S(–)amlodipine: new possibilities of pharmacotherapy of arterial hypertension. Pharmacological group of the substance Levamlodipine

Gross formula

Pharmacological group of the substance Levamlodipine

CAS code

Model clinical and pharmacological article 1

Pharma action. BMKK, a dihydropyridine derivative, S(-) isomer of amlodipine; has a more pronounced pharmacological effect than R (+) amlodipine. Blocks Ca 2+ channels, inhibits the transmembrane transition of Ca 2+ into the cell (to a greater extent in vascular smooth muscle cells than in cardiomyocytes). It has an antianginal effect, as well as a long-term dose-dependent hypotensive effect. A single dose provides a clinically significant decrease in blood pressure 2-4 hours after administration, which persists for 24 hours (in the supine and standing position).

Pharmacokinetics. The absorption of levamlodipine in the gastrointestinal tract does not change with food intake. Bioavailability - 65%; has a "first pass" effect through the liver. C max - 7.229-9.371 ng / ml, TC max - 1.85-3.61 hours. TCss - 7 days. Communication with proteins - 93%. Distribution volume — 21 l/kg; most of it is distributed in the tissues, the smaller part - in the blood. Penetrates through the BBB. Metabolism is 90% carried out in the liver (slow, but extensive) with the formation of inactive metabolites. The total clearance is 0.116 ml / s / kg (7 ml / min / kg, 0.42 l / h / kg). After the first dose T 1 / 2 - 14.62-68.88 hours, with repeated admission T 1 / 2 - 45 hours. With liver failure T 1 / 2 - 60 hours (long-term use increases the cumulation of the drug). In patients older than 65 years T 1/2 - 65 hours (which has no clinical significance). It is excreted by the kidneys (60% - in the form of metabolites, 10% - unchanged), intestines (20-25%), and also with breast milk. It is not removed by hemodialysis.

Indications. Arterial hypertension I st. (in monotherapy or in combination with other antihypertensive drugs).

Contraindications. Hypersensitivity, Prinzmetal's angina, severe arterial hypotension, collapse, cardiogenic shock, age under 18 years (efficacy and safety not established), pregnancy, lactation.

Carefully. SSSU, chronic heart failure of non-ischemic etiology in the stage of decompensation, moderate arterial hypotension, aortic and mitral stenosis, HOCM, myocardial infarction (and within 1 month after), diabetes mellitus, lipid metabolism disorders, liver failure, old age.

Dosing. Inside, the initial dose is 2.5 mg 1 time per day, the maximum dose is 5 mg 1 time per day.

Side effect. From the side of the cardiovascular system: palpitations, shortness of breath, a marked decrease in blood pressure, fainting, vasculitis, swelling of the lower extremities, "flushing" of blood to the skin of the face, rarely - arrhythmia (bradycardia, ventricular tachycardia, atrial fibrillation), chest pain, orthostatic hypotension, very rarely - the development or aggravation of heart failure, migraine.

From the nervous system: dizziness, headache, fatigue, drowsiness, emotional lability; rarely - convulsions, loss of consciousness, hyperesthesia, nervousness, paresthesia, tremor, vertigo, asthenia, malaise, insomnia, depression, unusual dreams; very rarely - ataxia, apathy, agitation, amnesia.

From the digestive system: nausea, vomiting, epigastric pain; rarely - increased activity of "liver" enzymes and jaundice (due to cholestasis), pancreatitis, dry mouth, flatulence, hyperplasia of the gum mucosa, constipation or diarrhea; very rarely - gastritis, increased appetite.

From the genitourinary system: rarely - pollakiuria, painful urge to urinate, nocturia, decreased potency; very rarely - dysuria, polyuria.

On the part of the skin: very rarely - xeroderma, alopecia, dermatitis, purpura, discoloration of the skin.

Allergic reactions: maculopapular erythematous rash, urticaria, pruritus, angioedema.

From the musculoskeletal system: rarely - arthralgia, arthrosis, myalgia (with prolonged use); very rarely - myasthenia gravis.

From the sensory organs: visual impairment, conjunctivitis, diplopia, eye pain, accommodation disorder, xerophthalmia; tinnitus, taste disturbance, rhinitis, parosmia.

Others: rarely - gynecomastia, hyperuricemia, weight gain / decrease, thrombocytopenia, leukopenia, hyperglycemia, back pain, dyspnea, epistaxis, hyperhidrosis, thirst; very rarely - cold sticky sweat, cough.

Overdose. Symptoms: pronounced decrease in blood pressure, tachycardia, excessive peripheral vasodilation.

Treatment: gastric lavage, activated charcoal, control of CCC functions, respiratory and excretory systems, BCC. It is necessary to give the patient a horizontal position with raised limbs; vasoconstrictor drugs (in the absence of contraindications); in / in calcium gluconate (to eliminate the blockade of Ca 2+ channels).

Interaction. Inhibitors of microsomal oxidation increase the concentration of the drug in blood plasma, increasing the risk of side effects, and inducers of microsomal liver enzymes reduce it.

Alpha-agonists, estrogens (Na + retention), sympathomimetics weaken the hypotensive effect.

Thiazide and "loop" diuretics, beta-blockers, verapamil, ACE inhibitors, nitrates enhance antianginal and hypotensive effects.

Amiodarone, quinidine, alpha-blockers, antipsychotics, BMCC may enhance the hypotensive effect.

Li + drugs - the risk of increased neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus).

Ca 2+ preparations can reduce the effect of BMCC.

Procainamide, quinidine and other drugs that prolong the QT interval enhance the negative inotropic effect and increase the risk of a significant prolongation of the QT interval.

Special instructions. During the treatment period, it is necessary to control body weight, Na + intake (an appropriate diet), observe dental hygiene, visit a dentist (to prevent soreness, bleeding and hyperplasia of the gum mucosa).

In elderly patients, T 1/2 and drug clearance are prolonged, therefore, careful monitoring is necessary when increasing the dose.

Despite the absence of a “withdrawal” syndrome in BMCC, a gradual reduction in doses is recommended before stopping treatment.

During the period of treatment, care must be taken when driving vehicles and engaging in potentially hazardous activities that require an increased concentration of attention and speed of psychomotor reactions.

State register of medicines. Official publication: in 2 volumes - M .: Medical Council, 2009. - V.2, part 1 - 568 p.; part 2 - 560 p.

Levamlodipine INN

International name: Levamlodipine

Dosage form: tablets

Pharmachologic effect:

BMKK, a derivative of dihydropyridine, S (-) isomer of amlodipine; has a more pronounced pharmacological effect than R (+) amlodipine. Blocks Ca2+ channels, inhibits the transmembrane transition of Ca2+ into the cell (to a greater extent into vascular smooth muscle cells than into cardiomyocytes). It has an antianginal effect, as well as a long-term dose-dependent hypotensive effect. A single dose provides a clinically significant decrease in blood pressure after 2-4 hours after administration, which persists for 24 hours (in the supine and standing position).

Pharmacokinetics:

The absorption of levamlodipine in the gastrointestinal tract does not change with food intake. Bioavailability - 65%; has an effect through the liver. Cmax - 7.229-9.371 ng / ml, TCmax - 1.85-3.61 h. TCss - 7 days. Communication with proteins - 93%. Distribution volume - 21 l/kg; most of it is distributed in the tissues, the smaller - in the blood. Penetrates through the BBB. Metabolism is 90% carried out in the liver (slow, but extensive) with the formation of inactive metabolites. The total clearance is 0.116 ml / s / kg (7 ml / min / kg, 0.42 l / h / kg). After the first dose T1 / 2 - 14.62-68.88 hours, with repeated administration T1 / 2 - 45 hours. With liver failure T1 / 2 - 60 hours (long-term use increases the cumulation of the drug). In patients older than 65 years, T1 / 2 is 65 hours (which has no clinical significance). It is excreted by the kidneys (60% - in the form of metabolites, 10% - unchanged), intestines (20-25%), and also with breast milk. It is not removed by hemodialysis.

Indications:

Arterial hypertension I st. (in monotherapy or in combination with other antihypertensive drugs).

Contraindications:

Hypersensitivity, Prinzmetal's angina, severe arterial hypotension, collapse, cardiogenic shock, age up to 18 years (efficacy and safety have not been established), pregnancy, lactation. With caution. SSSU, chronic heart failure of non-ischemic etiology in the stage of decompensation, moderate arterial hypotension, aortic and mitral stenosis, HOCM, myocardial infarction (and within 1 month after), diabetes mellitus, lipid metabolism disorders, liver failure, old age.

Dosing regimen:

Inside, the initial dose is 2.5 mg 1 time per day, the maximum dose is 5 mg 1 time per day.

Side effects:

From the side of the cardiovascular system: palpitations, shortness of breath, marked decrease in blood pressure, fainting, vasculitis, edema of the lower extremities, blood to the skin of the face, rarely - arrhythmia (bradycardia, ventricular tachycardia, atrial fibrillation), chest pain, orthostatic hypotension, very rarely - development or exacerbation of heart failure, migraine. From the nervous system: dizziness, headache, fatigue, drowsiness, emotional lability; rarely - convulsions, loss of consciousness, hyperesthesia, nervousness, paresthesia, tremor, vertigo, asthenia, malaise, insomnia, depression, unusual dreams; very rarely - ataxia, apathy, agitation, amnesia. From the digestive system: nausea, vomiting, epigastric pain; rarely - increased activity of enzymes and jaundice (due to cholestasis), pancreatitis, dry mouth, flatulence, hyperplasia of the gum mucosa, constipation or diarrhea; very rarely - gastritis, increased appetite. From the genitourinary system: rarely - pollakiuria, painful urge to urinate, nocturia, decreased potency; very rarely - dysuria, polyuria. On the part of the skin: very rarely - xeroderma, alopecia, dermatitis, purpura, discoloration of the skin. Allergic reactions: maculopapular erythematous rash, urticaria, pruritus, angioedema. From the musculoskeletal system: rarely - arthralgia, arthrosis, myalgia (with prolonged use); very rarely - myasthenia gravis. From the sensory organs: visual impairment, conjunctivitis, diplopia, eye pain, accommodation disorder, xerophthalmia; tinnitus, taste disturbance, rhinitis, parosmia. Others: rarely - gynecomastia, hyperuricemia, weight gain / decrease, thrombocytopenia, leukopenia, hyperglycemia, back pain, dyspnea, epistaxis, hyperhidrosis, thirst; very rarely - cold sticky sweat, cough. Overdose. Symptoms: pronounced decrease in blood pressure, tachycardia, excessive peripheral vasodilation. Treatment: gastric lavage, activated charcoal, control of the functions of the cardiovascular system, respiratory and excretory systems, BCC. It is necessary to give the patient a horizontal position with raised limbs; vasoconstrictor drugs (in the absence of contraindications); in / in calcium gluconate (to eliminate the blockade of Ca2 + channels).

Special instructions:

During the treatment period, it is necessary to control body weight, Na + intake (an appropriate diet), observe dental hygiene, visit a dentist (to prevent soreness, bleeding and hyperplasia of the gum mucosa). In elderly patients, T1 / 2 and clearance of the drug are prolonged, therefore, careful monitoring is necessary when increasing the dose. Despite the absence of BMCC syndrome, a gradual reduction in doses is recommended before stopping treatment. During the period of treatment, care must be taken when driving vehicles and engaging in potentially hazardous activities that require an increased concentration of attention and speed of psychomotor reactions.

Interaction:

Inhibitors of microsomal oxidation increase the concentration of the drug in blood plasma, increasing the risk of side effects, and inducers of microsomal liver enzymes reduce it. Alpha-agonists, estrogens (Na + retention), sympathomimetics weaken the hypotensive effect. Thiazide and diuretics, beta-blockers, verapamil, ACE inhibitors, nitrates enhance antianginal and hypotensive effects. Amiodarone, quinidine, alpha-blockers, antipsychotics, BMCC may enhance the hypotensive effect. Li + preparations - the risk of increased neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus). Ca2+ preparations can reduce the effect of BMCC. Procainamide, quinidine, and other drugs that prolong the QT interval increase the negative inotropic effect and increase the risk of a significant prolongation of the QT interval.

For citation: Baryshnikova G.A. Possibilities of amlodipine isomer in the treatment of arterial hypertension // BC. 2009. No. 7. S. 431

Despite recent advances in the treatment of cardiovascular disease (CVD), they continue to be the leading cause of death. Arterial hypertension (AH) is the most important risk factor for CVD due to its high prevalence (more than 40 million people suffer from hypertension in Russia) and insufficient effectiveness of the therapy. Epidemiological studies show that even with a slight increase in blood pressure (BP), the risk of stroke, myocardial infarction, heart failure, and cardiovascular death increases.

For many years, calcium antagonists (AK) are among the main 5 groups of antihypertensive drugs (ACE inhibitors, angiotensin II receptor blockers, AK, b-blockers, diuretics). AC both chemically and pharmacologically are a heterogeneous group of drugs. There are verapamil with diltiazem (pulse-lowering AKs) and a large group of dihydropyridine AKs, many of which (but not amlodipine!) Can increase heart rate. All AK, being peripheral vasodilators (to a greater extent - dihydropyridine, to a lesser extent - verapamil and diltiazem), affect the main pathophysiological mechanism of arterial hypertension - increased total peripheral vascular resistance.

Along with a powerful hypotensive effect, AKs have an organoprotective (primarily cardio- and angioprotective) effect, reduce the severity of left ventricular hypertrophy (LVH), prevent the progression of atherosclerosis, do not adversely affect the level of electrolytes, carbohydrate, lipid and purine types of metabolism, reduce bronchial hyperreactivity . According to the Russian recommendations "Diagnosis and treatment of arterial hypertension" (third revision) of the Committee of Experts of the VNOK (2008), the main indications for the use of dihydropyridine AKs in hypertension are: ISAH (elderly), coronary artery disease, LVH, atherosclerosis of the carotid and coronary arteries, pregnancy ( Fig. 1). In a number of situations, AK is prescribed due to the presence of contraindications to the use of other drugs. So, for example, AK can be prescribed for obstructive pulmonary diseases, intermittent claudication, type 1 diabetes mellitus, when taking b-blockers is contraindicated or undesirable. AKs do not cause metabolic disorders: they do not affect blood sugar levels (like diuretics), the level of potassium in the blood (like diuretics and ACE inhibitors), and the level of uric acid (like diuretics). AKs do not cause impotence (like b-blockers and diuretics) or cough (like ACE inhibitors).

Due to high efficiency and a small range of contraindications to their prescription (there are no absolute contraindications to the use of dihydropyridine AAs), AA quickly gained popularity among doctors and patients and by the mid-1990s became one of the most commonly prescribed drugs in cardiology for hypertension. However, at the same time, discussions began about the safety of long-term use of AKs, the reason for which was the data on the ability of short-acting dihydropyridine AKs to adversely affect the outcome of the disease in patients with unstable angina and acute myocardial infarction. It was soon shown that short-acting and long-acting AAs prescribed for the treatment of hypertension have different effects on the risk of myocardial infarction (Fig. 2). An analysis was published in the Lancet in 2000, which showed that long-term use of long-acting AAs in patients with hypertension is not only safe, but also leads to a significant decrease in the likelihood of stroke and complications of coronary artery disease. Currently, according to the well-known classification of AK T. Toyo-Oka, W.G. Nayler, 1996 (Table 1) all AKs are divided into 3 generations. The first generation includes AK - the ancestors (verapamil, diltiazem, nifedipine), all of them are short-acting and are not recommended for the treatment of hypertension (the use is possible only in urgent situations, for example, to stop a hypertensive crisis). According to this classification, amlodipine belongs to the III generation of AK.

Amlodipine is one of the most commonly prescribed drugs from the group of dihydropyridine AKs, successfully used for the treatment of hypertension. Like other dihydropyridine AKs, amlodipine does not affect the function of the sinus node and atrioventricular conduction, increases coronary blood flow, reduces myocardial oxygen demand, providing an anti-ischemic and antianginal effect. Among other AKs, amlodipine has unique pharmacokinetic properties (Table 2): the longest half-life (35-50 hours) and volume of distribution (21 l/kg body weight), which ensures the duration of the hypotensive and antianginal effects of the drug. Of great clinical importance is such a pharmacokinetic parameter as the time to reach the maximum concentration in blood plasma, which determines the rate of development of the therapeutic effect. This time after oral administration of amlodipine is from 6 to 12 hours, which guarantees the gradual development of a vasodilating effect without a pronounced reflex increase in the activity of the sympathetic-adrenal system, characteristic of the short-acting form of nifedipine, with the development of sinus tachycardia and other side effects characteristic of the rapid vasodilating effect ( headache, dizziness, palpitations, transient hypotension). In case of accidental skipping of the next dose of amlodipine, there is no withdrawal syndrome in the form of a pronounced rise in blood pressure, which once again proves the safety of therapy with this drug.

Amlodipine is one of the most well-studied AKs in terms of evidence-based medicine. In numerous controlled studies on long-term treatment of hypertension, as a rule, amlodipine was used as the AK. In the TOMHS study in patients with mild hypertension (I degree of BP increase), the effectiveness of representatives of the main classes of antihypertensive drugs (amlodipine, enalapril, chlorthalidone, acebutolol, doxazosin) and placebo were compared. Amlodipine demonstrated the same efficacy as β-blockers, diuretics, ACE inhibitors and α-blockers, and the decrease in DBP in the group of patients treated with amlodipine was the greatest.

In the ALLHAT study, in which for 6 years more than 42,000 patients studied the effect of AK, ACE inhibitor, diuretics and α-blockers on the likelihood of complications of hypertension, amlodipine was also chosen as a calcium antagonist. In this study, it was demonstrated that amlodipine was no different from chlorthalidone in terms of overall mortality, the incidence of coronary artery disease and its complications, cerebral stroke, although in terms of the incidence of heart failure, amlodipine was inferior to chlorthalidone.

The VALUE study, which lasted about 4 years, included 15,245 hypertensive patients older than 50 years who had an increased risk of cardiovascular complications. Half of the patients included in the study received the angiotensin II receptor antagonist valsartan 80–160 mg/day as the main antihypertensive drug, and half received amlodipine 5–10 mg/day. It was assumed that with the same decrease in blood pressure, valsartan would be more effective in preventing complications of hypertension, however, the incidence of cardiovascular complications during therapy with valsartan and amlodipine was almost the same (10.6 and 10.4%, respectively). The incidence of stroke was lower in the amlodipine group. It should be noted that in the first months of treatment, the hypotensive effect of amlodipine was more pronounced.

In the PREVENT and CAMELOT studies, the ability of amlodipine to slow down the progression of atherosclerosis in the carotid and coronary arteries was proven, which is important when prescribing it to patients with hypertension and concomitant coronary artery disease.

The ASCOT-BPLA, multicentre, randomized, controlled trial compared the effects of two therapeutic strategies on CV events in 19,257 patients with hypertension and three or more CV risk factors. In this study, patients with hypertension aged 40-79 years were divided into two groups. Patients of the first group (n=9639) received amlodipine 5-10 mg/day, to which, if necessary, perindopril was added at a dose of 4-8 mg/day; patients of the second group (n=9618) were prescribed atenolol 50-100 mg/day, to which, if necessary, the thiazide diuretic bendroflumethiazide 1.25-2.5 mg/day was added. The duration of the study was 5.5 years. The endpoints were non-fatal myocardial infarction and cardiovascular death. Amlodipine-based therapy resulted in significant reductions in fatal and nonfatal stroke, overall cardiovascular outcomes or revascularization procedures, and overall mortality. Along with this, in the amlodipine group, a decrease in the incidence of new cases of diabetes mellitus and renal failure was noted. It was concluded that the identified differences in the frequency of secondary endpoints cannot be explained only by the difference in the level of blood pressure (systolic blood pressure in the amlodipine group was lower by 2.7 mm Hg, diastolic blood pressure - by 1.9 mm Hg . compared with the atenolol group), but are determined by the additional properties of amlodipine (effect on endothelial function, anti-atherosclerotic effect, metabolic neutrality, etc.).

In recent years, a new promising direction in modern cardiology has been actively developing - the targeted clinical use of pure chiral forms of drugs. It has long been known about the existence of stereoisomerism, or chirality, when a molecule exists in two structurally identical forms (stereoisomers), which are mirror images of each other, which, however, cannot be superimposed on each other with spatial orientation in the same plane. Each of the two stereoisomers of a chiral molecule is called an enantiomer, or isomer. Enantiomers are subdivided into R and S varieties depending on whether they deflect the plane of the polarized beam to the right (clockwise) or to the left (counterclockwise). According to traditional technology, most drugs are obtained in the form of undivided chiral molecules, that is, a mixture of their left-handed and right-handed enantiomers in a 1:1 ratio (racemic mixture, or racemate). Optical isomers (enantiomers) of a racemic drug, despite the same composition and sequence of chemical bonds of atoms, may differ in pharmacokinetic and pharmacodynamic properties. With the development of experimental and clinical pharmacology, data have been obtained on the different roles of the R- and S-enantiomers of many racemate drugs used in practice in the implementation of both their beneficial and undesirable effects. In this regard, obtaining pure optical isomers has become a very urgent chemical and technological problem, and the clinical use of chiral molecules is proposed to be considered as a new direction in pharmacotherapy. A new impetus to the development of the "chiral" direction in clinical medicine was given by the development of W. Noles, R. Noyori and B. Charpless of a progressive technology for the separation of optical stereoisomers (Nobel Prize in Chemistry for 2001).

It has been established that amlodipine is also a racemic compound and consists of two isomers (S and R). The study of amlodipine showed that attachment to dihydropyridine receptors is stereoselective (Fig. 3) and binding to the S-isomer is 1000 times stronger than to the R-isomer. It was found that it is the S-isomer of amlodipine that has a vasodilating effect, i.e. has more pharmacological activity. It is clear that the use of the pure levorotatory pharmacologically active S-isomer of amlodipine instead of the racemic mixture has important advantages, as in this case, the dose and, accordingly, the risk of side effects can be reduced. It also turned out that the active S-form differs from the inactive R-form by a longer half-life (49.6 hours versus 34.9 hours). As a factor predisposing to greater safety of treatment with the pure S-isomer of amlodipine, the significant circumstance that its clearance is subject to less individual variations than the clearance of the R-isomer is also considered.

In order to study the clinical efficacy, safety and tolerability of S (-) amlodipine, a number of clinical studies have been conducted. One of the largest studies is the SESA (Safety and Efficacy of S-Amlodipine) multicenter study, the purpose of which was to evaluate the efficacy and tolerability of S (-) amlodipine in the treatment of essential hypertension. The study included 1859 patients with hypertension, the patients were divided into 2 groups receiving S(-)amlodipine 2.5 or 5 mg/day. within 4 weeks. In this study, it was proved that the hypotensive effect of S (-) amlodipine is largely dose-dependent (Fig. 4). As part of the SESA study, an analysis of the efficacy and safety of S (-) amlodipine in the treatment of isolated systolic hypertension (ISAH) was conducted - the MICRO-SESA-1 study. In the SESA database, 90 patients with ISAH were identified, with a mean age of 54.6±12.5 years. All patients received S(-)amlodipine 2.5-5 mg for 4 weeks. S(-)amlo-dipine significantly reduced systolic blood pressure (SBP). The average decrease in SBP compared with baseline was 21.5±13.9 mm Hg. The frequency of "response" to treatment was 73.3%. None of the patients experienced lower extremity edema or other adverse events. Of the 90 patients, 82 received S(-)amlodipine at a dose of 2.5 mg once daily, and only 8 patients required an increase in dose to 5 mg. In this way, S(-)amlo-dipine is a safe and effective drug for the treatment of ISAH. Moreover, in older patients, compared with younger patients, there is a more pronounced decrease in SBP compared to the initial level. These data are especially important given the fact that ISAH prevails in elderly people with hypertension (more than 50%), and the risk of cardiovascular complications increases significantly with an increase in pulse rate. An additional analysis in the SESA study was performed to determine the safety and efficacy of S(-) amlodipine in the treatment of hypertension in 339 elderly patients (mean age 70.4 ± 5.7) overall - MICRO-SESA II. After 4 weeks from the start of taking S (-) amlodipine at a dose of 2.5-5 mg once a day, the average decrease in SBP was 37.8 ± 19.6, DBP - 17.8 ± 12.2 mm Hg. (p<0,001). Доля «ответчиков» составила 96,46%. У 33 пациентов с сопутствующим сахарным диабетом удалось добиться более выраженного снижения САД (41,1±21,4 мм рт.ст.; p<0,0001) и ДАД (24,1±18,8 мм рт.ст.; p<0,0001). Как хорошо известно, жесткий контроль над уровнем АД у пациентов с СД обеспечивает дополнительное значительное снижение риска сердечно-сосудистых осложнений. Таким образом, S(-) amlodipine is a safe and effective drug for the treatment of hypertension in elderly patients, including those with diabetes..

It should be noted that the SESA study included 314 patients who had previously developed edema while taking racemic amlodipine. After switching them to S (-) amlodipine, edema remained only in 4 patients, i.e. compared with racemic amlodipine, a decrease in the development of edema by 98.7% was found (Fig. 5). The same results were obtained in another clinical study in which the replacement of racemate amlodipine (5 mg/day) in 256 patients with S(-)amlodipine (2.5 mg/day) caused the disappearance of previously detected edema in 252 (98 .43%) of patients. Such a striking effect on peripheral edema is associated with the absence of a vasodilating effect of S (-) amlodipine on precapillaries, and it is known that it is the expansion of precapillaries without a corresponding expansion of postcapillaries that leads to an increase in hydrostatic pressure with the appearance of peripheral edema. The frequent development of pretibial edema against the background of racemic amlodipine is also associated with the formation of nitric oxide under the influence of R-amlodipine, which enhances the dilatation of precapillaries.

It has been established that excessive dilatation of the precapillary-arteriolar link of the vessels of the lower extremities, due to excessive formation of NO, levels the implementation of an important physiological mechanism that prevents the development of edema of the tissues of the lower extremities when the body is in a vertical position - the so-called precapillary postural vasoconstrictor reflex.

In general, only 1.61% of patients developed side effects that were mild and did not require discontinuation of the drug. Thus, S(-)amlodipine at doses of 2.5 mg and 5 mg is an effective drug for the treatment of hypertension with the additional advantage of significantly fewer adverse events (primarily edema of the lower extremities). S(-) amlodipine was well tolerated by elderly and senile patients; in this age group, dose adjustment of S(-) amlodipine was not required.

In Russia, there is also experience in the use of S(-)amlo-dipine. Thus, in a randomized comparative clinical trial performed on the basis of the Federal State Institution of the State Research Center for Preventive Medicine under the guidance of Acad. RAMS, professor R.G. Oganov, the advantage of S(-)amlodipine at a dose of 2.5 mg was confirmed compared to the original preparation containing racemic amlodipine at a dose of 5 mg. The study included 36 patients with moderate and mild hypertension, of whom one group received 2.5 mg of S (-) amlodipine for 8 weeks, the second (control) group received 5 mg of racemic amlodipine. After 4 weeks of therapy, it was noted that S (-) amlodipine 2.5 mg more effectively reduces blood pressure than racemic amlodipine 5 mg (Fig. 4), and after 8 weeks of therapy, the hypotensive effect of S (-) amlodipine 2.5 mg and racemic amlodipine 5 mg proved to be comparable (Figure 6). Greater safety of the use of S (-) am-lo-di-pin was also noted.

It was shown that when taking 2.5 mg of S (-) amlodipine once a day and 5 mg of racemic amlodipine in the blood, the same maximum equilibrium concentration is created. S (-) amlodipine is well tolerated by patients. Monotherapy with S (-) amlodipine does not cause activation of the sympathetic-adrenal system, no effect on carbohydrate and lipid metabolism was found (sugar and total cholesterol levels do not change). There was no increase in the level of creatinine in the blood, which makes it possible to prescribe this drug in the treatment of hypertension in patients with diabetes mellitus, atherogenic dyslipidemia, and renal failure. Compared with racemic amlodipine, S(-) amlodipine has a more pronounced antihypertensive effect after 4 weeks of use with a minimal risk of developing peripheral edema. The latter is extremely important, since pretibial edema is the most common side effect of amlodipine, sometimes forcing patients to refuse to use it. For example, in the ASCOT-BPLA study, peripheral edema was almost 4 times more common in the amlodipine (racemic) group than in the atenolol group (23% vs. 6%, p<0,0001), хотя не следует забывать, что к атенололу у большинства больных добавляли тиазидный диуретик. S(-)амлодипин метаболически нейтрален, благодаря хорошей переносимости обеспечивает высокую приверженность к лечению.

For citation: Arsenyeva K.E. S(–)amlodipine: new possibilities of pharmacotherapy of arterial hypertension // BC. 2008. No. 21. S. 1466

Cardiovascular disease is now responsible for one in three deaths worldwide, and the WHO predicts this will increase to 37% by 2020. The leading place among this pathology belongs to arterial hypertension. According to epidemiological studies, between 450 and 900 million people suffer from hypertension among the world's population and more than 3 million die annually from complications of hypertension, which takes this pathology beyond the scope of a purely cardiological problem, giving it a multidisciplinary character. According to statistics, more than 40 million patients in Russia suffer from hypertension, more than 39% of men and 41% of women have elevated blood pressure.

As the results of numerous epidemiological studies and their meta-analyses have shown, elevated blood pressure, both diastolic and systolic, is associated with an increased risk of stroke, all forms of coronary artery disease, chronic heart failure, chronic renal failure, aortic dissection and other lesions of the extracardiac arteries and is associated with an increase in cardiovascular - vascular mortality. Moreover, this relationship is linear, starting from the level of blood pressure 110/70 mm Hg. . Therefore, the main goal of treating a patient with hypertension is to reduce the overall risk of cardiovascular morbidity and mortality. Along with achieving target levels of blood pressure, the main task of the doctor today is to influence all risk factors and treat comorbidities.
Calcium antagonists are widely used in the treatment of hypertension. These drugs are a chemically and pharmacologically heterogeneous group of drugs that act by regulating the entry of Ca2+ ions through the cell membrane. At the cellular level, calcium antagonists act primarily by inhibiting the entry of calcium ions Ca2+ through voltage-sensitive calcium channels. This effect is responsible for the ability of calcium antagonists to reduce SBP and DBP, contributes to their antiatherogenic and cardioprotective properties. The advantages of long-term use of calcium antagonists are the reduction of hypertension-induced hypertrophy of the vascular wall and left ventricular hypertrophy with an improvement in its diastolic function. Thus, the cardio- and vasoprotective properties of calcium antagonists are due to the ability to reduce the concentration of Ca2+ ions in the cell cytoplasm. L-type calcium channels are responsible for the depolarization-induced entry of Ca2+ ions into many cells and therefore play a major role in triggering cardiac and smooth muscle contraction. Due to this property, the clinically important classes of calcium channel blockers 1,4-dihydropyridine, phenylalkylamine and benzodiazepine have become powerful drugs for the treatment of hypertension. Due to their high concentration in lipid membranes, longer duration of action and slow onset of action, dihydropyridine calcium channel blockers are the most preferred for the treatment of hypertension.
Amlodipine belongs to the group of dihydropyridine calcium channel blockers that can be used to treat cardiovascular disease. Amlodipine is one of the most acceptable drugs from the group of calcium antagonists for the treatment of hypertension. The drug does not change the heart rate, does not affect the function of the sinus node and atrioventricular conduction, increases cardiac output and coronary blood flow, has a distinct peripheral vasodilation, reduces myocardial oxygen demand, improves myocardial diastolic function. Amlodipine has proven itself in the treatment of hypertension in the elderly, successfully performing the task of lowering systolic blood pressure and maintaining diastolic blood pressure at a level of at least 70 mm Hg. Due to the prolonged half-life of amlodipine, the missed dose is not significant, which is considered safer in comparison with short-acting drugs of this class. In the dose range of 2.5-10 mg per day, amlodipine causes a significant decrease in blood pressure. It has been shown to be effective in reducing both symptomatic and asymptomatic episodes of ischemia in patients with stable angina when taken with other antihypertensive drugs. Due to the gradual onset of action and long half-life, amlodipine does not cause reflex tachycardia or its manifestations are insignificant. Also one of the important advantages is the absence of withdrawal syndrome. One possible side effect of amlodipine is peripheral edema.
Amlodipine is a racemic compound with an equal proportion of the two isomers (S and R). S(-)amlo-dipine is responsible for all pharmacodynamic actions mediated by calcium channel blocking, including antianginal action. Optical isomers (enantiomers) of a racemic drug have the same composition and sequence of chemical bonds of atoms, but can have both different pharmacological properties and different pharmacokinetic and pharmacodynamic effects. Studies have shown that only the S (-) isomer has a vasodilating effect. The study of amlodipine showed that attachment to dihydropyridine receptors is stereoselective and the binding to the S (-) isomer was 1000 times stronger than with the R (+) isomer. The stereoselectivity of receptors for S(-) and R(+) isomers explains the differences in clearance, bioavailability and clinical activity of the drug. The use of the pure levorotatory pharmacologically active S(-) isomer of amlodipine instead of the racemic mixture has important advantages because the required dose and systemic toxicity can be reduced. It was found that the S (-) isomer of amlodipine has a greater pharmacological activity. The oral clearance of the active S-form appeared to be subject to much less variation between patients than for the inactive R(+) form. R (+) amlodipine was much more rapidly removed from plasma than S (-) amlodipine, with mean terminal half-lives of 34.9 h (R) and 49.6 h (S). It has been suggested that the observed enantioselectivity of oral amlodipine is due to differences in the systemic clearance of enantiomers from the blood.
The use of isolated S(-) amlodipine, the pharmacologically active isomer of amlodipine, instead of a racemic mixture could lead to great advantages since the required dose and systemic toxicity could be reduced.
In order to study the clinical efficacy, safety and tolerability of S (-) amlodipine preparations, a number of clinical studies have been conducted. One of the largest studies currently underway is the multicenter SESA study - Safety and Efficacy of S(-)amlodipine. The aim of the study was to evaluate the efficacy and tolerability of S(-)amlodipine in the treatment of essential arterial hypertension. The study included 1859 patients with arterial hypertension, the patients were divided into 2 groups receiving S(-) amlodipine 2.5 and 5 mg per day for 4 weeks. In the S (-) amlodipine 2.5 mg group, there was a decrease in systolic blood pressure from 161 to 129 mm Hg, diastolic blood pressure from 100 to 84 mm Hg; in the S (-) amlodipine 5 mg group, there was a decrease in systolic blood pressure from 179 to 107 mm Hg, diastolic blood pressure from 107 to 86 mm Hg. (Fig. 1). This study found that S (-) amlodipine has a pronounced hypotensive effect and is effective in all stages of hypertension.
In 314 patients included in the study, edema was noted in connection with the use of racemic amlodipine. After switching them to S(-) amlodipine, edema remained only in 4 patients - a decrease in the development of edema by 98.7% compared with racemic amlodipine. Only 30 patients (1.61% of cases) out of 1859 reported the development of side effects. All side effects were mild and did not require discontinuation of the drug. Thus, S(-)amlodipine at doses of 2.5 mg and 5 mg is an effective drug for the treatment of hypertension with the additional advantage of significantly fewer adverse events (especially lower extremity edema). S(-)amlodipine was well tolerated in the treatment of hypertension in elderly and senile patients. In addition, dose adjustment of S (-) amlodipine in patients over 65 years of age was not required.
A subgroup analysis in the SESA trial - MICRO-SESA-1 - The safety and efficacy study of S(-)amlodipine in the treatment of isolated systolic hypertension - was performed to determine the safety and efficacy of S(-)amlodipine in the treatment of stage I and II isolated systolic hypertension (ISG). In the SESA database, 90 patients with ISH (46 men, 44 women) were found, their average age was 54.63±12.5 years. 54 patients had stage I ISH, 36 patients had stage II ISH. All patients received S(-)amlodipine 2.5-5mg for 4 weeks. An analysis of the baseline characteristics of patients with ISH indicated a significant correlation between age and systolic pressure. S(-)amlodipine significantly reduced systolic blood pressure (SBP) in both stages of ISH. The average decrease in SBP compared to baseline was 21.50±13.85 mm Hg. with a 95% confidence interval of 18.63 mm Hg. (lower limit) and 24.36 mm Hg. (upper bound) for the entire GIS group. 15.20±7.28 mm Hg (95% CI 13.26 -17.14 mmHg) and 30.94±15.97 mmHg. (95% CI 25.72-36.16) in the subgroups of ICH stage I and ICH stage II, respectively. The overall treatment response rate was 73.33% for the entire ISH group, 74.07% and 72.22% in the ISH stage I and ISH stage II subgroups, respectively. A significant correlation was found between the mean decrease in SBP and age, with a better response in older patients. None of the patients experienced lower extremity edema or other adverse events. 82 out of 90 patients received S(-)amlodipine 2.5 mg once daily and 8 patients received 5 mg once daily. Thus, S(-)amlodipine is regarded as a safe and effective drug for the treatment of stage I and II ISH without any side effects. In the present study, a significant decrease in systolic blood pressure was noted at all stages of ISH. Although the decrease in the first days of treatment in stage I ISH was less significant, the overall significance is the same for all stages of ISH. There is a significant correlation between age and the average decrease in SBP, with older patients showing a more pronounced decrease in SBP compared with baseline. A similar trend was observed in earlier studies. These data are particularly noteworthy given that about 65% of hypertension in the elderly is due to isolated systolic hypertension (ISH), and the ratio of those with hypertension to ISH increases by 19% by age 40, by 34% in the 50s, by 44%. in the sixth decade, by 51% in the seventh decade, and by 57% in patients over 80 years of age, and the risk of cardiovascular disease increases with an increase in pulse pressure.
Another subgroup analysis in the SESA study was performed to determine the safety and efficacy of S(-) amlodipine in the treatment of hypertension in elderly patients - MICRO-SESA II. The SESA database identified 339 (209 men, 130 women) elderly patients with hypertension, their mean age was 70.4±5.37 years. All patients received S(-)amlodipine for 4 weeks. Of 339 patients, 260 received S(-)amlodipine 2.5 mg once daily and 79 patients received 5 mg once daily. The results showed that S(-)amlodipine significantly reduced systolic and diastolic blood pressure in elderly patients with hypertension. The mean decrease in SBP after 28 days was 37.76±19.57 mm Hg. with a 95% confidence interval (CI) of 35.65 mmHg. (lower limit) and 39.88 mm Hg. (upper limit). The mean decrease in DBP after 28 days was 17.79±12.24 mm Hg. with a 95% confidence interval (CI) of 16.47 mmHg. (lower limit) and 19.10 mm Hg. (upper limit). The overall response rate to treatment was 96.46%. In 33 patients with concomitant diabetes mellitus, there was a more pronounced decrease in SBP (41.09±21.43 mm Hg; p<0,0001) и ДАД (24,06±18,77 мм рт.ст.; p<0,0001) со 100% частотой реакции на лечение. В этом анализе обнаружено, что 100% пациентов с сопутствующим са-харным диабетом отреагировали на лечение S(-) амлодипином снижением артериального давления, в то время как пациенты, не страдающие сахарным диабетом, отреагировали в 96,46% случаев. Эти данные важны с той точки зрения, что примерно у 60% пациентов с сахарным диабетом в возрасте после 75 лет развивается гипертензия. Жесткий контроль над АД у пациентов с диабетом приносит выраженную клиническую пользу. Также в данном исследовании не было выявлено периферических отеков. Таким образом, S(-)амло-ди--пин расценен, как безопасный и эффективный препарат для лечения гипертензии у пациентов пожилого возраста.
No less interesting is the Russian experience of using S(-)amlodipine. So, in a randomized comparative clinical trial of S (-) amlodipine 2.5 mg (S-Numlo) and the original drug containing racemic amlodipine at a dose of 5 mg, on the basis of the Federal State Institution of the State Research Center for Preventive Medicine under the direction of Acad. RAMS, professor R.G. Oganov, the advantage of S (-) amlodipine was also confirmed. The study included 36 patients with moderate and mild hypertension, including 8 men and 28 women. For 8 weeks, one group received 2.5 mg of S(-) amlodipine and the control group received 5 mg of racemic amlodipine. After 4 weeks of therapy, it was noted that S (-) amlodipine 2.5 mg reduces blood pressure more effectively than racemic amlodipine 5 mg (Fig. 2), and after 8 weeks of therapy, the hypotensive effect of S (-) amlodipine 2.5 mg and racemic amlodipine 5 mg was comparable. Greater safety of the use of S (-) amlodipine was also noted.
Another randomized clinical trial compared the efficacy and safety of S (-) amlodipine 2.5 mg and the original racemic amlodipine 5 mg in the treatment of grade 1 hypertension. The main group taking S (-) amlodipine-2.5 mg included 43 patients with grade I arterial hypertension: 19 men (44.2%) and 24 women (55.8%). The mean age of the patients was 51.90±3.87 years. The control group taking racemic amlodipine 5 mg included 43 patients with grade I arterial hypertension: 21 men (48.8%) and 22 women (51.2%). The mean age of the patients was 52.88±3.67 years. The results of this study allow us to conclude that S(-)amlo-dipine in patients with mild and moderate AH reliably controls the level of blood pressure during the day, significantly reduces the average daily SBP and DBP, thereby preventing the risk of vascular accidents. Pharmacokinetic research methods have shown that when taking the drug S (-) amlodipine once a day at a dose of 2.5 mg, a maximum equilibrium concentration is created in the blood, comparable to the maximum equilibrium concentration obtained when taking racemic amlodipine at a dose of 5 mg once.
When using S (-) amlodipine in the treatment of arterial hypertension, the drug is well tolerated by patients. Monotherapy with S (-) amlodipine does not cause activation of the sympathetic-adrenal system, does not affect the metabolism of sugar and total cholesterol, does not increase the level of creatinine in the blood, which makes it possible to prescribe this drug in the treatment of hypertension in patients with diabetes mellitus, atherogenic dyslipidemia, renal failure. When compared with racemic amlodipine, the drug has a more pronounced antihypertensive effect after 4 weeks of use, minimal risk of developing peripheral edema, minimal stress on the liver, metabolic neutrality, clinical predictability, and high adherence to treatment.
S(-)numlo is registered in Russia by Actavis under the name EsCordi Cor. Escordi Cor - the first pure levorotatory isomer in Russia, dosage 2.5 and 5 mg No. 30, has shown itself to be a highly effective and safe drug for the treatment of arterial hypertension.

Literature
1. Mcahon S., Peto R., Cutler J. et al. Blood pressure, stroke and CHD. Part 1. Prolonged differences in blood pressure: Prospective Observational studies collected for the regression dilution bias // Lancet. - 1990. - Vol. 335. - P. 765-774.
2. Staessen J.A., Fagard R., Thijs L. et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension // Lancet. - 1997. - Vol. 350.-P. 757-764.
3. Weber M.A., Julius S., Kjeldsen S.E. et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial // Lancet. - 2004. - Vol. 363. - P. 2049-2051.
4. Nailer W.G. Pharmacological aspects of calcium antagonism. Short term and long term benefits. Drugs 1993;46 (Suppl) 2:40-7.
5. Mason RP, Mason PE. Critique of a biologic mechanism linking calcium antagonists to increased risk for cardiovascular events in diabetes. Am J Cardiol. 1998 12;82(9B):29R(+)31R.
6. Abernethy DR, Soldatov NM. Structure-functional diversity of human L-type Ca2+ channel: perspectives for new pharmacological targets. J Pharmacol Exp Ther 2002;300(3):724-8.
7 Laurence DR et al. Arterial Hypertension, Angina Pectoris’ Myocardial information. Clinical Pharmacology eighth edition, Churchill Livingstone 1997: pp 425 - 457.
8. Webster J, Robb OJ, Jeffers TA, et al. Once daily Amlodipine in the treatment of mild to moderate hypertension. Br J Clin
9. Amlodipine reduces transient myocardial ischemia in patients with coronary artery disease: double-blind Anti-Ischemia Program in Europe (CAPE Trial). J Am Coll Cardiol 1994; fifteen; 24(6):1460-7.
10. Ch. Satoskar R.S. et al. Pharmacotherapy of Hypertension. In Pharmacology and Pharmacotherapeutics, Popular Prakashan. pp 386-417.
11 Ohmori M, Arakawa M, Harada K et al. Stereoselective pharmacokinetics of Amlodipine in elderly hypertensive patients. American Journal of Therapeutics 2003; 10:29-31.
12. Burges RA, Gardiner DG, Gwilt M, et al Calcium channel blocking properties of amlodipine in vascular smooth muscle and cardiac muscle in vitro: evidence for voltage modulation of vascular dihydropyridine receptors. J Cardiovasc Pharmacol 1987; 9(1):110-9
13. SESA study - Safety and efficacy of S(-)Amlodipine. JAMA-India. 2 (8): 87-92, August 2003.
14. Rocha E. et al - Isolated systolic hypertension - epidemiology and impact in clinical practice. Rev Port Cardiol. 22(l):7-23, 2003 Jan.
15. Alam M.G. — Systolic blood pressure is the main etiology for poorly controlled hypertension. Am J Hypertens. 16(2): 140-143, 2003, Feb.
16. Grimm R.H. Jr et al -Amlodipine versus chlorthalidone versus placebo in the treatment of stage I isolated systolic hypertension. Am J Hypertens. 15(1 Pt 1):31-36, Jan 2002.
17. Kannel W.B. — Prevalence and implications of uncontrolled systolic hypertension. Drugs Aging.20(4):277-286, 2003.
18. Webster J. et al - a comparison of amlodipine with enalapril in the treatment of isolated systolic hypertension. Br J Clin Pharmacol. 35(5):499-505, May 1993.
19. Benetos A. et al - Efficacy, safety, and effects on quality of life of bisoprolol/hydrochlorothiazide versus amlodipine in elderly patients with systolic hypertension. Am Heart J. 14O(4):E11, Oct 2000.
20. Volpe M. et al — Comparison of the blood pressure- lowering effects and tolerability of Losartan- and Amlodipine-based regimens in patients with isolated systolic hypertension. Clin Ther. 25(5): 1469-1489, May 2003.
21. Malacco E. et al — A randomized, double-blind, active-controlled, parallel-group comparison of valsartan and amlodipine in the treatment of isolated systolic hypertension in elderly patients: the Val-Syst study. Clin Ther. 25(ll):2765-2780, Nov 2003.
22. Branch "Clinical pharmacology" GU NTs BMT RAMS Academician of RAMS Kukes V.G. Report on the results of a comparative clinical study "S-NUMLO". Moscow 2006.
23. Report on the conduct of a clinical study, Federal State Institution "GNITs PM Roszdrav" under the leadership of Academician of the Russian Academy of Medical Sciences Oganov R.G., 2006

Included in medications

C.08.C.A Dihydropyridine derivatives

C.08.C.A.01 Amlodipine

IX.I10-I15.I15 Secondary hypertension

IX.I10-I15.I10 Essential [primary] hypertension