reduced when RAAS blockers are added to the treatment, which can also reduce the incidence of hypokalemia caused by TD. On the other hand, the use of β-blockers is associated with an increase in the incidence of diabetes mellitus (DM), and when using a combination of TD with β-blockers, a more significant increase in the frequency of newly diagnosed DM is likely, however, paradoxically, this does not increase the frequency of cardiovascular events associated with such diabetes. -vascular endpoints, as shown in the ALLHAT study. The NICE guidelines provide data from a meta-analysis that found an increase in the incidence of newly diagnosed DM with the use of β-blockers and TD compared with more "newer" drugs.
The findings are based on the assumption that there are no differences in long-term morbidity and mortality between drugs within the same class. Among AKs, amlodipine has the largest evidence base. In studies on the study of ACE inhibitors and ARBs as part of combination therapy in patients with hypertension and other cardiovascular diseases, various representatives of these classes were studied, and no differences were found between them. There is an opinion that among thiazide and thiazide-like diuretics, chlorthalidone at medium doses (compared to other TDs at lower doses) has the greatest evidence base for long-term benefits. Unfortunately, further studies comparing drugs in this class seem unlikely.
The most commonly used β-blocker in studies was atenolol, and it has been repeatedly said that if other members of this class had been used in trials, the results would have been different. This seems unlikely, since Adverse events identified in the ASCOT study, which consisted of an effect on blood pressure variability and an increase in central intra-aortic pressure compared with amlodipine (both are associated with increased cardiovascular risk), most likely occur with most β-blockers. Studies investigating the effect of therapy with β-blockers with additional pharmacological properties (for example, β-1, β-2 and α-blocker carvedilol) on long-term outcomes in patients with hypertension have not been conducted.
Fixed combinations
and their advantages in influencing the prognosis
A recent review of the potential benefits of fixed-dose combinations (FDC) over the corresponding drugs taken alone found that FDC was associated with a significant improvement in adherence and a modest increase in the duration of dosing. The degree of adherence to treatment using FDA, according to a meta-analysis of 9 studies, is higher by 26% compared with taking the same drugs separately.
According to studies containing information on blood pressure values, the use of FDC is associated with a slight additional decrease in systolic and diastolic blood pressure (4.1 and 3.1 mm Hg, respectively). If maintained over a long period of time, these differences in blood pressure can translate into real benefits in cardiovascular outcomes.
Conclusion
Most patients with hypertension require therapy with two or more drugs from different classes of antihypertensive drugs to achieve target BP values. Combination antihypertensive therapy should be given to patients with BP greater than 20/10 mmHg above target. Rational (preferred) and possible (acceptable) drug combinations should be used. Fixed combinations increase adherence to therapy, which increases the frequency of achieving BP targets.
Literature
1. Page I.H. The MOSAIC theory // Hypertension Mechanisms. - New York: Grune and Stratton, 1987. P. 910-923.
2. Mimran A., Ribstein J., Du Cailar G. Converting enzyme inhibitors and renal function in essential and renovascular hypertension // Am. J. Hypertens. 1991 Vol. 4 (Suppl. 1). 7S-14S.
3. Dickerson J.E., Hingorani A.D., Ashby M.J. et al. Optimization of antihypertensive treatment by cross-over rotation of four major classes // Lancet. 1999 Vol. 353. P. 2008-2013.
4. Law M.R., Wald N.J., Morris J.K., Jordan R.E. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomized trials // BMJ. 2003 Vol. 326. P. 1427-1435.
5. Attwood S., Bird R., Burch K. et al. Within-patient correlation between the antihypertensive effects of atenolol, lisinopril and nifedepin // Hypertens. 1994 Vol. 12. P. 1053-1060.
6. Chobanian A.V., Bakris G.L., Black H.R. et al. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh Report of the joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure // Hypertens. 2003 Vol. 42. P. 1206-1252.
7. Russian Medical Society for Arterial Hypertension (RMOAG), All-Russian Scientific Society of Cardiology (VNOK). Diagnosis and treatment of arterial hypertension. Russian recommendations (fourth revision) // Systemic hypertension. - 2010. - No. 3. - C. 5-26.
8. Messerli F.H., Mancia G., Conti C.R. et al. Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with artery disease be dangerous? // Ann. Intern. Med. 2006 Vol. 144. P. 884-894.
9. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP) // JAMA. 1991 Vol. 265. P. 3255-3264.
10. Rothwell P.M., Howard S.C., Dolan E. et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension // Lancet. 2010 Vol. 375. P. 895-905.
11. Nice guidelines. Management of hypertension in adults in primary care. 2007. www.nice.org.uk.
12. Jamerson K., Weber M.A., Bakris G.L. et al. ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients /// NEJM. 2008 Vol. 359. P. 2417-2428.
13. Julius S., Kjeldsen S. E., Brrunner H. et al. VALUE trial. VALUE trial: Long-term blood pressure trends in 13,449 patients with hypertension and high cardiovascular risk // Am. J. Hypertens. 2003 Vol. 7. P. 544-548.
14. Williams B., Lacy P.S., Thom S.M. et al. CAFE Investigators; Anglo-Scandinavian Cardiac Outcomes Trial Investigators; CAFE Steering Committee and Writing Committee. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study // Circulation. 2006 Vol. 113. P. 1213-1225.
15. Makani H., Bangalore S., Romero J. et al. Effect of rennin-angiotensin-system blockade on calcium channel blockers associated peripheral edema // Am. J. Med. 2011 Vol. 124. P. 128-135.
16. Pepine C.J., Handberg E.M., Cooper-DeHoff R.M. et al. INVEST Investigators. A calcium antagonist vs. a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial // JAMA. 2003 Vol. 290. P. 2805-2819.
17. Alviar C.L., Devarapally S., Romero J. et al. Efficacy and Safety of Dual Calcium Channel Blocker Trerapy for the Treatment of Hypertension: A Meta-analysis // ASH. 2010.
18. Alvares-Alvares B. Management of resistant arterial hypertension: role of spironolactone versus double blockade of the rennin-angiotensin-aldosterone syste // J. Hypertens. 2010. Jul 21. .
19. Bailey R.R., Neale T.J. Rapid clonidine withdrawal with blood pressure overshoot exaggerated by beta-blockade // BMJ. 1976 Vol. 6015. P. 942-943.
20. Chapman N., Chang C.L., Dahlof B. et al. For the ASCOT Investigators. Effect of doxazosin gastrointestinal therapeutic system as third-line antihypertensive therapy on blood pressure and lipids in the Anglo-Scandinavian Cardiac Outcomes Trial // Circulation. 2008 Vol. 118. P. 42-48.
21. Chapman N., Dobson J., Wilson S. et al. On behalf of the ASCOT Trial Investigators. Effect of spironolactone on blood pressure in subjects with resistant hypertension // Hypertens. 2007 Vol. 49. P. 839-845.
22. Gupta A.K., Arshad S., Poulter N.R. Compliance, safety and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis // Hypertens. 2010 Vol. 55. P. 399-407.
23. Bangalore S., Kamalakkannan G., Parkar S., Messerli F.H. Fixed-dose combinations improve medication compliance: a meta-analysis // Am. J. Med. 2007 Vol. 120. P. 713-719.
Antihypertensive drugs: principles of therapy, groups, list of representatives
Antihypertensive drugs (antihypertensives) include a wide range of medicines designed to lower blood pressure. Since about the middle of the last century, they began to be produced in large volumes and massively used in patients with hypertension. Until that time, doctors had only recommended diet, lifestyle changes, and sedatives.
Beta-blockers change carbohydrate, fat metabolism, can provoke weight gain, so they are not recommended for diabetes and other metabolic disorders.
Substances with adrenoblocking properties cause bronchospasm and slow heart rate, and therefore they are contraindicated in asthmatics, with severe arrhythmias, in particular, atrioventricular block II-III degree.
Other antihypertensive drugs
In addition to the described groups of pharmacological agents for the treatment of arterial hypertension, additional drugs are also successfully used - imidazoline receptor agonists (moxonidine), direct renin inhibitors (aliskiren), alpha-blockers (prazosin, cardura).
Imidazoline receptor agonists act on the nerve centers in the medulla oblongata, reducing the activity of sympathetic vascular stimulation. Unlike drugs of other groups, which at best do not affect carbohydrate and fat metabolism, moxonidine is able to improve metabolic processes, increase tissue sensitivity to insulin, and reduce triglycerides and fatty acids in the blood. Taking moxonidine in overweight patients promotes weight loss.
Direct renin inhibitors represented by the drug aliskiren. Aliskiren helps to reduce the concentration of renin, angiotensin, angiotensin-converting enzyme in the blood serum, providing hypotensive, as well as cardioprotective and nephroprotective effects. Aliskiren can be combined with calcium antagonists, diuretics, beta-blockers, but the simultaneous use with ACE inhibitors and angiotensin receptor antagonists is fraught with impaired renal function due to the similarity of the pharmacological action.
Alpha blockers are not considered drugs of choice, they are prescribed as part of combination treatment as a third or fourth additional antihypertensive agent. Medicines of this group improve fat and carbohydrate metabolism, increase blood flow in the kidneys, but are contraindicated in diabetic neuropathy.
The pharmaceutical industry does not stand still, scientists are constantly developing new and safe drugs to reduce pressure. Aliskiren (rasilez), olmesartan from the group of angiotensin II receptor antagonists can be considered drugs of the latest generation. Among diuretics, torasemide has proven itself well, which is suitable for long-term use, safe for elderly patients and patients with diabetes mellitus.
Combined preparations are also widely used, including representatives of different groups “in one tablet”, for example, the equator, combining amlodipine and lisinopril.
Folk antihypertensives?
The described drugs have a persistent hypotensive effect, but require long-term use and constant monitoring of the pressure level. Fearing side effects, many hypertensive patients, especially elderly people suffering from other diseases, prefer herbal remedies and traditional medicine to taking pills.
Hypotensive herbs have a right to exist, many really have a good effect, and their action is associated mostly with sedative and vasodilating properties. So, the most popular are hawthorn, motherwort, peppermint, valerian and others.
There are ready-made fees that can be bought in the form of tea bags at a pharmacy. Tea Evalar Bio, containing lemon balm, mint, hawthorn and other herbal ingredients, Traviata is the most famous representatives of herbal antihypertensive drugs. Proved well and. At the initial stage of the disease, it has a general strengthening and calming effect on patients.
Of course, herbal preparations can be effective, especially in emotionally labile subjects, but it should be emphasized that self-treatment of hypertension is unacceptable. If the patient is elderly, suffers from heart disease, diabetes, then the effectiveness of traditional medicine alone is doubtful. In such cases, drug therapy is required.
In order for drug treatment to be more effective, and the dosage of drugs to be minimal, the doctor will advise patients with arterial hypertension to first change their lifestyle. Recommendations include quitting smoking, normalizing weight, and limiting salt, fluid, and alcohol intake. Adequate physical activity and the fight against physical inactivity are important. Non-pharmacological measures to reduce pressure can reduce the need for drugs and increase their effectiveness.
Video: lecture on antihypertensive drugs
What drugs should be prescribed in the selection of antihypertensive therapy in the first place? Science is still developing different methods and approaches, new groups of drugs are being tested. Different doctors may have their own treatment regimen. However, there are general concepts based on statistics and research.
At the initial stage
In uncomplicated cases, drug antihypertensive therapy often begins with the use of proven "conventional" drugs: beta-blockers and diuretics. In large-scale studies involving 48,000 patients, it has been shown that the use of diuretics, beta-blockers reduces the risk of cerebrovascular accident, sudden death, and myocardial infarction.
An alternative option is the use of captopril. According to new data, the incidence of heart attacks, strokes, deaths with conventional treatment or with captopril is almost the same. Moreover, in a special group of patients who have not previously been treated with antihypertensive drugs, captopril shows a clear advantage over conventional therapy, significantly reducing the relative risk of cardiovascular events by 46%.
Long-term use of fosinopril in patients with diabetes, as well as arterial diabetes, is also associated with a significant reduction in the risk of death, myocardial infarction, stroke, exacerbation of angina pectoris.
Therapy for left ventricular hypertrophy
As an antihypertensive therapy, many doctors practice the use of angiotensin-converting enzyme (ACE) inhibitors. These drugs have cardioprotective properties and lead to a decrease in the mass of the LV myocardium (left ventricle). When studying the degree of influence of various drugs on the LV myocardium, it was found that the reverse degree of development of its hypertrophy is most pronounced in ACE inhibitors, since antiotensin-2 controls the growth, hypertrophy of cardiomyocytes and their division. In addition to cardioprotective effects, ACE inhibitors have a nephroprotective effect. This is important, because despite all the successes of antihypertensive therapy, the number of patients who develop terminal renal failure is growing (4 times compared to the "eighties").
Therapy with calcium antagonists
Increasingly, calcium antagonists are being used as first-line drugs. For example, long-acting dihydropyridine calcium channel blockers are effective in isolated systemic arterial hypertension (AH). A four-year study of 5000 patients showed a significant effect of nitrendipine on the incidence of cerebral stroke. In another study, the base drug was a long-acting calcium antagonist, felodipine. 19,000 patients were followed up for four years. As blood pressure (blood pressure) decreased, beneficial effects increased, there was a significant decrease in the risk of developing cardiovascular complications, and the frequency of sudden death did not increase. The "SystEur" study, which involved 10 Russian centers, also showed a 42% reduction in the incidence of strokes when using nisoldipine.
Calcium antagonists are also effective in pulmonary arterial hypertension (this is systemic hypertension that occurs in patients with obstructive pulmonary disease). Pulmonogenic hypertension develops several years after the onset of a pulmonary disease, and there is a clear connection between the exacerbation of the pulmonary process and pressure rises. An advantage of calcium antagonists in pulmonary hypertension is that they reduce calcium-mediated hypoxic vasoconstriction. The delivery of oxygen to tissues increases, hypoxia of the kidneys and vasomotor center decreases, blood pressure decreases, as well as afterload and myocardial oxygen demand. In addition, calcium antagonists reduce the synthesis of histamine, kinin, serotonin in tissues, swelling of the bronchial mucosa and bronchial obstruction. An additional advantage of calcium antagonists (in particular, isradipine) is their ability to change metabolic processes in hypertensive patients. By normalizing or lowering blood pressure, these drugs can prevent the development of dyslipidemia, glucose and insulin tolerance.
Calcium antagonists showed a clear relationship between dose, plasma concentration and pharmacological hypotensive effect. By increasing the dose of the drug, it is possible, as it were, to control the hypotensive effect, increasing or decreasing it. For long-term treatment of hypertension, long-acting drugs with a low absorption rate (amlodipine, a long-acting gastrointestinal form of nifedipine, or osmoadolat, a long-acting form of felodipine) are preferred. When using these drugs, smooth vasodilation occurs without reflex activation of the sympathetic-adrenal system, the release of catecholamines, reflex and increased myocardial oxygen demand.
Myotropic vasodilators, central alpha-2-adrenergic agonists, and peripheral adrenergic agonists are not recommended as first-choice drugs, taking into account tolerability.
