Principles for choosing antihypertensive drugs

Principles for choosing antihypertensive drugs

A.A.
UPNITSKY ,
Russian National Research Medical University named after. N.I. Pirogova, Moscow Arterial hypertension (AH) and its complications are widespread in the population today and carry a high risk of disability and death among the population, mainly of working age (cerebral stroke, myocardial infarction, chronic heart failure, end-stage renal failure, cardiac arrhythmias, etc.) .
At the same time, the effectiveness of blood pressure control in patients with hypertension remains unacceptably low for various reasons. This article presents an attempt to streamline the prescription of antihypertensive drugs by applying a specific algorithm for their prescription, including adequate monitoring of the ongoing antihypertensive therapy. The article uses the latest ESC/ESH-2013 recommendations, as well as the American JNC-8 of December 2013 for the treatment of hypertension (JAMA-2014, December, online). The work provides an original algorithm for choosing antihypertensive therapy, including methods and timing for assessing both the effectiveness and safety of antihypertensive therapy. At the beginning of the article, it is appropriate to provide a classification of arterial hypertension according to blood pressure level ( Table 1

).

Table 1. Classification of arterial hypertension by blood pressure level

Relationship between blood pressure and damage to the cardiovascular system and kidneys

The relationship between blood pressure and cardiovascular and renal complications and mortality has been studied in a large number of observational studies. Their main results are as follows:

1. Office BP is directly associated with the incidence of stroke, myocardial infarction, sudden death, heart failure and peripheral arterial disease (PAD), as well as end-stage renal disease (ESRD). 2. In individuals over 50 years of age, SBP appears to be a better predictor of clinical events than DBP. In elderly and senile people, pulse pressure (the difference between SBP and DBP) plays a possible additional prognostic role. This is also evidenced by a particularly high cardiovascular risk in patients with elevated SBP and normal or low DBP - isolated systolic hypertension (ISAH). 3. Blood pressure values ​​measured outside the office, such as those obtained during ABPM and home blood pressure monitoring (HBP) are also related to clinical events. 4. The relationship between cardiovascular morbidity and mortality varies depending on the presence of other concomitant cardiovascular risk factors listed below.

Risk stratification criteria for arterial hypertension (recommendations of VNOK-2004)

Risk factors

Basic

• Men > 55 years old.
• Women > 65 years old.
• Smoking.
• Cholesterol > 6.5 mmol/L, or low-density lipoprotein cholesterol >.4.0 mmol/L, or high-density lipoprotein cholesterol < 1.0 mmol/L.
• Family history of early CCP (women <65 years, men <55 years).
• AO (OT ≥ 102 cm for men or ≥ 88 cm for women).
• CRP ≥ 1 mg/dl.

Additional

• NTG.
• Low physical activity.
• Increased fibrinogen.

Target organ damage (stage II hypertension) Left ventricular hypertrophy (ECG, echocardiography, radiography).
Microalbuminuria (30-300 mg/day). Ultrasound signs of thickening of the arterial wall (thickness of the intima-media layer of the carotid artery ≥ 0.9 mm) or atherosclerotic plaques of the great vessels. A slight increase in serum creatinine 115-133 µmol/l for men or 107-124 µmol/l for women. Associated clinical conditions (stage III hypertension)

Cerebrovascular diseases

• Ischemic stroke.
• Hemorrhagic stroke.
• Transient ischemic attack

Heart diseases

• Myocardial infarction.
• Angina pectoris.
• Coronary revascularization.
• Congestive heart failure

Kidney diseases

• Diabetic nephropathy.
• Renal failure (creatininemia > 2.0 mg/dL).
• Proteinuria (>300 mg/day).

Peripheral artery diseases

• Dissecting aortic aneurysm.
• Symptomatic peripheral artery disease

Hypertensive retinopathy

• Hemorrhages or exudates.
• Swelling of the optic nerve nipple.

Thus, to reduce cardiovascular risk and prevent the above-mentioned consequences of hypertension, along with a number of non-drug measures (control of body weight, metabolic profile, smoking control, limiting salt intake, cyclic aerobic exercise of sufficient intensity and duration, a full night’s sleep), it is necessary to achieve target blood pressure levels using primarily antihypertensive drugs.
So, how to choose them correctly? Requirements for the treatment of hypertension [1]:

• Smooth decrease in blood pressure.
• Patient compliance.
• Regression of target organ damage.
• Increasing life expectancy and improving its quality.
• Stable maintenance of blood pressure at the target level.

Target blood pressure is the blood pressure level at which the minimum risk of cardiovascular morbidity and mortality is recorded ( Table 2
).

Table 2. Target blood pressure levels

We propose to select antihypertensive drugs according to a certain scheme - an algorithm consisting of three main fundamental stages. The use of such an algorithm should help the doctor treating such patients to achieve maximum effectiveness and at the same time minimize the risk of side effects of the pharmacotherapy.

The first stage of choosing an antihypertensive drug is pathogenetic ( Fig. 1

). In a patient with hypertension, we suggest two steps at this stage. The first is compiling a list of drugs that effectively affect the pathogenesis of the symptom - high blood pressure. In other words, the doctor should try in each specific case to determine which hemodynamic factor “warms up”, so to speak, increased blood pressure [1-3].

Figure 1. Pathogenetic stage of selection of antihypertensive drugs

Selection of drugs depending on the cause of increased pressure

Selection of drugs in accordance with their organoprotective properties

This factor may be, for example, increased cardiac output (in the “hyperkinetic” version of hypertension, as in hyperthyroidism, or in the early stages of hypertension in young and sometimes middle-aged people).
In patients with “experienced” hypertension, cardiac output is extremely rarely increased, and increased peripheral resistance comes to the fore in maintaining elevated blood pressure. First, it is caused by transient increases in peripheral arterial vascular resistance in response to increases in blood pressure (the meaning of this phenomenon is the protection of peripheral organs and tissues from hyperperfusion). Over time, hypertrophy of the middle muscular layer of arterioles—resistance vessels—develops, and increased peripheral resistance is fixed at the organic level. Another component of this “equation” may be an increased circulating blood volume (CBV), the so-called. volume-dependent hypertension. As a rule, these are patients with obesity (there are many small vessels in the adipose tissue with additional blood volume), with swelling or pastiness of the legs, if they are not caused by chronic venous insufficiency.

According to the assessment of the hemodynamic variant of hypertension by the attending physician, in the first case, the list of effective drugs will include those that reduce cardiac output (beta-blockers, centrally acting drugs, “rhythm-slowing” calcium antagonists) [1, 4]

In the second, this will be a list of drugs that reduce total peripheral vascular resistance (TPVR): ACE inhibitors, angiotensin II receptor antagonists of the 1st subtype (sartans), calcium antagonists (all), centrally acting drugs (I1 receptor agonists - rilmenidine, moxonidine etc.), sympatholytics (dopegit), beta-blockers with a vasodilating effect (carvedilol, nebivolol, etc.), long-acting alpha-blockers (doxazosin, terazosin, etc.), diuretics (with regular use for at least 2-3 weeks .). The latter reduce OPSS due to the removal of sodium from the vascular wall, which leads to a decrease in OPSS both by reducing its edema and by reducing its response to vasoconstrictor stimuli.

In the third case, preference will be given to diuretics. It should be remembered that mixed hemodynamic options are possible, and in such cases, drugs are combined [5].

But, given the importance of target organ damage in hypertension and organ protection, the doctor must identify in each patient with hypertension his version of target organ damage: this could be the brain and its vessels (“cerebral” version according to the old classification), the heart - in the form changes in the left sections (hypertrophy or dilatation of the left atrium and ventricle), as well as damage to the coronary arteries with an obvious or latent form of myocardial ischemia (cardiac form of hypertension); kidneys (microalbuminuria); hyperazotemia indicates advanced stages of kidney damage in hypertension. It is also possible to detect changes in the vessels of the retina or arteries of the lower extremities (also often asymptomatic, but detected during a targeted examination).

In accordance with the identified “target” organ (“targets”), the doctor compiles, still at the same first stage, a list of antihypertensive drugs that have appropriate organoprotective properties for hypertension (cardio-, cerebro- or nephroprotective).

ACE inhibitors, angiotensin II receptor antagonists of the 1st subtype (sartans), beta-blockers, calcium antagonists (to varying degrees), indapamide have proven cardioprotective properties; centrally acting antihypertensive drugs have moderate effects [1, 6–8].

Calcium antagonists (nimodipine) have cerebroprotective properties in hypertension, although this issue is not yet completely clear.

Nephroprotective properties in hypertension have been proven for ACE inhibitors, especially with a combination of hypertension and diabetes mellitus, angiotensin II receptor antagonists of the 1st subtype (sartans), as well as calcium antagonists.

Having now compared both lists (“hemodynamic” and “organoprotective”), the doctor should leave in the final list of the 1st stage only those drugs that are present in both lists simultaneously. This will be the final list of the 1st stage - a list of drugs that are effective in this particular case, but not yet taking into account their safety for the patient.

This aspect of drug selection is the subject of the second stage, in which the list of antihypertensive drugs that are effective for a given patient in a given situation, compiled at the first stage, should be considered from a different angle, namely: whether all effective drugs from this list will be safe for this patient. To solve this problem, we must return to the anamnesis (indications in the anamnesis of intolerance or unsatisfactory tolerability of certain drugs, including those related to those prescribed). Next, you should review the list of concomitant diseases in this patient - contraindications to taking certain medications may also be identified here. For example, if you have a history of bronchial asthma, drugs from the group of beta-blockers are contraindicated. These same drugs, with the exception of beta-blockers, which have vasodilating properties, are contraindicated in patients with stenosing atherosclerosis of the arteries of the lower extremities, with intermittent claudication. Beta-blockers are also contraindicated in cases of atrioventricular block above degree I/bradycardia less than 50 per minute. Alpha-blockers are contraindicated in case of concomitant angina pectoris, as they can cause an increase in anginal attacks. Sympatholytics, which have recently been used extremely rarely, are contraindicated in persons with peptic ulcer disease. Calcium antagonists are contraindicated in patients with gastroesophageal reflux disease (GERD) because they cause relaxation of the lower esophageal sphincter and thereby may worsen the symptoms of GERD. Calcium antagonists, primarily verapamil, can significantly aggravate constipation and are therefore contraindicated in this category of patients. Diuretics can increase the level of uric acid in the blood, and therefore hyperuricemia and gout are contraindications for them. For carbohydrate metabolism disorders, the only safe diuretic is indapamide. A number of antihypertensive drugs can have a negative effect on the course and outcome of pregnancy. Therefore, a limited range of antihypertensive drugs is prescribed for it [1, 6, 7]:

• Methyldopa.
• Labetolol.
• Pindolol.
• Oxprenolol.
• Nifedipine SR.
• Hydralazine.
• For kidney disease - diuretics.

Thus, after the 2nd stage of selection, only drugs that are effective and at the same time safe for a patient with hypertension will remain on the list.
The third and final stage of choosing an antihypertensive drug is the stage of individualization of pharmacotherapy.

The first step is to decide what pharmacotherapy is indicated for this patient (mono-or combined). When resolving this issue, one should proceed from the degree of increase in blood pressure and the duration of hypertension. With long-term hypertension, with high numbers, you should start with a combination of antihypertensive drugs from the very beginning. At the same time, rational and irrational combinations of antihypertensive drugs are distinguished ( Fig. 2

).

In cases of mild hypertension, not corrected by non-drug treatment methods (see above), and moderate hypertension, monotherapy is possible in some cases.
However, in the treatment of hypertension there is a rule: combinations of antihypertensive drugs with different mechanisms of action are preferable to high-dose monotherapy. Firstly, in combination, the effect is achieved by influencing different parts of the pathogenesis of hypertension, and secondly, with the right combination, the side effects of the drugs are mutually neutralized. For example, “escape” of the hypotensive effect due to the activation of counter-regulatory mechanisms manifests itself when taking arteriolar vasodilators by increasing cardiac output; when taking all antihypertensive drugs, except diuretics, due to sodium and water retention in the body; when taking diuretics – due to the activation of the body’s neurohormonal systems, in particular the renin-angiotensin-aldosterone system [1, 5, 6]. The choice of method of administration of an antihypertensive drug is determined by the clinical situation: in case of an acute rise in blood pressure, drugs are administered parenterally (intravenously or intramuscularly), as well as sublingually (Capoten, Prazosin, Corinfar, etc.) ( Table 3

). It should be noted that these drugs have a short onset of effect and at the same time a short half-life. That is, they should be used specifically in acute situations, and are much less suitable for long-term use. The fact is that when taking short-acting drugs, there are constant fluctuations in their concentration in the blood, and after them, fluctuations in their hypotensive effect, which is accompanied by significant variability in blood pressure during the day. The latter is an unfavorable factor; in particular, the risk of hypertension complications increases. In addition, when taking the last dose of such a drug, even before bedtime, it still does not prevent the morning rise in blood pressure.

Table 3. Medicines for self-relief of blood pressure rise (according to M.V. Leonova, 2012, as amended)

Here it should be recalled that in case of exacerbation of hypertension, one should try to identify its cause.
In this case, we may encounter the patient’s abuse of table salt, alcohol, taking non-steroidal anti-inflammatory drugs to relieve pain (arthrosis, arthritis, sciatica, headaches, etc.), constant lack of sleep for some reason, non-compliance with the recommended pharmacotherapy (skipping medications). Therefore, long-acting drugs with a long half-life are indicated for continuous maintenance antihypertensive therapy. Another important advantage of drugs with a long duration of action is the possibility of taking them once or twice a day, which helps to increase patient adherence to treatment (according to some data, in the treatment of hypertension during the year it is about 40%). Obviously, this does not mean adequate blood pressure control.

In this regard, the antagonist of angiotensin II receptor subtype 1, candesartan, is of interest; it has the longest half-life of all drugs in this group (more than 24 hours), which makes it possible to achieve blood pressure control also in the morning. In addition, candesartan has advantages over other drugs in cases of combination of hypertension with chronic heart failure, type 2 diabetes mellitus, diabetic nephropathy, proteinuria, and left ventricular myocardial hypertrophy.

To date, the results of 14 placebo-controlled studies with candesartan in 3,377 patients with hypertension are available. Daily doses of the drug ranged from 2 to 32 mg with a follow-up period of 4 to 12 weeks. Baseline blood pressure (diastolic) (DBP) ranged from 95 to 114 mmHg. Art. Within this dosage range, 2,350 patients received active candesartan therapy and 1,027 patients received placebo. In all studies, a significant hypotensive effect of candesartan was noted, which was dose-dependent, i.e., it was more pronounced the higher the dose of candesartan.

From a safety standpoint, the absence of a “first dose effect” was demonstrated, i.e., when taking the first dose of candesartan, there was no sharp decrease in blood pressure. As with other antihypertensive drugs, the hypotensive effect of candesartan increased during the first two weeks and by the end of this period was already clearly expressed. Similar to other antihypertensive drugs, the maximum effect was observed at the end of the 1st month of therapy. Moreover, the hypotensive effect of candesartan did not depend on the age or gender of patients, as well as on race and ethnicity. Of particular note is the good tolerability of candesartan even at a daily dose of 32 mg.

As for the stability of the hypotensive effect, in studies lasting up to one year there was no evidence of the hypotensive effect of candesartan.

Comparative studies of candesartan and losartan in hypertension were also conducted (CANDLE, CLAIM I and II studies, meta-analysis by Zhenfeng Zh, Huillan Shi, Junya Jia et al.), which demonstrated the advantage of candesartan in terms of the severity of blood pressure reduction and its tolerability by patients.

Thus, candesartan has a long-term pronounced hypotensive effect, which depends on the dose of the drug.

The intervals between doses of antihypertensive drugs, with the exception of diuretics, are 2-3 half-lives of the drug and are indicated in the instructions for it. At the same time, one should keep in mind the possibility of reducing the duration of action of antihypertensive drugs when they are accidentally simultaneously prescribed with drugs that are inducers of hepatic metabolism, accelerating the metabolism of antihypertensive drugs in the liver and their excretion from the body. Inducers of hepatic metabolism include, in particular, phenobarbital, other anticonvulsants, rifampicin, etc. In such cases, the intervals between doses of antihypertensive drugs should be reduced [1, 6].

Duration of treatment. With a certain “experience” of hypertension in the body, a “reconfiguration” (“resetting”) of blood vessels, kidneys, brain, and heart occurs to work at elevated blood pressure. In addition, the body retains mechanisms that support hypertension (except for rare cases of surgical treatment of arterial stenosis, removal of adrenal aldosteroma, pheochromocytoma, thyroidectomy and some others). That is why, after normalization and stabilization of blood pressure, antihypertensive therapy should not be stopped. Another thing is that over time, especially in the warm season, it is permissible to reduce the dose and amount of antihypertensive drugs under the control of blood pressure and well-being, provided that all non-drug methods of lowering blood pressure are followed. Criteria for assessing the effectiveness and safety of antihypertensive therapy

To assess the effectiveness, along with assessing the dynamics of the patient’s well-being, office BP measurements should be used, as well as additional methods: 24-hour BP monitoring - ABPM, home measurement (HBP) by the patient.

When measuring office blood pressure, this should be done repeatedly at intervals of 2 minutes, following certain rules. In addition, to assess the safety of antihypertensive therapy, especially alpha-blockers, diuretics, ACE inhibitors and their combinations, blood pressure should be measured in clinostasis (lying down, after 5 minutes) and in orthostasis (after 2 minutes in an upright position). A pronounced decrease in blood pressure in orthostasis (by 20 mm Hg or more) increases the risk of cardiovascular complications and may adversely affect the patient’s well-being.

Additional methods of blood pressure control (ABPM and DMBP) make it possible to avoid unnecessary and unsafe therapy for the patient in the case of “white coat hypertension”, to identify patients with a predominantly nocturnal rise in blood pressure or with an insufficient or excessive decrease in blood pressure at night. The information obtained is valuable for the correct selection and evaluation of antihypertensive therapy [1, 2, 6–8].

To help the practitioner, we provide a list of some fixed combinations of antihypertensive drugs ( Table 4

).

Table 4. Fixed combinations of antihypertensive drugs

In conclusion, we urge all doctors involved in the treatment of hypertension in outpatient and inpatient settings to approach the diagnosis and treatment of patients with hypertension thoughtfully, clearly understanding the sequence of actions for diagnosis and selection of antihypertensive therapy, and we wish them good luck on this thorny path.
BIBLIOGRAPHY

1. Recommendations for the treatment of arterial hypertension. ESH/ESC 2013. Russian Journal of Cardiology, 2014, 1: 5-92. 2. VNOK. Prevention, diagnosis and treatment of arterial hypertension. Russian recommendations (fourth revision). M., 2010. 3. Recommendations of VNOK. Diagnosis and treatment of arterial hypertension. M., 2009: 5-34. 4. Bauchner H, Fontanarosa PB, Golub RM. Updated guidelines for management of high blood pressure: Recommendations, review, and responsibility. JAMA, 2013, December 18. 5. James PA, Oparil S, Carter BL et al. 2014 Evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA, 2013, December 18. 6. Peterson ED, Gaziano JM, Greenland P. Recommendations for treating hypertension: What are the right goals and purposes? JAMA, 2013, December 18. 7. Sox HC. Assessing the trustworthiness of the guideline for management of high blood pressure in adults. JAMA, 2013, December 18. 8. Wood S. JNC 8 at Last! Guidelines Ease Up on BP Thresholds, Drug Choices. Medscape, December 18 (https://www.medscape.com/viewarticle/817991).

Drugs for the treatment of hypertension

Hypertension has many causes, which are explained by breakdowns in different organs and at different levels.

Pharmacologists are trying to find points of influence for each of them, so there are several classes of drugs for the treatment of hypertension. However, they should not always be used together, and some should absolutely not be combined.

Groups of drugs for hypertension

There are five main classes of medications for treating hypertension. Probably the most famous are β-blockers

(propranolol, carvedilol, metaprolol, nebivolol). They reduce the body's sensitivity to adrenaline and norepinephrine - hormones responsible for saving from danger and therefore increasing blood pressure and heart rate. Therefore, when taking β-blockers, blood pressure and heart rate (HR) decrease.