Blockers of opiate receptors Tranquilizers. Medical treatment of obesity: past, present and future. Opium alkaloids and derivatives

The problem of obesity in combination with various metabolic disorders is the focus of the attention of modern medical science and health, since it leads to the development of a number of serious diseases that reduce the quality of life and increase the mortality rate among the working-age population. So, the risk of occurrence sugar diabetes (SD) of the 2nd type increases 2 times in obesity of the I degree, 5 times in obesity of the II degree and more than 10 times - in obesity of the III-IV degree. In addition, it is well known that more than 80% of patients with the 2nd type SD note the obesity of varying degrees. Excessive body and obesity is also the risk factors for the development of ischemic heart disease. In an prospective study of Ischaemic Heart Disease Risk Factors Study, it is shown that among patients with metabolic syndrome, the ischemic heart disease developed 3-4 times more often and the mortality from this disease was 3-5 times higher than patients without metabolic disorders. The danger of obesity is associated with an increased risk of arterial hypertension (AG), ischemic stroke, night apnea syndrome, malignant tumors of some localizes (colon cancer, breast and endometrial, etc.) and osteoarthrosis, and also have a negative impact on the psychosocial health of patients and their quality of life. According to reports by the World Health Organization (WHO) experts from obesity diseases, 320 thousand people are died annually in Europe. Demonstrated that more high level Obesity is associated with increasing mortality rate, primarily from cardiovascular diseases, diabetes and certain types of cancer.

In the treatment of obesity, measures aimed at the normalization of metabolic disorders and a decrease in body weight are primary and pathogenetically reasonable. Currently, the effectiveness of treatment with obesity patients remains extremely low, since most patients have a body weight decrease very slowly, they occupy a passive position at the stabilization stage of the reduced body weight. It is impossible not to note the pessimism of doctors relative to the efforts of patients to reduce body weight. It should be emphasized that a deliberate decrease in body weight, associated with a decrease in blood pressure (AD) in patients with AG, leads to an improvement in the lipid profile and reduce the incidence of SD. This review discusses the issues of drug therapy in the historical aspect.

Means for reducing appetite or rising saturation affect various neurotransmitters of the central nervous system (CNS) (Noradreengic and serotonergic).

Sympathomimetics Press the appetite, stimulating the release of norepinephrine and dopamine nerve endings in the center of saturation of the hypothalamus. Other effects caused by sympathomimetics, such as suppressing gastric secretion and an increase in energy consumption, may also contribute to the decrease in appetite and reduce body weight. For the treatment of obesity in the United States, it is allowed to use such drugs such as fentermine, diethylpropion, phendimethrazine, benzfetamine and mazindol. At the same time, Phentermin is the most appointed drug. At the same time, these drugs are not included in the list of drugs that are means of choosing in obesity. In modern therapy schemes, the purpose of sympathomimetics is limited to several weeks due to the risk of drug dependence, although there are data and on more long-term use (6 months or more). TO by-effects This group of drugs belong to insomnia, dry mouth, constipation, euphoria, heartbeat and increased blood pressure. Noradreengic medicines are contraindicated in the presence of pronounced atherosclerosis, cerebrovascular disease, high and severe, thyrotoxicosis, glaucoma, mental excitation, medicinal dependence.

Phentermin refers to the B-phenylethylamine family; Allowed in 1959. Food and Drug Administration (FDA) for short-term (up to 3 months) applications for obesity. Data on the efficacy and safety of fentermines during long-term use is not enough, especially in the form of monotherapy. Currently, in routine clinical practice for the treatment of obesity, the purpose of the preparations of the B-phenylethylamine family is limited and not used for long-term therapy. In a controlled clinical study, Phenermine treatment for 36 weeks led to a decrease in body weight by 12.2 kg compared with 4.8 kg in a placebo group (p< 0,001). По данным метаанализа, включавшего 6 рандомизированных клинических исследований длительностью от 2 до 24 нед, на фоне терапии фентермином наблюдалось дополнительное снижение массы тела в среднем на 3,6 кг по сравнению с плацебо. В двойном слепом плацебо-­контролируемом исследовании 74 пациента с контролируемым СД, АГ или дислипидемией, страдающих ожирением, были рандомизированы на прием фентермина с контролируемым высвобождением (в дозе 30 мг/сут) или плацебо. Через 12 нед лечения фентермином показано существенное уменьшение массы тела (на 9,3 ± 3,4 кг против 1,8 ± 3,1 кг, р < 0,001) и окружности талии (7,2 ± 0,5 см против 2,1 ± 0,6 см, р < 0,001) по сравнению с группой плацебо. В группе фентермина с контролируемым высвобождением клинически значимого снижения массы тела (≥ 5%) достигли 95,8% пациентов (против 20,8% в группе плацебо, p < 0,001), 62,5% уменьшили массу тела более чем на 10% от исходной (против 4,7% в группе плацебо, р < 0,001). Продемонстрировано благоприятное влияние фентермина с контролируемым высвобождением на содержание общего холестерина (ХС) и ХС липопротеинов низкой плотности (ЛПНП). Существенных различий по систолическому и диастолическому АД между группами не отмечено, тогда как частота сердечных сокращений (ЧСС) значительно увеличивалась в основной группе по сравнению с плацебо (р = 0,02).

The most frequent undesirable phenomena were dry mouth and insomnia who were carrying transit. Thus, a short-term treatment with a controlled release fentermin led to a significant decrease in body weight and a waist circle, improving the parameters of a lipid profile, along with the absence of severe side effects. Due to the fact that Phentermin refers to sympathomimetics, it should be taken into account the possibility of developing such side effects as insomnia, dry mouth, dizziness, heartbeat, tremor of the hands, an increase in blood pressure and heart rate. That is why when prescribing sympathomimetic drugs, it is recommended to control the blood pressure and heart rate.

Diethylpropion. It is similar to amphetamine, but differs from the latter with a slightly pronounced sympathomimetic activity and fewer side effects. In the US, the diethylpropion was approved for the treatment of obesity in 1959. Metaanalysis 13 studies to assess the effectiveness of diethylpropion therapy for an average of up to 20 weeks in obesity patients showed that an additional decrease in body weight was 3.0 kg compared to placebo. The Brazilian study studied the effectiveness and tolerability of diethylpropione during treatment within 1 year. After screening, the duration of 2 weeks 69 patients with obesity (body mass index (BMI) 30-45 kg / m 2) recommended a low-calorie diet, and then they were randomized into a diethylpropion group of 100 mg / day (37 persons) and a placebo group (32 patients) by 6 months. After that, the study was open and for the next 6 months all patients were prescribed diethylpropion. After the first 6 months in the Diethylpropion group, a significant decrease in body weight was observed by 9.8% (on average by 9.3 kg), while in the placebo group, the decrease was 3.7% (3.1 kg), which was statistically reliable. After 12 months in the group of initial drug intake, a decrease in body weight amounted to 10.6% (10.1 kg), while in the group we switched to the reception of diethylpropion after 6 months - 7.0% (an average of 6.7 kg). Analysis of blood pressure, heart rate, electrocardiographic and psychological examination did not reveal significant differences between groups. In the Diethylpropion group, only such side effects were reliably more often as dryness and insomnia and only for the first 3 months.

Fentermine and diethylpropion refer to the IV class (according to the classification of the US drug control agency), which indicates a low risk of developing the abuse of these drugs and corresponds to the greatest security for patients.

Serotonergic preparations (Fenfluramin, Dexfenofluramine) increase the concentration of serotonin in the brain, inhibiting its reverse grip. A significant decrease in body weight for 1 year with the greatest effect in the first 6 months is due to a decrease in daily energy production by 10-15%. In 1997, both of these drugs were withdrawn from the medicinal market due to the development of the pathology of the heart valves and pulmonary hypertension.

Sibutramine Combines the effects of serotonin inhibitor, norepinephrine, dopamine effects. Initially, the drug passed clinical studies as an antidepressant, during which his pronounced anorexgenic effect was revealed. Sibutramine and its active metabolites inhibit the reverse seizure of serotonin and norepinephrine, thus prolonging the interaction of these neurotransmitters with their postsynaptic receptors. As a result, a sense of saturation is enhanced and prolonged, which reduces the amount of food consumed and, accordingly, reduces energy flow. At the same time, the drug is a weak dopamine reverse capture inhibitor. In contrast to phenfluramine and dexphonfluramine, Sibutramine does not enhance the release of serotonin and does not cause valve violations. In addition, Sibutramine increases energy consumption as a result of amplifying thermogenesis, which increases the ability of the drug to reduce body weight.

For the treatment of obesity, Sibutramine was allowed to medical use in Mexico in 1997, after which it was registered in 80 countries of the world. The metaanalysis of a number of randomized placebo-controlled studies of the effectiveness of sybutramine, which included patients with obesity duration of 12 months, demonstrated a decrease in body weight, exceeding the placebo group data by 4.2-4.45 kg. According to numerous studies, on the background of the treatment with a sybutramine at a dose of 10-15 mg / day per 12 months, an effective and clinically significant decrease in body weight (by 5-10%) was observed more than 86% of patients with obesity of varying degrees. The addition of sibutramine to standard non-drug therapy led to a significantly greater decrease in body weight (by 11.3 kg for the first 6 months of treatment) than just modifying the lifestyle. At the same time, the depot of visceral fat has favorably. Against the background of the therapy, the sybutramine has improved a lipid spectrum of blood plasma with his shift in the direction of anti-studiogenic orientation (the levels of triglycerides decreased and the high density lipoproteins (HDL) increased, and the glucose concentration in the fluid plasma and insulin level decreased. At the same time, in meta-analyze, which included 10 studies with a total number of participants in 1213 persons who took Sibutramine or placebo for 6-12 months, the relationship between the treatment of a sybutramine and a decrease in the level of total XC after amendment to reduce body weight was not detected. In general, Sibutramine was well tolerated patients. To the side effects observed when taking a sibutramine include dry mouth, headache, insomnia and constipation. The most significant adverse reactions of the drug were an increase in Hell and heart rate. So, against the background of treatment with sybutramine, a decrease in the effectiveness of antihypertensive therapy was noted.

At the initial stages of widespread use, Sibutramine was the cause of many discussions and administrative decisions in a number of countries due to suspected suspicions for the development of severe complications, mainly from of cardio-vascular system. In 2002, the SIBUTRAMINE CARDIOVASCULAR OUTOME TRIAL was launched, with the participation of 10,742 patients in 300 medical centers located in 16 countries of the world. The purpose of the study is the assessment of the balance of efficiency / safety of Sibutramine in persons with obesity of increased risk (97% have the cardiovascular diseases, in 88% - hypertension and 84% of the 2nd type SD). It was demonstrated that people with cardiovascular diseases have long-term (5 years) treatment with sybutramine contributed to a significant increase in the risk of myocardial nefatal infarction (by 16%) and non-phaatny stroke. At the same time, the average difference between the mass of the body of patients receiving sybutramine and placebo was only 2.5%. Such a benefit / risk ratio was found to be found and the European Medicine Agency (EMEA) recommended suspension of Sibutramine's marketing in the European Union. In October 2010, Abbott Labatoriz recalled the original preparation of Sibutramine from the sale from the US and the European Union's markets due to the presence of increased risk of myocardial infarction and stroke.

Other drugs with anorexigne effect

Cannabinoid Antagonists CB 1 -receptors

Currently, much attention is paid to the endocannoid system that occupies a key place in the pathogenesis of Morbid obesity. The close dependence of the receptor of the endocannabinoid system with biologically active substances of visceral adhesive tissue was revealed. The regulating role of the endocannoid system in the control of appetite, as well as the metabolism of glucose and lipids, is proved.

Romanobant - The first representative of the new class of drugs - blockers of cannabinoid receptors of the first type (SV 1). By selectively binding to central and peripheral SV 1 -receptors, Romanobant modulates a hyperactive endocannabinoid system. The results of the RiO program, which included 4 double-blind placebo-controlled studies of phase III with the participation of more than 6 thousand patients with overpressive body or obesity, were similar: Reception of Roman Banta for 1-2 years led to a statistically significant reduction in body weight, as well as essential Mobilization of abdominal adipose tissue, which was manifested by a rather pronounced decrease in the waist circle. Moreover, in patients with overpressive body or obesity and CD of the 2nd type and without it, the positive effect of the roman on cardiometabolic risk factors, in particular, the content of triglycerides, HS HPP, C-reactive protein, blood pressure levels, insulin resistance, along with Good drug tolerance. However, in later reports it is indicated that the use of Roman Bank is associated with an increase in the risk of mental disorders, including the alarm, depression and suicidal thoughts. Thus, according to four studies, adverse mental psychiatric phenomena were noted in 26% of participants in the Roman Band Group compared with 14% of patients in the placebo group, and the risk of developing depressive disorders was 2.5 times higher than in the placebo group. According to experts, the emergence of symptoms of mental disorders Against the background of the use of modifiers (antagonists or reversible agonists) cannabinoid receptors are quite expected from a generalistical point of view, since endocannabinoids are important modulators in pathological conditions in the form of alarming, depressive, post-traumatic stress disorders and phobias. The suicidality indicator, including suicidal thoughts, is also higher: the ratio of chances \u003d 2.0 (from 1.2 to 3.4) with a risk difference of 0.34 (from 0.14 to 0.54) compared with placebo. At the same time, neurological and gastrointestinal disorders are manifested in the form of dizziness, nausea and diarrhea. As a result, in June 2007, the manufacturer of the commercial pharmaceutical product of Romanobant withdrew the application for its licensing in the United States after the recommendation of the FDA does not allow its sale in the country due to the need to conduct further research of side effects, and in November 2008 in Europe, EMEA recalled permission on Romanobant.

Antidepressants

There are two drugs that reduce body weight, which can be used to treat obesity only by special indications. One of them is fluoksetin - The selective inhibitor of serotonin reverse capture, selectively blocks the reverse seizure of serotonin (5-HT) in the synapses of the TSN neurons, reduces the appetite, which can lead to a decrease in body weight. It reduced body weight at a dose of 20-40 mg / day during short observational placebo-controlled studies (on average by 5%). It is reported a significant reduction in body weight in studies using fluoxetine at a dose of 60 mg / day for 6-8 weeks with a maximum effect to 12-20 weeks and its subsequent increase. With long-term reception of the drug (within 52 weeks), a significant difference in the influence of body weight between groups of fluoxetine and placebo is not marked. At the same time, 8-month combined fluoxetine therapy with dexphenfluramine led to a significantly greater decrease in body weight compared with placebo (13.4 versus 6.2 kg in placebo group). There are reports of the use of fluoxetine / phentermine combination in clinical practice, but there are no evidence of its effectiveness and safety during long-term treatment. Indications for the purpose of fluoxetine are neurotic bulimia, a nutritional depression and the presence of depressive or alarming-depressive disorders in patients with obesity. The side effects of fluoxetine include headache, weakness, nausea, diarrhea, drowsiness, insomnia, nervousness, sweating and tremor.

Another drug - antidepressant bupropion, reducing nicotine dependence in smokers. Its main pharmacological action is selective inhibition of the reverse seizure of norepinephrine and dopamine. It is selectively captured by dopamine transport (DAT), but the main therapeutic effect caused by inhibiting the reverse grip of norepinephrine. It also acts as antagonist nicotine acetylcholine receptors. This served as the basis for clinical trials to assess the possibility of a dosage form of bupropion with slow release for the treatment of obesity.

Initially developed and focused on sale as an antidepressant, bupropion soon proved its effectiveness in the treatment of nicotine addiction. In a number of studies, it has been established that bupropion in a dose of 100-300 mg / day causes a slight decrease in body weight (about 5%). In the meta-analysis of drugs for the treatment of obesity, which included three studies using bupropion, carried out using placebo and double spit method, demonstrated the efficiency of bupropion at a dose of 400 mg / day for the treatment of obesity. So, during the period of 6-12 months, the average decrease in body weight in the group that took the bupropion was significantly large (4.4 kg) than in a group that took placebo (1.7 kg). In addition, the statistical identity of the results of the body weight reduction during the reception of bupropion and other drugs to reduce it, such as sybutramine, orlistat and diethylpropion are noted. However, despite the pronounced decrease in body weight, the use of bupropion led to an increase in the incidence of AG. Indications for receiving bupropion are depression against the background of obesity and the situation when a long smoking patient with obesity intends to abandon smoking.

Evaluation of the effectiveness of the combination of bupropion with zonizamide and bupropion with Naltrexon is presented below.

Preparations that reduce nutrition suction

Orlistat. - The first and today is the only drug peripheral preparation used in clinical practice for the treatment of obesity since 1998. Orlistat is a synthetic derivative of Lipstatin, the product of the life of mold mushroom Streptomyces toxytricini.which inhibits gastric and pancreatic lipases. Gastrointestinal lipases - key enzymes involved in the hydrolysis of food triglycerides, release fatty acids and monoglycerides, which are then absorbed through the intestinal mucous membrane. Due to the structural similarity of orlistat with triglycerides, the drug interacts with the active sector of the enzyme, covalently binding to its serine residue. The binding is slowly reversible, but in physiological conditions the overwhelming effect of the drug during the passage through the gastrointestinal tract (gastrointestinal tract) remains unchanged. As a result of this, about a third of the triglycerides of food is not digested and not absorbed, which allows you to create an additional calorie deficiency compared to the use of only a diet. At the same time, Orlistat does not affect the exchange of carbohydrates, proteins and phospholipids. Thus, Orlistat has a local action mechanism, which is limited by the gastrointestinal tract. Less than 1% of the Orlistate that has fallen into the gastrointestinal tract is absorbed, so it does not have a systemic effect on lipase. About 97% of the adopted dose of the drug was shown with a fee, where 87% - Orlistat unchanged. The effectiveness of the Orlistate is optimal when taking the drug during or within up to 1 h after receiving a meal containing less than 30% of calorie content due to fats. Orlistat takes 3 times a day at 120 mg during meals or within 1 h after it.

The effectiveness of orlistat relative to the reduction of body weight is demonstrated in a number of randomized clinical studies. In the study of SJOSTROM and co-authors, which included 743 patients with obesity to study the effectiveness of Orlistat, a decrease in body weight and its subsequent maintenance was established. Studies have shown that against the background of the use of Orlistate, not only the overall decrease in the mass of adipose tissue, but also a decrease in the mass of visceral-abdominal fat. This contributes to an increase in insulin sensitivity, reduced hyperinsulinemia, which is the powerful prevention of the development of the 2nd type SD. In a 4-year-old Double-blind placebo-controlled XEDOS study (Xenical in the prevention of Diabetes in Obese subjects), which included 3305 patients with obesity (CMT ≥ 30 kg / m 2) and normal (79%) or disturbed (21%) tolerance To glucose, the effectiveness of the Orlistate in combination with the modification of the lifestyle relative to the prevention of the 2nd type SD is studied. The demonstrated combination of Orlistate with a modification of a lifestyle led to a decrease in body weight by 5.8 kg against 3.0 kg in a placebo group and a significant reduction in the risk of development of the 2nd type SD (6.2 against 9% in the placebo group). At the same time, the cumulative incidence of 2-type SD in the main group was 37.3% lower than in the control group. In several double-blind placebo-controlled studies, the duration of the use of Orlistat was 2 years. After 12 months of treatment, a significant decrease in body weight by 2.89 kg was noted (with amendment to change body weight in the control group). The greatest decline in body weight is noted during the first 6 months of treatment and further remained stable and smaller than in the control group against the background of further receiving the drug.

Compliance with very low-energy diets (ODED; 400-800 kcal / day) with a significant amount of protein can contribute to a pronounced decrease in body weight in a short time, but data on long-term maintenance of the result achieved is usually disappointed. In this regard, it is very important how long Orlystat prevents the increase in body weight after staying on the ODED in patients with obesity and metabolic risk factors. In a clinical study involving patients who have a major reduction in body weight achieved with the help of ODED, randomized to the reception of Orlystat or placebo for 3 years. Reducing the body weight after 8 under the observance of the ODED was 14.3 ± 2.0 kg in the group of Orlistate and 14.5 ± 2.1 kg in the placebo group. Increasing body weight for 36 months from the moment of completion of the ODED compliance was significantly less in the group of Orlistat (4.6 ± 8.6 against 7.0 ± 7.1 kg; p< 0,02). Поддержание массы тела сопровождалось существенным улучшением ряда метаболических параметров. Так, ретроспективный анализ показал, что лечение орлистатом приводило к снижению уровня триглицеридов и общего ХС в плазме крови, улучшению толерантности к глюкозе, снижению систолического и диастолического АД.

Treatment of obesity in children and adolescents is a difficult task, a change in lifestyle in many cases does not lead to a clinically significant decrease in body weight, especially in adolescents. According to experts, no more than 4-5% of children can achieve a significant reduction in body weight without pharmacological support. Therefore, in recent years, research has been conducted on the efficiency and safety of the use of drugs in this age group. In several studies, the effectiveness of Orlistat has adolescents. In a double-blind placebo-controlled study, which included 539 adolescents aged 12-16 years with obesity, after 1 year of treatment of BMI decreased by 0.55 kg / m 2 in the Orlistate group and increased by 0.31 kg / m 2 in the placebo group (p \u003d 0.001). The change in the waist circle was as follows: a decrease in the main group and an increase in the placebo group. Nevertheless, in another double-blind randomized placebo-controlled study with the participation of 40 adolescents, the 6-month reception of Orlistat did not have a significant impact on the BMI. Therefore, further research is needed in this direction.

Side effects of Orlistat are limited to the symptoms from the head of the gastrointestinal tract and develop approximately 15-30% of patients. Unwanted Orlistat phenomena include oily selection from the rear pass, the fatty chair, the increase in defecation, the urge to defecation, flatulence. Usually, these phenomena are light or moderate in nature, their frequency is reduced as the duration of treatment increases, but almost in 9% of cases they cause the abolition of Orlistat. In 7% of patients who received Orlistat, the symptoms of the incontinence of feces are noted compared with 1% in the placebo group. The use of Orlistat can lead to impaired suction of fat-soluble vitamins (A, D, E and K) and B-carotene, and therefore preventive reception of vitamin supplements are recommended. Systemic side reactions of Orlistat are extremely rare due to the lack of systemic absorption.

Increased admission of fats in a thick bowel causes concern about increasing the risk of developing colon cancer. In this direction, further research is needed. In addition, under the action of lipase inhibitors, an increase in oxalate absorption and an increase in the risk of nephrolithiasis and renal failure is possible.

Prospects for drug therapy obesity

Pramlithid - The synthetic analogue of the amyline pancreatic hormone, originally synthesized as a drug for the treatment of SD 1st and 2nd type. In the US, the drug is approved for use as an additional insulin therapy. Pramlithide is introduced subcutaneously before meals. The drug suppresses the generation of glucagon depending on glucose and reduces predominantly postprandial fluctuations in glycemia. The subsequently established relationship with a decrease in appetite, food intake and rapid saturation associated with motorcycle gastrointestinal motorcycle. It is currently being studied as a potential preparation for the treatment of obesity. In a 16-week randomized clinical study with escalation of doses, a reliably greater decrease in body weight in the Pramlithide group at a dose of 240 μg by 3.7% compared with placebo (p< 0,001); доля пациентов с уменьшением массы тела ≥ 5% составила 31% пациентов (p < 0,001) . В клиническом исследовании , включавшем 411 пациентов с ожирением, рандомизированных на прием прамлинтида (6 подгрупп в дозах 120, 240 и 360 мкг 2 и 3 раза в сутки) или плацебо в течение 4 мес, и далее продленном до 1 года. Уменьшение массы тела восстанавливалось в группе плацебо, но сохранялось во всех группах прамлинтида, кроме лиц, получавших препарат в дозе 120 мг 2 раза в сутки. Наиболее частым побочным эффектом была тошнота.

Analogs of glucagon-like peptide

Currently, new therapeutic approaches in the treatment of obesity are also associated with the modulation of the activity of the level of glucagon-like peptide (GPP-1) by appointing analogs and mimetics of GPP-1 (Exnaenatid, Liraglutid, CJC-1131) developed and approved for the treatment of SD 2- th type. For this class of drugs, a double mechanism of action is characterized, namely the effect on the gastrointestinal tract and brain. Thus, signals stimulating the secretion of leptin, a key mediator between the adipose tissue and the hypothalamic-pituitary system, which leads to a decrease in appetite, energy consumption and the emptying speed of the stomach, comes from the head of the brain. In research on models in animal and healthy volunteers, it is shown that GPP-1 is one of the important regulators of the amount of food consumed, strengthens the sense of saturation and reduces the feeling of hunger. The main advantage with the long-term use of Liraglutide and Exenatide is to reduce the level of glycolized hemoglobin (HBA1C) and the level of systolic blood pressure.

Liraglutid - Analogue of human GPP-1, produced by biotechnology by recombinant deoxyribonucleic acid using the Saccharomyces Cerevisiae strain having 97% homologousness with human GPP-1, which binds and activates the GPP-1 receptors in humans. The GPP-1 receptor serves as a target for a native GPP-1 - endogenous hormone inrecotin, causing stimulation of glucose-dependent insulin secretion in the B-cells of the pancreas. In the double-blind placebo-controlled study, which included 564 patients with obesity and high risk of development of the SD, were compared Liraglutide with an orlistat inhibitor. The duration of the study was 20 weeks. It has been established that the daily reception of Liraglutide at a dose of 1.2; 1.8; 2.4 and 3.0 mg led to an average decrease in body weight by 4-8 kg (p \u003d 0.003), 5.5; 6.3 and 7.2 kg (P< 0,0001 для дозирований 1,8–3,0 мг) соответственно. При этом в группе плацебо уменьшение массы тела составило 2,8 кг, а в группе орлистата - 4,1 кг. Лечение лираглутидом в наиболее высокой дозе приводило к уменьшению массы тела на ≥ 5% у 75% пациентов и на ≥ 10% - у более 25% обследованных больных. Кроме того, выявлено благоприятное действие лираглутида на уровень ХС ЛПНП в плазме крови и систолическое АД. В целом отмечена хорошая переносимость лираглутида, в то же время 10% пациентов были исключены из исследования вследствие развития side effects. The side effects of Liraglutid were observed mainly by the head of the gastrointestinal tract, and most of them were estimated as moderate. The most frequent undesirable phenomena in the Liraglutide group were nausea and vomiting. Individual intolerance was noted in 20-50% of patients, depended on the dose of the drug and was manifested by nausea. The feeling of the fence in taking the drug most often noted at the very beginning of use.

Exenatid It is a synthetic peptide, the amino acid sequence of which is 53% identical to such a human hormone - Incretin GPP-1, which allows the exnaenathide to act as a powerful receptor agonist to GPP-1 in humans. The use of exenatide in patients with a type of type 2 and excess body or obesity also leads to a progressive and resolved decrease in body weight. In all clinical studies, the use of exnaenatide led to a reliable progressive decrease in the body weight of patients, observed after 2-4 weeks of treatment in the majority of patients with overweight. The noted effect was maintained during a 2-year period of treatment within open studies, which were a continuation of placebo-controlled studies of the III phase. The dose-dependent effect of the exrenathide for body weight is established. In persons who fully completed the 2-year period of the study, the treatment of exnaenathide at a dose of 10 μg 2 times a day made it possible to achieve a decrease in body weight by 1.6; 2.4 and 4.7 kg after 12; 30 and 104 weeks of treatment, respectively. A decrease in body weight was noted in 81% of patients of the 2nd type SD received expenatid for 2 years, despite the fact that there were no special requirements for compliance with the diet and the program. exercise.

According to the results of a systematic review and meta-analysis, in patients receiving agonists of the GPP-1 receptors, a more significant decrease in body weight, as well as normalization of blood pressure and levels, regardless of the presence of a 2-type SD is revealed. The metaanalysis included 25 randomized controlled studies (total 10,560 participants), in which patients accepted GPP-1 agonists (Liraglutide or Exnaenatid) for at least 20 weeks. The decrease in body weight was observed in patients as without SD (a weighted average difference was -3.2 kg; 95% di from -4.3 to -2.1) and from the SD (weighted average difference -2.8 kg; 95 % Di from -3.4 to -2.3). At the same time, the greatest reduction in body weight was associated with higher doses of agonists GPP-1. Analysis of subgroups of patients receiving exnaenatid 2 times a day (-2.8 kg; 95% di from -2.9 to -2.7 kg), exnytid 1 time per week (-2.8 kg; 95% di 5.2 to -0.3 kg) or Liraglutide (-2.2 kg; 95% di from -3.5 to -0.9 kg), revealed a significant decrease in body weight. Additional analysis showed that GPP-1 agonists improved the systolic and diastolic blood pressure indicators, the level of xc and the control of glycemia. The authors concluded that GPP-1 agonists used in patients with obesity, in the presence of or without CD, leads to a clinically significant positive effect on the reduction of body weight. In this case, an additional positive effect on the blood pressure and the level of total hs may be observed.

Efficiency taranabanta - inversion agonist cannabinoid CB 1 -receptors, reduced appetite and increasing energy consumption, studied in patients with obesity. In a randomized clinical study, a dose-dependent reduction in body weight is shown against the background of a 12-week drug intake. The data of four studies of the III phase of clinical trials have been published, in two of which the benefits / risk of the drug in low and high doses are estimated, in one - the effectiveness of therapy in patients with the 2nd type SD. After 1 year of therapy, TaranaBant in a dose of 0.5; 1 and 2 mg was observed a decrease in body weight on average by 5.0; 5.2 and 6.4 kg, respectively, compared with 1.4 kg in the placebo group (all p< 0,001) . Уменьшение массы тела на ≥ 5 и ≥ 10% достигнуто у большего количества пациентов в группах активной терапии по сравнению с плацебо (р < 0,001 для всех доз). Частота побочных эффектов в группах таранабанта была выше, чем в группе плацебо . В двойном слепом рандомизированном плацебо-контролируемом исследовании применялись более высокие дозы (2, 4 и 6 мг) в течение 104 нед. На основе анализа польза/риск терапия в дозе 6 мг была остановлена в течение 1-го года (пациенты с дозы 6 мг были переведены на 2 мг или плацебо) и в дозе 4 мг - в течение 2-го года (доза снижена с 4 до 2 мг). На 52 нед терапии среднее уменьшение массы тела составило 2,6; 6,6 и 8,1 кг соответственно в группах плацебо и таранабанта в дозе 2 и 4 мг (обе дозы р < 0,001 по сравнению с плацебо). У лиц, полностью завершивших 2-летний период лечения, изменения массы тела по сравнению с исходными данными были следующими: –1,4; –6,4 и –7,6 кг соответственно в группах плацебо и таранабанта в дозе 2 и 4 мг (обе дозы р < 0,001 по сравнению с плацебо). Продемонстрировано, что побочные эффекты значительно повышаются с увеличением дозы, особенно психические нарушения (депрессия, депрессивное настроение, тревога, суицидальные мысли, гнев и агрессия) . Таким образом, данные III фазы исследования показали, что и эффективность, и побочные эффекты ассоциировались с дозированием препарата, причем высокие дозы были более эффективны, но и побочных эффектов было больше. Эти данные послужили основой для прекращения клинических испытаний таранабанта для лечения ожирения.

LORKSERIN - Powerful I. selective SEROTONIC SERYONIC AGONIST 5-HT 2C -Repceptors With a number of properties like phenflumamines, acting on serotonin 5-HT 2B -Repceptors, and associated with heart defects. In clinical studies, the pronounced efficiency of LORKSERIN was noted in reducing body weight compared with placebo, along with good profile security. In two clinical trials of the III Test Phase Bloom (Behavioral Modification and Lorcaser for Overweight and Obesity Management) 6380 Patients with BMI 27-45 kg / m 2 were randomized to receive 10 mg LORKSERIN 2 times a day or placebo. The duration of the study was 52 weeks. A greater decrease in body weight on the background of Lorksener therapy is demonstrated compared with placebo. An analysis of the combined research data showed that 52 weeks therapy was noted a decrease in body weight by 5.8% in a group applying LORKSERIN, and 2.5% in the placebo group (p< 0,0001) . В исследовании BLOOM среднее уменьшение массы тела через 1 год терапии составило 5,8 ± 0,2 кг в основной группе и 2,2 ± 0,1 кг в группе плацебо (p < 0,001) и удерживалось в течение 2 лет у 67,9% пациентов основной группы и 50,3% группы плацебо (р < 0,001). Уменьшение массы тела достигало более 5% от исходного уровня у 47,1 и 22,6% пациентов основной группы и плацебо соответственно . Наиболее частыми побочными эффектами были головная боль, головокружение и тошнота, существенно не отличавшиеся между группами.

In 2010, the drug was rejected by the FDA for security reasons, in particular during experiments on animal models, tumors were recorded. However, according to new data, the risk of cancer in individuals is insignificant when using the drug. But the risk of the development of hypertension and other adverse reactions from the cardiovascular system is preserved. In May 2012, the Expert Council of the FDA recommended that the drug Lorkaserin is approved to reduce body weight, despite the continuing doubts about the safety of the drug for the cardiovascular system. If the FDA approves the drug, it will be the first new drug to reduce body weight available in the US market over the past 10 years.

Tezofenzine - inhibitor of the inverse neuronal seizure of serotonin mediators, dopamine and norepinephrine in the structures of the brain responsible for appetite. Its effect is achieved by suppressing the feeling of hunger and fast saturation when making food. Initially, Tezofenzine was developed for the treatment of Parkinson's diseases and Alzheimer, however, during the study, the ability of the drug was established to reduce body weight. Moreover, this effect was dose-dependent. Thus, the average change in body weight in patients with obesity against the background of 14-week therapy with teesofenzine at a dose of 0.125; 0.25; 0.5 and 1.0 mg amounted to 2.1; 8.2; 14.1 and 20.9%, respectively. In general, 32.1% of patients noted a decrease in body weight at least 5% on the background of therapy with Tezofenzine (P< 0,001 в дозе 0,25; 0,5 и 1,0 мг по сравнению с плацебо). Из нежелательных явлений отмечено увеличение ЧСС с повышением дозы препарата. Изменений АД в основной группе не выявлено. Еще одним доказательством было рандомизированное двойное слепое плацебо-контролируемое исследование , включавшее 203 пациента с ожирением, средняя масса тела которых составляла чуть более 100 кг. Всем больным назначалась диета, а также прием тезофензина в одной из 3-х дозирований либо плацебо. Период наблюдения составил 6 мес. У пациентов, принимавших тезофензин в дозе 0,25; 0,5 и 1,0 мг, отмечалось уменьшение массы тела соответственно на 6,7; 11,3 и 12,8 кг, что достоверно превышало данные группы плацебо (p < 0,0001). Доля больных, достигших уменьшения массы тела на ≥ 5 кг составила 59, 87 и 91% на фоне терапии тезофензином в дозе 0,25; 0,5 и 1,0 мг соответственно по сравнению с 29% в контрольной группе. Применение тезофензина сопровождалось существенным увеличением ЧСС во всех исследуемых группах, а в группе лиц, получавших наиболее высокую дозу препарата, - повышением АД и высокой частотой изменения настроения . В связи с этим в III фазе клинических испытаний, согласованной с FDA, изучается эффективность и безопасность тезофензина в двух дозах 0,5 и 0,25 мг.

Cetilistat - inhibitor of the pancreatic lipase, enzyme that splits triglycerides in the intestine. Inactivated enzymes are not able to hydrolyze fir feed triglycerides to absorbed free fatty acids and monoglycerides. This drug is similar to the allowed FDA, Orlistat, but due to various molecular structureIt is assumed that it is characterized by the best tolerance and fewer side effects. The phase I of clinical trials in obesity patients is over in 2006. Tetilistat treatment in 3 doses (60, 120 and 240 mg) for 12 weeks led to a significantly greater decrease in body weight than in the placebo group. In addition, the proportion of patients who have achieved at least a decrease in the initial mass of the body by 5% was larger in all 3-treat groups than in the placebo group. In the II phase of clinical trials, 612 patients with obesity and SD randomized to the reception of Cetilistat or placebo were participated. The duration of the study was 12 weeks. It was demonstrated that treatment with cetilestatom at a dose of 80 and 120 mg led to a significant decrease in body weight compared with placebo (3.85 and 4.32 against 2.86 kg, respectively). At the same time, the decrease in body weight was similar to the results of therapy with Orlistat (3.78 kg). It is noted good tolerability of cetilestat and the smaller frequency of the discharge of the drug due to side effects. Thus, the number of undesirable effects on the gastrointestinal tract was 12% for Orlistat and 1-3% - for Cetielistat. However, the reasons for these differences are unclear. Currently, in Japan, the III phase of clinical trials of the Cellite is held.

Naltrexon - A long-acting antagonist of opioid receptors with high atticness to the latter. The drug is used to treat opioid and alcohol addiction, but in the medical group Against the background of therapy, a decrease in food consumption leading to a decrease in body weight is noted. It is assumed that opioid receptors in the CNS are associated with the activation of edible behavior. It has been established experimentally that the introduction of naloxone in rats leads to a short-term reduction in food consumption by means of the B-endorphine blockade. In clinical studies using Naltrexone (Naloxone analogue), unequal effects were observed relative to the reduction in body weight in persons with excessive and insufficient body weight.

Combined therapy

Combination of Bupropion / Naltleson (Both preparations with slow release of the active substance (Sustained Release - SR) - Contrave drug). The specified drug appeared after it was found that naltrexone blocks an indoor-reigned B-endorphine inhibition of pepopiomethanokortin (VERO) - a turnman supporting the secretion of A-melanocyte-stimulating hormone (A-MSH), while the bupropion (through dopamine receptors) activates PAM neurons and enhances the secretion of anorexgenic neuropeptide A-MSH in the hypothalamus. The combination of bupropion nodexone acts on the processes of food intake (dopamine effect) and pleasure / taste of food (opioid effect). In a clinical study, according to the effectiveness of various doses of Naltrekson / bupropion combination, it has been shown that the increase in the dose of Naltrexone did not lead to a greater decrease in body weight. At the same time, within 24 weeks therapy, a decrease in body weight was maintained. It has been demonstrated that against the background of combination therapy NTTelson SR / bupropion SR, conducted within 24 weeks, there was a significant improvement in the symptoms of depression, a decrease in body weight and improved power control in excess body and obesity in women with depression.

In a randomized controlled study of COR-1 (Contrave Obesity Research 1) included 1742 patients with BMI 30-45 kg / m 2 and a light degree of obesity or CMT 27-45 kg / m 2 and high content of LDL or high blood pressure. In accordance with the design of the study, the patients appointed a low-calorie diet and physical exercise and 1 of 3 therapy modes:

1) Naltrexon with a slow release of the active substance SR in a dose of 32 mg / day + bupropion SR at a dose of 360 mg / day in one tablet with fixed doses of preparations (NB32 group);

2) Nttleson SR at a dose of 16 mg / day + bupropion SR 360 mg / day in one tablet with fixed doses of drugs (NB16 group);

3) Placebo Group.

The duration of the study was 56 weeks. The average body of the patient's body to the study was about 100 kg (220 pounds). After treatment, a decrease in body weight was noted by 1.4 kg in the placebo group, 4.9 kg in the NB16 group and 6.1 kg in the NB32 group. The proportion of patients reached a decrease in body weight by 5% or more was also different for each of the groups: 48% in the group NB32, 39% in the group NB16 and 16% in the placebo group. Most of the patients from the Nb32 group (25%) and the NB16 group (20%) reduced the body weight by more than 10% compared with the placebo group (7%). At the same time, a decrease in body weight from 5 to 10% contributed to better control of glucose content in blood plasma, a decrease in the level of hs in the blood plasma and risk of AG.

In a double-blind placebo-controlled study, COR-diabetes was included 505 patients with overpressure or obesity and 2-type SD (HBA level of HBA 1C from 7 to 10%, an average of 8%), randomized to the combined Natrexon SR 32 mg / bupropion SR 360 mg or placebo. The duration of the study was 56 weeks. A significant decrease in body weight in the group of combination therapy Naltrekson / Bupropion (5 versus 1.8%, p< 0,001). При этом уменьшение массы тела ≥ 5% отмечено у 44,5% пациентов в основной группе по сравнению с 18,9% в группе плацебо. Показано улучшение контроля гликемии в группе комбинированной терапии по сравнению с группой плацебо. При этом целевой уровень HbA1C < 7% достигнут более чем у 44% пациентов в группе комбинированной терапии по сравнению с 26% в группе плацебо (p < 0,001). Авторы заключили, что в целом изучаемая комбинация препаратов хорошо переносилась. Наиболее частым побочным эффектом была тошнота.

However, in February 2011, the FDA suspended the sale of a medicinal product, explaining such a solution to the need for an additional study of its side effects.

Combination of bupropion / zonismid. The combination of bupropion with an antiepileptic drug with zipper is estimated in three studies of the II phase of clinical trials. Zivismitide has a multicomponent mechanism of action: there is an inhibitory effect on voltage-dependent sodium channels and T-type calcium channels, enhances the release of gamma-amine oil acid and suppresses the release of glutamate. In case of treatment with suclision, there is a tendency to reduce body weight. In a randomized clinical study, in patients who received a bupropion with suitsmid for 24 weeks, a larger decrease in body weight (9.2%) was noted than in the monotherapy and placebo monotherapy groups (6.6; 3.6% and 0 , 4%, respectively). Similar results were obtained in a randomized open study. The most frequent side effects were headache, nausea and insomnia. A greater decrease in body weight on the background of combination therapy of bupropion / suclosimide is noted than with a combination of bupropion / nantleson for the same observation period.

Combined fentermine therapy with phenfluram. In a 28-week randomized clinical study, according to the effectiveness of this combination in obesity patients, a significant decrease in body weight was revealed compared with placebo (15.5 versus 4.9%,< 0,001). Однако в 1997 г. фенфлюрамин был отозван с рынка США в связи с появлением данных о формировании легочной гипертензии и клапанных пороков сердца на фоне применения указанным препаратом .

Fentermine / Topiramate combination. Topiramate - gamma-amine-oil acid agonist refers to anti-epileptic drugs, tested as monotherapy to reduce body weight. It is assumed that the decrease in appetite under the action of this drug is associated with Cainat / AMP-subtype of glutamate receptors, potential-dependent sodium channels and the activity of gamma-aminobacing acid. However, the exact mechanism of the Topiramate action to reduce body weight is not known. In a number of randomized clinical studies, it was noted that compared with placebo monotherapy Topiramat led to a significant decrease in body weight, which was noted during the entire period of the study. Concerning relatively side effects from the CNS and the peripheral nervous system led to the III phase of Topiramate tests, which, due to the high frequency of unwanted phenomena, were stopped. The assumptions about the best tolerance of a slow-release topiramate were not confirmed.

There are data on the effectiveness of the combination of topiramate with controlled release and fentermine in a low dose in the treatment of obesity. In a randomized clinical study, 28-week therapy with a fluhermine / Topiramate combination led to a decrease in body weight by 9.2% compared with monotherapy with Topiramat, fentermine and placebo by 6.4; 6.1 and 1.7%, respectively. Evaluation of the portability and security of combination therapy (Equate, Equip, Conquer study) made it possible to establish such side effects as the increase in pulse, mental disorders (depression, suicidal thoughts, memory violation and concentration), as well as congenital abnormalities. In accordance with the data on portability and security in the fall of 2010, the FDA rejected the assertion of the combination of a psychostimulator of a fentermine and anticipant Topiramate (Qnexa).

Pramlithida combinations. Neurogormonal body weight control includes a complex of interactions between leptin and amiline. It is experimentally established that rodents with obesity treatment with amiline and leptin was accompanied by a significant decrease in body weight due to a decrease in the mass of adipose tissue. These data served as the basis for the appearance of a new combined drug, including a ramlithide (analogue of the natural hormone of amylin) and meterleptin (metreleptin) (analogue of the human leptin hormone), synthesized by adipocytes, is an important regulator of the energy exchange involved in body weight control. In small clinical studies, it was noted that the combination therapy of pramlithid with mereletin was more effective in reducing body weight than the monotherapy is each separately. So, after 20 weeks, a decrease in body weight Against the background of the combination therapy, Pramlithd / meterleptin was 12.7 ± 0.9% compared with 8.4 ± 0.9% in the Pramlithid group (P< 0,001) и 8,2 ± 1,3% в группе метрелептина (p < 0,01) . Поэтому комбинацию прамлинтида с метрелептином стали рассматривать как новый интегрированный нейрогормональный подход в фармакотерапии ожирения. Однако в августе 2011 г. на этапе II фазы клинических испытаний было объявлено о прекращении испытаний комбинированного препарата прамлинтид/метрелептин для лечения ожирения.

There are clinical data on estimating rapid effects in combination with sybutramine and phentermine. In an open study, which included patients with obesity, a decrease in body weight Against the background of a 24-week combination therapy of pramlithide with a sybutramine was 11.1 ± 1.1%, in a group obtaining pramlithd with fentermine - 11.3 ± 0.9%, Monotherapy Pramlithid - 3.7 ± 0.7% and 2.2 ± 0.7% - in the placebo group (p< 0,001). Общими побочными эффектами комбинированной терапии были тошнота и учащенное сердцебиение. Отмечено значительное повышение ЧСС и АД на фоне комбинированной терапии прамлинтид/сибутрамин (3,1 ± 1,2 уд./мин, p < 0,05; 2,7 ± 0,9 мм рт. ст., p < 0,01) и прамлинтид/­фентермин (4,5 ± 1,3 уд./мин, p < 0,01; 3,5 ± 1,2 мм рт. ст., p < 0,001). В настоящее время изучается эффективность комбинированной терапии прамлинтидом с агонистом рецепторов ГПП-1 - эксе­натидом для лечения ожирения у пациентов с СД и без этого заболевания .

Conclusion

Like many other health problems of the national and global level, prevention and treatment of obesity are far from solving, which is defined by both many source factors and conditions and the polycomponation of the task itself. The basis of treatment is tough observance of lifestyle, raising physical activity and changing food habits. Despite the fact that anorexigne drugs are the main pharmacotherapeutic agents for the treatment of obesity, it is necessary to remember that the mechanism of action of these drugs often leads to potentially adverse side effects. When planning drug therapy should be based on the patient an assessment of the benefit / risk of anorexigne drugs. Currently, only Orlistat is approved for long-term therapy of obesity. At the same time, priority is the development of new drugs affecting various violations in the system of regulating the energy exchange and allowing not only to reduce body weight, but also opposing the development of recurrences of the disease.

The reference list is in the editorial office.

Opioid analgesics are substances of natural or synthetic origin, which are agonists of opioid receptors, that is, stimulants of endogenous opiopeptides in the central nervous system (CNS).

As mentioned above, opioid analgesics are agonists of opioid receptors. We will describe more opioid receptors.

Opioid receptors are divided into three main subtypes:

• Or1 (δ or delta)
• Or2 (to or kappa)
• OP3 (μ or MJ).

In anesthetics, all these three types of recerns are involved. They are located in the central nervous system, but the most main role The OR3 (MJ) recenters play. The excitation of the MJ receptors leads to the oppression of breathing, euphoria and physical drug addiction. Peripheral opioid receptors regulate intestinal motorcycle. When stimulating the intestinal receptors, the intestine is developing (constipation).

All types of opioid receptors are associated with a special G-protein. The transmission of the signal from the membrane receptor is carried out through:

• inhibition of adenylate cyclase,
• modulating the level of intracellular calcium,
• changing the permeability of potassium channels.

Opioid analgesics violate the neural transmission of pain pulse Due to the fact that the emission of pain mediators (glutamate, acetylcholine, norepinephrine, serotonin and substance P) decreases into a synaptic slit, and the postsenptic neural membrane is stabilized due to the opening of potassium channels.

In recent years, it has been found that opioid analgesics (endogenous and exogenous) can cause analgesia through action also on peripheral tissues. In the endings of peripheral sensitive nerves, MJ receptors were found. The pain of an inflammatory nature is also sensitive to the peripheral action of opioid analgesics. Thus, the appointment in the knee joint of the violated analgesics during arthroscopic surgery at the knee joint brought a decrease in pain. Therefore, work is underway to find opioid analgesics with selective peripheral action for the treatment of inflammatory pain.

Endogenous opioid analgesics differ in the affinity of opioid receptors - Leu Enkefalin has a high affinity for the receptor delta, and dinorphine to kappa. In order to reduce the risk of drug dependence and oppression of breathing, the search was purposefully medicinal substances With a predominant action on kappa receptors. An example of such substances are, for example, opioid analgesics BUTORFANOLOL and NALBUFIN. However, they cause dysphoria and rather weak.

Classification of opioid analgesic

Opioid analgesics and their antagonists can be divided:

1. on the chemical structure and origin,
2. by influence on opioid receptors.

For a practitioner, the second, the so-called clinical classification is indispensable.

On chemical structure and origin

Natural opioid analgesics (Fenantrene derivatives): Morphine, Codeine.

Synthetic opioid analgesics:

• Phenentrene derivatives: heroin, oximorphon, Nalcomorphone Nalbughin, buprenorphine;
• Pipeteridine derivatives: Promedol (trimeperidine), meperidine, pyritramide, fentanyl, lofentanyl, carfentanyl, soufentanyl, etc.;
• PhenylGephylamina: Meptazinol, methadone;
• Benzomorphans: Pentazocine;
• Morphinans: Levorfanol, Buturofanol, Dextromethorphan;
• Cyclohexanola: Tramadol.

By influence on opioid receptors

Clean agonists

• Strong agonists: morphine, trimeperidine (commotol), meperidine, methadone, fentanyl et al.;
• Weak agonists: codeine, propoxyphen, oxycodone, hydrocodone;

Mixed antagonist agonists and partial agonists: buprenorphine, buthorofanol, pentazocine, tramadol.

Clean opioid receptor antagonists: Naloxone, Nalmefen, Naltrekson, Alvimopan, Methylnatrexon.

Pure opioid receptor agonists eliminate the effects of opioid analgesics. Naloxone and Nalmefen are indispensable in the oppression of respiration caused by overdose of opioid analgesics, Naltrekson - in the treatment of opioid drug addiction, alcoholism. The last two substances do not penetrate into the CNS and are used to eliminate the constipation-caused by opioids.

The mechanism of action of opioid analgesics

Opioid analgesics eliminate pain By stimulating specific opioid receptors regulating transmission and modulating pain and located mainly in the head and spinal cord. They slow down the release of exciting mediators from afferent neurons and oppress the transmission of pain pulse in the dorsal horns of the spinal cord, and on the supraspinal level - violate the transmission and modulation of pain.

Especially an important point is the modulation of the discount paths, including the front brain keel, a gray pericorial zone and Locus Ceruleus. Opioid analgesics suppress all these neurons and contribute to the release of endogenous opiopeptides, which, in turn, act on the other than the opioid analgesics themselves, types of receptors. Therefore, there is no selective to one type of receptors of analgesics.

Effects of opioid analgesic

The prototype of opioid analgesics is morphine. Other opioid analgesics cause only morpho-like effects. All morphine effects can be divided into central and peripherals.

Central Effects Morphine

Effects of oppression CNS.

Analgesiacaused by a change in perception of pain, a change in the reaction to pain (pain perceived as something outsasual) and euphoria (the strongest sense of satisfaction and well-being). In healthy people who have no pain, sometimes there may be a dysphoria. The most pronounced action is the strong MJ receptor agonists.

Foreignness of breathingcaused by a decrease in the sensitivity of the respiratory center to carbon dioxide. The respiratory frequency is reduced and an overdose may be stopped (death). Reducing the respiratory rate caused by morphine is useful when breathing, accompanying pulmonary edema (the fear of the patient is reduced from the shortness of breath). Accumulation carbon dioxide When disgraving, respiration leads to the relaxation of cerebral vessels and an increase in intracranial pressure (and this is dangerous during head injuries).

Suppression of a cough center It is not proportional analgesic action. Thus, weak opioid analgesics Codein and Deteromethorphan have a strong antitussive effect.

Sleep, which is explained by the consequence of eliminating pain - the patient calms down and falls asleep.

Effects of excitation CNS.

Vomot (As a result of stimulation of chemoreceptors, the starting zone of the pussy center) often happens in patients who are in motion, and is not accompanied by unpleasant sensations. With the chronic use of vomiting there is no.

MIOS. (The narrowing of the pupil) caused by the stimulating influence of parasympathetic innervation on the tone of the kernel of the ocudual nerve. This effect is maintained in chronic use (i.e. there is no addictive). MIO, bradypit (rare breathing) and coma are reliable diagnostic symptoms of overdose by ophiode analgesics.

Cramps. This is an extremely rare effect of meperidine, trimespyridine (priedol) when they are overdose against the background of renal failure due to the accumulation of toxic metabolites.

Muscle rigidity torso Reduces the volume of respiratory movements and can disrupt the patient's breathing. It is most pronounced with rapid intravenous appointment of large doses of opioid analgesics with high lipid solubility (fentanyl and substances close to it). For the removal of rigidity (the reason for its - opioid analgesics act on the supracinal level), strip-like muscle relaxants are prescribed.

Peripheral effects of morphine

Constipation Due to the suppression of the intestinal peristaltics while simultaneously increasing the tone of the smooth muscles of the thick bowel and the anal sphincter spa. All this leads to a slowdown in the promotion of chimus (food lump), suction of water and to the constation. This effect is widely used with a diarrhea of \u200b\u200bnon-infectious origin. In diarrhea, opioid analgesics are considered the most efficient group of substances. Related chemical structures are used with opioid analgesics Loperamide (Imodium) and diphenoxylate. They are safe, as they do not penetrate into the central nervous system and therefore do not cause euphoria nor analgesia or drug addiction.

Spasm of muscles of biliary tract (Can cause hepatic colic).

Increase the tone of the ureter, detrumery and bladder sphincterWhat can strengthen the flow and (with prostate adenoma) cause urine delay.

Cardiovascular system varies only by substances with a M-choline-blocking effect. For example, Trimperidine (Promedol) and Metheridine may cause tachycardia. However, against the background of stress, opioid analgesics can cause a small hypotension due to the selection of histamine and reduce the tone of the vasomotor center.

Histamine selection of fat cells It leads to the expansion of the vessels of the skin, which is why a minor decrease in blood pressure is possible. There may also be skin itching, urticaria and bronchospasm from asthmatics.

Reducing the excretory function of the kidneys: Reducing renal blood flow and glomerular filtering.

Reducing the tone of the uterusWhat can cause a slowdown in childbirth. The mechanism of this effect is unknown.

Pharmacokinetics

Opioid analgesics in the absolute majority are well absorbed in the gastrointestinal tract, Then they are metabolized in the liver and in the form of metabolites (glucuronides, etc.) stand out with urine. However, there are differences in the speed and magnitude of suction in the gastrointestinal tract (therefore, opioid analgesics are most often appointed parenterally, it is a more accurate method) and the peculiarities of the liver metabolism. For example, the appointment of a large dose of morphine against the background of renal damage leads to accumulation in the organism of the neurotoxic morphine metabolite (morphine-3-glucuronide), which can cause cramps. Such effect may be with the accumulation of metabolites of meperidine or its analogues. With repeated assignments of large doses of opioid analgesics (especially with high lipophilicity, like fentanyl), it is possible to accumulate them in adipose tissue, which creates a danger of toxic effects.

Combinations with opioid analgesics

The oppressive effects of opioid analgesics (including analgesia) increase:

• neuroleptics (Fentanyl + Droperidol combination is used for neuroleptanalgesia),
• sedatives I. sleeping equipmentthat increases the risk of oppression;
• antidepressants - a combination with Mao inhibitors is contraindicated due to the risk of a hyperpirex coma;
• amphetamines paradoxically enhance the analgesia of opioid analgesics.

Comparative characteristics of opioid analgesics

Opioid analgesics differ from each other by duration of action, severity (strength) of individual effects, risk of drug addiction.

The duration of action opioid analgesics are divided into substances:

• short action (about 30 minutes), for example, fentanyl;
• average duration of action (about 6 hours), for example, morphine;
• long-term action (about 25 hours), for example, methadone.

• anesthetic: for example, morphine about 70 times weaker fentanyl;
• spasm Smooth Musculature: The smallest of all in Promedol, meperidine, which have similarities on the structure with atropine;
• anti-Action: Strong - Codeine, very weak - at Promedol (Trimeperidine).

According to the risk of drug dependence, opioid analgesics are divided into substances, the purpose of which is associated:

• with high risk of addiction (strong agonists);
• with low risk of addiction (mixed antagonist agonists and partial agonists). Although this group is trying to give preference, if necessary, long-term treatment, but their effectiveness is not always sufficient to eliminate pain. In addition, they can cause unwanted mental effects: hallucinations, nightmares, alarm. With simultaneous admission with strong agonists of opioid formarots, they behave like antagonists - that is, they displacing the last due to opioid receptors. At the same time, drug addicts will be abstinence, and in patients with pain - decreased analgesia.
• without risk of drug addiction: Anti-stage opioids (Loperamide, diphenoxylate) and anti-op opioid dextromethorphan. Actually, the substances of this group are not true opioid analgesics (since they do not cause analgesia), but very close to them in the chemical structure.

Indications for the use of opioid analgesics

Opioid analgesics are applied in cases:

Cile sharp pain (Myocardial infarction, injuries, burns, colic) and strong chronic pain of an inflammatory character (cancer). The anesthesia must be adequately by the power of pain and from time to time to be reviewed in the direction of increasing or decreasing dosages. For example, with hepatic or renal colic after the introduction of opioids, pain may, on the contrary, increase, and not decrease. This is due to an increase in the spasm of smooth muscles. Therefore, with colic it is important to increase the dose of opioids, which will cause effective anesthesia. In case of inoperable cancer, it is possible to even take the risk of drug addiction in such patients (large doses of substances, constant introduction), but to achieve effective anesthesia.

In other cases, preference is given to strong agonists (with acute pain) and partial agonists in chronic pain (due to the small risk of drug addiction). It should be borne in mind that partial agonists are inferior in efficiency to strong agonists

Anesthesia in surgical operations (Premedication and directly during the operation). Particularly used fentanyl and its derivatives.

Pulmonary edema (Reducing the frequency of respiration reduces the fear of the patient) and reducing the preload and post-loading on the heart (due to the expansion of venous and arterial vessels). Morphine is most often used.

Pain in childbirth. The CIS uses an analogue of foreign meperidine - Trimeperidin (Promedol). It is weak, compared to morphine, inhibits the breath of the fetus. In addition, its metabolism (rapid demethylation) is safe for the fetus, compared with morphine metabolism (slow conjugation in the liver). Unlike other opioid analgesics, trimeperidine and meperidine do not weaken, and enhance the generic activities.

Cough: Codeine, dextromethorphan;

Diarrhea (not infectious): diphenoxylate (realaks), Loperamide (IMODIUM).

Side Effects of Opioid Analgesics

Opioid analgesics have side effects that are the continuation of their pharmacological action: the oppression of breathing, constipation, drug addiction, nausea, vomiting and (toxic doses of trimeperidine, meperidine, tramadol, less often - morphine) cramps. In agonists there may be psychotomimetic reactions (hallucinations, nightmares and anxiety).

Contraindications

According to side effects, opioid analgesics are contraindicated at:

• oppression of breathing (except for patients on IVL);
• with an attack of bronchial asthma or when it is severe, even outside of the attack;
• with paralytic ileus.

Drug addiction and opioid analgesics

The reason for drug dependences is not fully found out. Among possible causes - Changing the functioning of opioid receptors with constant purpose of opioid analgesics (reducing the number of receptors and their affinities for agonists), dysfunction of the chain structural interaction: receptor - G-protein - secondary cell mediators - ion channels. In particular, great importance It is attached to a specific complex with ion channels - the NMDA receptor (found that ketamine, the NMDA receptor antagonist blocks the development of addiction and physical dependence).

Characteristics of drug addiction drug addiction. It is very heavy (mental and physical) and is accompanied by severe addiction (tolerance) to all the effects of opioid analgesics, with the exception of Mios and constipation. The person dependent on them (drug addict) requires an increasing and large dose of opioid analgesics, and the cessation of their reception is extremely severe (but usually not a fatal abstinence syndrome).

Abstineent syndrome is a sign of the presence of physical drug addiction. At first (first 12 hours after receiving the last dose of morphine) there are signs of mental dependence, nervousness, sweating and thirst for drugs. They are softened by the appointment of placebo. Then there are signs of severe physical dependence, mostly associated with a violation of the function of the autonomic nervous system: mydriasis, tachycardia, goose skin, intestinal colic, pain in the muscles, vomiting, diarrhea, shortness of breath, fever, yawning, tremor, sneezing, tear, and also Anorexia and depression. Morphine has a maximum of abstinentation for 1-2 day, and its duration is about 5 days. In most cases, the addict does not stand it and returns to drugs.

Treatment of drug addiction is carried out methadone. This is a durable strong opioid receptor agonist, close to morphine. The peak of the abstineent syndrome (significantly softer than the morphine) is the first week, the duration is three weeks. Instead of methadone, the partial agonist of opioid receptors buprenorphine is increasingly used. Both substances are prescribed in tablets with a gradual decrease in the daily dose to their complete cancellation. A long-range (48 hours) antagonist of opioid receptors Naltrekson is prescribed inside in the treatment of drug addicts. It eliminates the meaning of drug-opioids of drug addicts, as it blocks opioid receptors and prevents all effects that are performed by opioid analgesics. For the treatment of drug addicts, clonidine (clofelin) recently was used, which eliminates the symptoms of the hyperactivity of the symatic nervous system observed in opioid abstinence.

Poisoning opioid analgesics

Acute poisoning of morphine and its analogues is eliminated by intravenous administration of naloxone opioid analgesic antagonist. Within 30 seconds, it displaces opioid analgesics from the cells of the respiratory center and restores the normal respiration of the poisoned person. The action of it is short-term (1-2 hours), which requires repeated administration Naloxone in poisoning by durable opioid analgesics. In the latter case, namphnene is preferable (the duration of about 8-10 hours), which is a derivative of Naltrexone, but is assigned only intravenously.

List: opioid analgesics and their features

Morphine

Morphine refers to the group opioid analgesics - their prototype. It is slow and in an individually changeable amount absorbed inside, exposed to the strong effect of the first passage. Therefore, its parenteral administration gives a more predictable effect. Acts for a long time (about 4-6 hours). The liver of newborns is weakly, compared with adults, metabolizes (conjugation with glucuronic acid) metformin. Because of this, morphine cannot be prescribed for pain relief and newborn.

Almost identical to morphine according to the properties, although it is not similar to it in structure, pyrimide. The only difference from the morphine of the hydromorphon and the oximorphon is a longer action. Obanopon is a naogalenya opium preparation containing morphine and other opium alkaloids, including papaverine. Acts similarly, but weaker morphine. However, the spasm of a smooth muscles of urine and biliary tract is less, as it contains an antispasmodic in its composition - Papaverin.

Promedol

Trimeperidine (Promedol) belongs to the group opioid analgesics, it is weaker morphine and inhibits the respiratory center. Therefore, this substance is considered a drug selection in obstetrics and pediatrics. It has weak M-choline-blocking properties therefore does not cause such a strong spampum of a smooth muscles like morphine, can cause tachycardia, dry mouth and the expansion of pupils. It does not have a noticeable antitussive action, which can be useful in patients with lung diseases when it is necessary to keep the cough reflex. Also does not have a clinically significant overpressure effect. It is better absorbed in the gastrointestinal gastrointestinal tract, but inferior to him on the strength and duration of action (2-4 hours). Trimeperidine is close in structure and properties to a foreign analogue of meperidine. The characteristic effect of overdose of these substances is neurotoxicity (tremor and convulsions).

Methadone

Methadon refers to the group opioid analgesics, completely absorbed into the gastrointestinal tract, has a longer action (half-life about 24 hours) than morphine and is not inferior to him, but due to the slow effect of the effect causes a smaller euphoria. Prolonged action and good absorption when taking inside make it the main drugs for the release of drug addicts from suffering caused by the abstinence syndrome (since, due to prolonged action, methadone causes significantly softer abstineent syndrome than morphine and other strong asioid receptor agonists). At the same time, methadone is given in a gradually decreasing daily dose. Levorfanol is very similar to the properties of methadone, but stronger.

Fentanyl

Fentanyl refers to the group opioid analgesics, acts much stronger than morphine, but briefly (up to 30 minutes). Frequently used with the neuroleptics droperidol, which enhances its action. This combination is used to anesthetize surgical operations (neuroleptanalgesia). Close by the properties to Fentanyl Falentanil, Sufentanil, Remifentanil.

Codeine

Codeine refers to the group Opioid analgesics is a weak analogue of opioid receptors, so rarely and only with long-term use in large doses, it creates a threat to the development of drug addiction. Like other weak agonists (hydrocodone, oxycodone, propoxyphen) applied in combination with paracetamol or aspirin to eliminate the rope pain. Great absorbed in the gastrointestinal tract. It is highly effective when coughing in those doses that do not cause analgesia, but at present it is ousted by dextomeluorfan, since the latter does not cause drug addiction at all.

Pentazocin

Pentazocin belongs to the Opioid Analgesics Group - acts briefly, suction from the gastrointestinal tract. It belongs to antagonist antagonists of opioid receptors, that is, some receptors (kappa) excites, while others (MJ) blocks. Unlike morphine, pentazocin causes tachycardia and an increase in blood pressure (contraindicated with ischemic heart disease). The drug addicts the abstinence causes, that is, acts as an antagonist of opioid receptors. It often causes a dysphoroid (due to the excitation of the sigma receptors), therefore drug addiction is rarely developed. Chemically close to the Pentazocin of Disocine (however, it is primarily the MJ agonist, and then kappa receptors).

Buprenorphin

The buprenorphine refers to the group opioid analgesics, has a large affinity for MJ receptors, but excites them weakly. On the delta and kappa receptors, it acts as an antagonist. That is, it refers to antagonist antagonists of opioid receptors, so Rick development of drug addiction is small. The buprenorphine has a long action and is also used to treat opioid drug addiction. Specifies for a long time, about 9 hours. Can be given under the tongue. The risk of developing drug addiction from the Bucrenorphine itself is low. It does not cause constipation, does not affect the SCC, but often when using pentazocin. It is used for postoperative pains, strong pains in the abdominal organs.

Tramadol.

Tramadol (tram) belongs to the group opioid analgesics, the chemical structure resembles Codein. Compared to morphine, this is a relatively selective, but weak agonist (\u003d partial agonist) MJ receptors. In addition, the effects of tramadol are also associated with a strengthening of serotonergic processes (blockade of the inverse neural seizure of serotonin) in the CNS. Tramadol does not affect the respiratory center and on the SCC. It has a significant sedative action (it is impossible to assign drivers, etc.). When using high doses (400 mg), drug addiction may occur. The specific side effect of tramadol is an increase in the risk of convulsion due to a decline in a convulsive threshold. Abstineent syndrome is also accompanied by convulsions. Application similar to other partial agonists, and is also prescribed for atypical pains (chronic neuropathic pain) caused by the destruction of nerve fibers (herpetic, diabetic neuropathy, and so on).

Heroin

Heroin (Diacetyl Morphinon) belongs to the Opioid Analgesics Group - due to high lipophilicity, very quickly penetrates into the CNS and causes the strongest euphoria. Therefore, dependence is very rapidly developing to it, which is why it does not apply in medicine.

Propoxyphen

Propoxyphen refers to the opioid analgesics group - methadone derivative. Weak analgesic (even weaker coder). It is used inside, most often, in combination with paracetamol or (aspirin). In case of overdose, breathing and cardiotoxic effects occur.

Bujofanol

Butorofanol refers to the group opioid analgesics - stronger analgesic than Petnazocin. Buturofanol and nalbuphine predominantly stimulate cappa receptors. These two substances have a small risk of drug addiction and respiratory oppression, however cause dysphoria and rather weak. Botorofanol is used, most often, with postoperative pains. For an unknown reason, it is significantly more effective in women than in men.

Nalbufin

Nalbufin refers to the Opioid Analgesics Group - a strong capppon agonist receptor and the MJ receptor antagonist, less depressing breathing than morphine. Does not affect the CCC (safe with IHD).

An increase in the amount of drug addicts increases the demand for narcotic blockers. This is one of the preventive options, as well as the method of combating drug use.

The use of blockers

NC "Mosnarkology" is the embodiment of the newest methods for treating dependence in drug addicts. Our team of professionals doctors will help to cope with your disease, will give advice and hold a full course of treatment over dependency to the victorious end.

Specialists of the Mosnarkology Center, if the patient is desired and the presence of testimony will be blocked by drugs. The appointment of the blocker, his choice and the introduction of a drug-dependent patient doctors are engaged.

The essence of the lock methodology is simple and is in the introduction medicinal preparation In the patient's body. The action of the blocker can be different, more or less long and depends on the type of blocking preparation.

More efficiently, the use of blockers together with rehabilitation courses for drug addicts, which are regularly carried out in the Mosnarkology Narcological Center. For complete cure, restoration is required not only physical, but also mental dependence.

The mechanism of action of opioid receptor blockers

Thrust for drugs is so great that returns dependent on the vicious circle again and again. To somehow solve this problem, medication blockers were found.

I had to deceive the body of the drug addict. It is injected into its body, which blocks brain receptors. After the adoption of a narcotic dose, the patient now does not feel the hadive pleasure. The pathological effect of the drug is blocked. As a result, interest in drug treatment disappears.

IN this case The blockers perform the role of an anti-inflicted drug. At the heart of treatment - artificial creation of such a situation when the reception of large doses of drugs becomes impossible due to a serious deterioration of well-being.

Codings and blockers from drugs or "prohibitive techniques"

Do you need help? We not only know how you can help, but do it! The narcological clinic "Mosnarkology" will provide you with a fairly effective comprehensive treatment from dependencies in the comfortable chambers of our clinic.

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Description

This group includes narcotic analgesics (from Greek. Algos - pain and AN - without), which have a pronounced ability to relax or eliminate the feeling of pain.

Analgesic activity is exhibiting substances having a different chemical structure, and it is implemented by various mechanisms. Modern analgesics are divided into two main groups: narcotic and nonarcotic. Narcotic analgesics, as a rule, strong analgesic effect, cause side effects, the main of which is the development of preferences (addiction). Nonarcotic analgesics act less strongly than narcotic, but do not cause drug addiction - drug addiction (see).

For opioids, a strong analgesic activity is characterized, ensuring the possibility of their use as highly efficient painful agents in different fields of medicine, especially in injuries, surgical interventions, injuries, etc. and for diseases accompanied by severe pain syndrome (malignant neoplasms, myocardial infarction, etc.). Having a special impact on the CNS, opioids cause euphoria, changing the emotional paint pain and reaction to it. The most significant disadvantage is the danger of mental and physical dependence.

This group of analgesics includes natural alkaloids (morphine, codeine) and synthetic compounds (trimeperidine, fentanyl, tramadol, nalpanfin, etc.). Most synthetic preparations were obtained according to the principle of modification of the morphine molecule while preserving the elements of its structure or its simplification. By chemical modification of the morphine molecule, substances are also obtained, which are its antagonists (Naloxone, Naltrekson).

According to the severity of analgesic effects and side effects, drugs differ in each other, which is associated with the peculiarities of their chemical structure and physicochemical properties and, accordingly, with the interaction with receptors involved in the implementation of their pharmacological effects.

In the understanding of the neurochemical mechanisms of operation of opioids, the opening of specific opiate receptors and their endogenous peptide ligands - enkephalins and endorphins played a major role in the 70s. Opiate receptors are concentrated mainly in the CNS, but are also contained in peripheral organs and tissues. In the brain, opiate receptors are mainly in the structures related to the transmission and coding of pain signals. Depending on the sensitivity to different ligands among opiate receptors, subpopulations are isolated: 1- (MJ), 2- (kappa), 3- (delta), 4- (sigma), 5- (epsilon) having different functional significance.

By the nature of interaction with opiate receptors, all opioergic drugs are divided into:

Agonists (activate all types of receptors) - morphine, trimeperidine, tramadol, fentanyl, etc.;

Partial agonists (activate mainly MJ receptors) - buprenorphine;

Antagonist agonists (activate kappa- and sigma and block the MJ and delta-opiate receptors) - pentazocin, nallane (blocks mainly MJ opiate receptors and does not apply as analgesics);

Antagonists (block all types of opiate receptors) - Naloxone, Naltrekson.

The mechanism of action of opioids plays a role to the oppressive effect on the thalamic centers of pain sensitivity, conducting pain impulses to the cerebral cortex.

In medical practice, a number of opioids are applied. In addition to the morphine, its prolonged dosage forms are created. A significant amount of synthetic highly active analgesics of this group (trimeperidine, fentanyl, buprenorphine, butorofanol, etc.), which have high analgesic activity with different degrees of "addictricular potential" (the ability to cause painful addiction) is also obtained.