1. INTRODUCTION

Neuropharmacology is a section of pharmacology that studies the effect of pharmacological agents on the nervous system.

Substances (pharmac. Agents) that act on the central nervous system are called neurotropic substances.

Nerve cells are very sensitive and therefore respond to all changes in the external and internal environment of the body. The nervous system (NS) is involved in the formation of the body's response to the effects of almost all pharmacological substances. However, only those substances that have a direct direct effect on NA are called neurotropic .

All substances acting on the central nervous system (neurotropic), by the nature of the action are divided into:

1. Inhibitors (blockers) of the CNS: narcotic and hypnotic drugs, as well as aliphatic alcohols.

2. Analgesics: narcotic and non-narcotic.

3. Antipsychotics: antipsychotics, antidepressants, mania treatments.

4. Sedatives and tranquilizers (valerian and bromine salts, propane diol carbonates, benzadiazepine and its derivatives, depressants).

5. Psychostimulants. Analeptics. Nootropic drugs.

6. Local anesthetics.

GENERAL PHARMACOLOGY

In general pharmacology

1 shows the general patterns of pharmacokinetics and pharmacodynamics of drugs.

Ф А Р М А К О К И Н Е T And К A is a section of pharmacology about absorption, distribution in the body, deposition, metabolism and excretion of substances.

PHARMACODYNAMICS are the biological effects of substances, as well as the localization and mechanism of their action.

2 - the basic properties of substances that determine their physiological activity are considered

3 - the dependence of the effect on the conditions and application of these substances and the state of the body, which is directed to their action, is considered.

4 - the most important types of pharmacotherapy are discussed, as well as the general patterns of adverse and toxic effects of drugs.

WAYS OF INTRODUCTION OF MEDICINES. SUCTION

From the route of administration depends on the speed of development of the effect, its expression and duration, in some cases determines the nature of the action of substances.

Routes of administration are divided into enteral (through the digestive tract) and parenteral (bypassing the digestive tract).

Enteral routes include administration through the mouth, under the tongue, transbukkalno, into the duodenum, into the rectum (rectal).

The most common route of administration is through the mouth (by mouth; per os). The absorption (absorption) of a number of substances occurs partly from the stomach, but most medicines are absorbed in the small intestine (the significant absorption surface of the intestinal mucosa (approximately 200 m ² ) and its intensive blood supply).

The main mechanisms of absorption.

1. Passive diffusion through the cell membrane. It is determined by the concentration gradient of substances.

2. Filtration through the pores of membranes (water, some ions, as well as small hydrophilic molecules).

3. Active transport (transport systems of cell membranes are involved in this process) is characterized by selectivity and the possibility of competition between two substances for one transport mechanism, the possibility of transport against a concentration gradient and energy expenditure (metabolic poisons inhibit active transport).

4. During pinocytosis , the invagination of the cell membrane occurs, followed by the formation of a vesicle (vacuole).

The mechanisms of passage of substances are important not only for the absorption of substances, but also for their distribution in the body and excretion.

Sometimes drugs are injected through the probe into the duodenum (for example, magnesium sulfate as a choleretic), which allows you to quickly create a high concentration of the compound in the intestine.

With the introduction of the rectum (per rectum) a significant part of the substance (about 50%) enters the bloodstream, bypassing the liver, and the substance is not exposed to the enzymes of the digestive tract.

Medicinal substances having the structure of proteins, fats and polysaccharides are not absorbed in the colon.

The transplant route includes subcutaneous, intramuscular, intravenous, intraarterial, intrasternal, intraperitoneal, inhalation, subarachnoid, suboccipital, and some others.

The most common is the introduction of substances under the skin, into the muscle and into the vein. The effect is especially fast when administered intravenously, somewhat slower with intramuscular and subcutaneous administration. In order to prolong the pharmacotherapeutic effect, medicinal substances are introduced into the muscle in a poorly soluble form (suspension) in the bases that delay the absorption of substances from the injection site (oil).

Intramuscularly and subcutaneously should not be administered substances that have a pronounced irritant effect.

Intravenously, insoluble compounds, oil solutions (the possibility of embolism), agents with a pronounced irritant effect (may lead to the development of thrombosis, thrombophlebitis), drugs that cause blood clotting or hemolysis cannot be administered.

Negative features of these 3 routes of administration are their relative complexity, as well as pain, the need for sterility of drugs, the participation of medical personnel.

Intra-arterial injection allows creating high concentrations of the substance in the region. In this way, anticancer agents, radiopaque preparations are sometimes administered, which allows to accurately determine the localization of the tumor, thrombus, vasoconstriction, aneurysm.

Intrasternal route of administration (in the sternum) is usually used for technical impossibility of intravenous administration (in children, people of old age).

Intraperitoneal drugs are rarely injected (for example, antibiotics during celiac surgery).

Sometimes drugs are prescribed intrapleurally (in the pleural cavity).

For gaseous and volatile compounds, the main route is the inhalation route of administration. Absorption of substances during their inhalation occurs quickly. The expression of the effect is easy to control by changing the concentration of the substance in the air we breathe.

Drugs that poorly penetrate the blood-brain barrier can be administered under the lining of the brain (subarachnoid, subdural, or suboccipital).

Some drugs (usually high lipophilic) are absorbed and have a resorptive effect when applied to the skin (for example, nitroglycerin).

Sometimes use ionophoretic introduction of ionized substances (from the skin or mucous membranes). Their absorption is provided by a weak electric field.

Some drugs are prescribed intranasally (in particular, adiurecrin). Absorption in this case occurs from the mucous membrane of the nasal cavity.

DISTRIBUTION OF MEDICINES IN THE ORGANISM. BIOLOGICAL BARRIERS. DEPOSIT

After absorption of the substance into the blood, and then into different organs and tissues. Most drugs are unevenly distributed.

Biological barriers affect the distribution of substances: capillary wall, cell (plasma) membranes, blood-brain and placental barriers.

Through the wall of capillaries (the pore size in humans is about 2 nm), most drugs pass quite easily. Exception: plasma proteins and their complexes with drugs.

The passage of many substances through the blood-brain barrier is difficult . This is due to the structural features of the brain capillaries. Through the blood-brain barrier poorly pass polar compounds. Lipophilic molecules penetrate the brain tissue easily. There are some small areas of the brain (the region of the pineal gland, the posterior lobe of the pituitary, etc.), in which the blood-brain barrier is practically ineffective. In some pathological conditions (for example, inflammation of the meninges), the permeability of the blood-brain barrier increases.

Placental barrier. Lipophilic compounds pass through it (by diffusion). Ionized polar substances penetrate poorly. The placenta also has a P-glycoprotein pump.

The distribution depends on the affinity of the drugs for certain tissues, on the intensity of the blood supply to the organ or tissue. Drugs are bound to form extracellular and cellular depots.

Substances can accumulate in the connective tissue (some polar compounds, including quaternary ammonium salts), in the bone tissue (tetracyclines).

Binding of drugs in cells is possible due to proteins, nucleoproteins and phospholipids.

Fat depots are of particular interest, as they can delay lipophilic compounds (in particular, some drugs for anesthesia).

Medicinal products are deposited, as a rule, due to reversible bonds. Very long retained in the body, for example, heavy metal ions.

The distribution of substances, as a rule, does not characterize the direction of their action. The latter depends on the sensitivity of tissues to them. from the affinity of drugs to those biological substrates that determine the specificity of their action.

CHEMICAL TRANSFORMATIONS (BIOTRANSFORMATION, METABOLISM) OF MEDICINES IN THE ORGANISM

Most drugs undergo biotransformation in the body. In unchanged form, highly hydrophilic ionized compounds are released. Of lipophilic substances, an exception is made for inhalation anesthesia, the main part of which does not enter into chemical reactions in the body. They are displayed light in the same form. In biotransformation the most important role belongs to microsomal liver enzymes (located in the endoplasmic reticulum). They metabolize lipophilic compounds. Non-microsomal enzymes of the liver, intestines and other tissues, as well as plasma, are essential, especially in the case of biotransformation of hydrophilic substances.

There are 2 main types of transformations: 1) metabolic transformation and 2) conjugation.

Metabolic transformation is the transformation of substances through oxidation, reduction and hydrolysis.

Conjugate is a biosynthetic process, accompanied by the adherence to a drug substance or its metabolites of a number of chemical groups or molecules of endogenous compounds.

WAYS OF EXTRACTION OF MEDICINES FROM THE BODY

Drugs, their metabolites and conjugates are mainly excreted in the urine and bile.

Low molecular compounds dissolved in plasma (not associated with proteins) are excreted in the kidneys.

Excretion of substances largely depends on the process of their reabsorption (reabsorption) in the renal tubules. Mainly by simple diffusion, for example, lipophilic non-polar compounds.

A number of drugs (tetracyclines, penicillins, difenin, colchicine, and others), and especially the products of their conversion in large quantities, are excreted in the bile into the intestine, from which they are partially excreted with excrement.

Gaseous and many volatile substances (for example, agents for inhalation anesthesia) are mainly excreted by the lungs.

Separate drugs are secreted by the salivary glands (iodides), sweat glands (ditephalic leprosy), the stomach glands (quinine, nicotine) and the intestines (weak organic acids), lacrimal glands (rifampicin).

During lactation, many substances are secreted by the mammary glands, which a nursing mother receives (sleeping pills, painkillers, ethyl alcohol, nicotine, etc.).

Elimination (removal) of substances from the body is quantitatively characterized by a number of parameters: the elimination rate constant (KeNm) "half-life" (t1 / 2) and total clearance (CIT).

The elimination rate constant (KeNm) reflects the rate of removal of a substance from the body.

To judge the rate of excretion of substances from the body, the parameter “half-life” (semi-elimination) - t1 / 2 'is also used, which reflects the time required to reduce the concentration of a substance in the blood plasma by 50%:

In addition, for the quantitative characterization of the rate of elimination of substances, the parameter clap (Cl) is used, which reflects the rate of purification of blood plasma from the substance (expressed in volume per unit time, if necessary, taking into account body mass or its surface: ml / min, ml / kg / min , l / m ² / h, etc.). Allocate total (total) clearance (CIT), as well as renal (CIR) and hepatic (CIH) clearance.

LOCAL AND RESORBATIVE EFFECTS OF MEDICINES. DIRECT AND REFLECTOR ACTION. LOCALIZATION AND MECHANISM OF ACTION. "TARGETS" FOR MEDICINES. REVERSIBLE AND IRREVERSIBLE ACTION. ELECTORAL ACTION

The action of a substance that occurs at the place of its application is called local. The action of a substance that develops after its absorption, entering the general bloodstream and then into the tissue is called resorptive. Resorptive effect depends on the route of administration of drugs and their ability to penetrate biological barriers.

With local and resorptive action, drugs have either a direct or reflex effect. The first is implemented at the site of direct contact of the substance with a cloth. In the case of a reflex effect, substances affect the exteroter or interoceptors and the effect is manifested by a change in the state of either the corresponding nerve centers or the executive organs. Thus, the use of mustard plasters in the pathology of the respiratory organs reflexively improves their trophism (essential mustard oil stimulates the exteroceptors of the skin).

The main task of pharmacodynamics is to find out where and how medicines act, causing these or other effects. For neurotropic drugs, those structures of the nervous system are established, the synaptic formations of which have the highest sensitivity to these compounds.

Receptors, ionic channels, enzymes, transport systems and genes serve as "targets" for drugs.

Receptors are called active groups of substrates macromolecules with which the substance interacts. Receptors that provide the manifestation of the action of substances, called specific.

The following 4 types of receptors are distinguished.

1. Receptors that directly control the function of ion channels. (n-cholinergic receptors, GABAA receptors, glutamate receptors).

P. Receptors coupled to the effector through the system "G-proteins - secondary transmitters" or "G-proteins-ion channels". Such receptors are available for many hormones and mediators (m-cholinergic receptors, adrenoreceptors).

IP. Receptors that directly control the function of the effector enzyme.

Iv. DNA transcriptional receptors. Unlike membrane receptors of 1-111 types, these are intracellular receptors (soluble cytosolic or nuclear proteins). Steroid and thyroid hormones interact with such receptors.

Substances that cause the same effect as the mediators themselves are called agonists (mediators).

Substances that cause a reverse effect to the mediators and interfere with the action of the mediator are called antagonists.

Mechanisms of interaction of pharmaceutical substances with receptors :

1) The allochronic mechanism suggests structural similarities between the pharmacological substance and the endogenous mediator and its interaction directly with the reactive active groups of the receptor.

The allosteric mechanism of action of active substances is a process where the pharmaceutical agent does not act on the active functional groups of the receptor, but on other parts of the receptor macromolecule, which leads to disruption of the conformation of the entire molecule. As a result, the reactivity of the functional group of the molecule (receptor) changes. Considering the effect of substances on postsynaptic receptors, it should be noted the possibility of allosteric binding of substances of both endogenous (eg, glycine) and exogenous (for example, benzodiazepine anxiolytics) origin. Allosteric interaction with the receptor does not cause a "signal". There is, however, a modulation of the main mediator effect, which can both be amplified and weakened. The creation of substances of this type opens up new possibilities for regulating the functions of the CNS. A special feature of neuromodulators of allosteric action is that they do not have a direct effect on the main mediator transmission, but only modify it in the desired direction.

Substances that interact by this mechanism should not have structural similarity with the mediator.

To assess the pharmacoactivity of a substance, two properties are distinguished :

1. "affinity" of the substance to the receptor;

2. the internal activity of the substance.

The affinity of a substance to a receptor, leading to the formation of a “substance-receptor” complex with it, is denoted by the term “a F F and n and te”. The ability of a substance to interact with the receptor to stimulate it and cause a particular effect is called intrinsic activity.

Substances that, when interacting with specific receptors, cause changes in them that lead to a biological effect, are called agonists (they also possess intrinsic activity). The stimulatory effect of an agonist on receptors can lead to the activation or inhibition of cell function. If the agonist, interacting with receptors, causes the maximum effect, it is called a complete agonist. В отличие от последнего частичные агонисты при взаимодействии с теми же рецепторами не вызывают максимального эффекта. Вещества, связывающиеся с рецепторами, но не вызывающие их стимуляцию, называют антагонистами. Внутренняя активность у них отсутствует (равна О). Их фармакологические эффекты обусловлены антагонизмом с эндогенными лигандами (медиаторами, гормонами), а также с экзогенными веществами-агонистами.

У самых близких агонистов к медиатору имеется большое сродство и высокая внутренняя активность.

А у антагонистов имеется сродство к рецептору, но отсутствует внутренняя активность.

Внутренняя активность определяется следующим образом: при одной и той же величине функционирующих рецепторов (эффект) зависит от внутренней активности вещества.

Внутренняя активность эндогенного медиатора или стандартного агониста принимается за единицу, а отношение максимальной реакции, которая вызывает вещество к максимальному эффекту медиатора, называется мерой внутренней активности.

"а" медиатора = 1

Сродство агониста к рецептору определяют по его концентрации, которая способна прореагировать с половиной рецепторов, то есть дать половину максимального эффекта.

По сути, концентрация вещества - это эффективная доза вещества, даёт 50% эффекта.

Отрицательный логарифм, вызывающий половину эффекта (рД ₂ ) - это есть мера сродства (медиатора к рецептору).

Для антагонистов оценка сродства к рецептору определяется по концентрации антагониста, при которой необходимо повысить вдвое концентрацию эндогенного медиатора, чтобы получить тот же эффект, что и в отсутствии антагониста.

2) Отрицательный алгоритм этой концентрации есть мера конкурентного антагонизма, которая основана на сродстве антагониста к рецептору (рА ₂ ).

Эффект совместного действия, конкурирующих за рецептор агониста и антогонисат (кто быстрее сможет воздействовать) зависит от количества рецепторов, связанных с агонистом и антагонистом. А это определяется концентрацией агониста и антагониста и коэффициентом диссоциации "вещество - рецептор" (насколько прочно присоединяются) агониста и антагониста.

Если они занимают те же рецепторы, с которыми взаимодействуют агонисты, то речь идет о конкурентных антагонистах, если другие участки макромолекулы, не относящиеся к специфическому рецептору, но взаимосвязанные с ним, то - о неконкурентных антагонистах. При действии вещества как агониста на один подтип рецепторов и как антагониста - на другой, его обозначают агонистом-антагонистом. Например, анальгетик пентазоцин является антагонистом - и агонистом 8- и к-опиоидных рецепторов.

Когда возникает конкурентный антагонизм, то кривая не изменяется по форме, а смещается в область увеличения дозы (концентрации).

Признаком конкурентного действия антагониста является сдвиг вправо, то есть в область больших концентраций кривой соотношения "концентрации и эффекта" агониста, при неизменной форме кривой.

При изменении формы кривой агониста "концентрация-эффект" говорят, что между агонистом и антагонистом существуют неспецифичные, неконкурентные отношения.

Мерой неспецифичного антагонизма является тот же самый отрицательный логарифм концентрации вещества, который приводит к увеличению в два раза концентрации агониста, чтобы получить прежний эффект при отсутствии антагониста (рД ₂ ).

2) конкурентный;

3) неспецифический, неконкурентный.

Важную роль для понимания механизмов регуляции синаптической передачи сыграло открытие пресинаптических рецепторов. Были изучены пути гомотропной ауторегуляции (действие выделяющего медиатора на пресинаптические рецепторы того же нервного окончания) и гетеротропной регуляции (пресинаптическая регуляция за счет другого медиатора) высвобождения медиаторов, что позволило по-новому оценить особенности действия многих веществ.

Взаимодействие «вещество-рецептор» осуществляется за счет межмолекулярных связей. Наиболее прочная связь - ковалентная. Она известна для небольшого числа препаратов (α-адреноблокатор феноксибензамин, некоторые противобластомные вещества). Менее стойкой является распространенная ионная связь, осуществляемая за счет электростатического взаимодействия веществ с рецепторами. Последняя типична для ганглиоблокаторов, курареподобных средств, ацетилхолина. Важную роль играют ван-дер-ваальсовы силы, составляющие основу гидрофобных взаимодействий, а также водородные связи.

В зависимости от прочности связи «вещество-рецептор» различают обратимое действие (характерное для большинства веществ) и необратимое (как правило, в случае ковалентной связи).

Если вещество взаимодействует только с функционально однозначными рецепторами определенной локализации и не влияет на другие рецепторы, то дейcтвиe такого вещества считают избирательным. Так, некоторые курареподобные средства довольно избирательно блокируют холинорецепторы концевых пластинок, вызывая расслабление скелетных мышц. В дозах, оказывающих миопаралитическое действие, на другие рецепторы они влияют мало.

Основой избирательности действия является сродство (аффинитет) вещества к рецептору. Это обусловлено наличием определенных функциональных группиpoвoк, а также общей структурной организацией вещества, наиболее адекватной для взаимодействия с данным рецептором, т.е. их комплементарностью.

Реакция ткани на прямое воздействие веществ называется «первичной фармакологической реакцией». Это взаимодействие между атакующими молекулами и макромолекулами (рецепторами) живого субстрата.

В основном все лекарственные средства обладают обратимым действием , то есть таким, который прекращается после выведения или разрушается от введённого в организм вещества.*

Этот процесс имеет место при слабом взаимодействии между микро- и макромолекулами, то есть оно основано на образовании лабильных связей вещество-рецептор. Этот процесс связан с тем, что молекулы обладают непрочными связями.*

Рецепторы, как правило, обладают избирательной реагирующей способностью на естественные агенты (внутренние эндогенные). Если экзогенные вещества сходны по своей структуре и свойствам м эндогенными, то они также могут взаимодействовать с рецепторами организма => их избирательность.

Фармовещества, которые могут реагировать с постсинаптическими рецепторами, называются синаптическими или медиаторными средствами.

Обладая влиянием на место передачи неравного импульса, медиаторные средства оказывают мощное нейтронное воздействие.

Пример: при сильных болях принимают болеутоляющее - таким образом НС блокирует нервные импульсы.

Самые сильные из них – наркотические вещества. Действуя на эндоморфины, они снимают боль.

Кроме рецепторов, нейтронные средства могут воздействовать и не тканевые энзимы (ферменты, катализаторы). Определённые вещества взаимодействуют с определёнными энзимами.

Пример: в НС существует ацетилхолин (наиболее встречается в периферических НС), нонадреналин – в центральной НС.

Когда вводятся антихолинэстеразные вещества, может служить примером, которые связывают холинэстеразу, что ведёт к накоплению ацетилхолина.

Пример: кроме этого существуют алкалоиды группы кофеина, которые угнетают активность фосфодиэстеразы, в результате чего в тканях повышается содержание циклической 3,5 АМФ (аденазимонофосфат).

Кроме этого, блокирование цианидами цитохромоахсидазы.

Действие вещества на НС зависит от действия физиохимических свойств вещества:

степень липидофильности; электрический заряд; растворимость; степень диссоциации (разделяется на ионы).

Липидофильность обеспечивает различное распространение вещества в фе-ме, то есть вещества, которые обладают высокой степенью липидофильности, могут проникать в гемато(кровь)-энцефалический (головной мозг) барьер и одинаково действую и на периферическую и на ЦНС.

ЗАВИСИМОСТЬ ФАРМАКОТЕРАПЕВТИЧЕСКОГО ЭФФЕКТА

ОТ СВОЙСТВ ЛЕКАРСТВЕННЫХ СРЕДСТВ И УСЛОВИЙ ИХ ПРИМЕНЕНИЯ

А) ХИМИЧЕСКОЕ СТРОЕНИЕ, ФИЗИКО-ХИМИЧЕСКИЕ

И ФИЗИЧЕСКИЕ СВОЙСТВА ЛЕКАРСТВЕННЫХ СРЕДСТВ

Свойства лекарственных средств в значительной степени обусловлены их химичecким строением, наличием функционально активных группировок, формой и размером их молекул. Для эффективного взаимодействия вещества с рецептором необходима такая структура лекарственного средства, которая обеспечивает наиболее тесный его контакт с рецептором. Для взаимодействия вещества с рецептором особенно важно их пространственное соответствие, т.е. комплементарность.

Многие количественные и качественные характеристики действия веществ зависят также от таких физико-химических и физических свойств, как растворимость в воде, липидах, для порошкообразных соединений - от степени их измельчения, для летучих веществ - от степени летучести и т.д. Важное значение имеет степень диссоциации.

Б) ДОЗЫ И КОНЦЕНТРАЦИИ

The effect of drugs is largely determined by their dose. Depending on the dose (concentration), the rate of development of the effect, its severity, duration, and sometimes character, change. Usually with increasing dose (concentration) decreases the latent period and increases the severity and duration of the effect.

The dose is the amount of substance at one time (usually referred to as a single dose).

For a more accurate dosage of drugs calculate their number per 1 kg of body weight. In some cases, it is preferable to dispense substances based on the size of the body surface (per 1 m ² ).

Минимальные дозы, в которых лекарственные средства вызывают начальный биологический эффект, называют пороговыми, или минимальными действующими. В практической медицине чаще всего используют средние терапевтические дозы, в которых препараты у преобладающего большинства больных оказывают необходимое фармакотерапевтическое действие. Кроме того, выделяют токсические дозы, в которых вещества вызывают опасные для организма токсические эффекты, и смертельные дозы.

Для веществ, вводимых ингаляционно (например, газообразные и летучие средства для наркоза), основное значение имеет их концентрация во вдыхаемом воздухе (обозначается в объемных процентах).

В) ПОВТОРНОЕ ПРИМЕНЕНИЕ ЛЕКАРСТВЕННЫХ СРЕДСТВ

При повторном применении лекарственных средств действие их может изменяться в сторону как нарастания, так и уменьшения эффекта.

Увеличение эффекта ряда веществ связано с их способностью к кумуляции материалыюй кумуляцией накопление в организме фармакологического вещества Функционалыюй кумуляции при которой «накапливается» эффект, а не вещество.

Снижение эффективности веществ при их повторном применении - привыкание (толерантность). Оно может быть связано с уменьшением всасывания вещества, увеличением скорости его инактивации и (или) повышением интенсивности выведения. Возможно, что привыкание к ряду веществ обусловлено снижением чувствительности к ним рецепторных образований или уменьшением их плотности в тканях.

Some substances (usually neurotropic) with their repeated administration develops drug dependence. It manifests itself as an irresistible desire to take a substance, usually with the aim of raising the mood, improving well-being, eliminating unpleasant experiences and sensations, including those that arise when the substances causing drug dependence are canceled. There are mental and physical drug dependence. In the case of mental drug dependence, stopping drug administration (for example, cocaine, hallucinogens) causes only emotional discomfort. When taking certain substances (morphine, heroin), physical drug dependence develops . This is a more pronounced degree of dependence. The abolition of the drug in this case causes a serious condition, which, in addition to drastic mental changes, manifests itself in various and often serious somatic disorders associated with the disorder of the functions of many body systems, up to and including death. This is the so-called withdrawal syndrome, or the phenomenon of deprivation.

Prevention and treatment of drug dependence is a serious medical and social problem.

D) INTERACTION OF MEDICINES

In medical practice, often use several drugs at the same time. At the same time, they can interact with each other, changing the severity and nature of the main effect, its duration, as well as enhancing or weakening the side and toxic effects.

Drug interactions can be classified as follows.

1. Pharmacological interaction:

1) based on changes in the pharmacokinetics of drugs;

2) based on changes in the pharmacodynamics of drugs;

3) based on the chemical and physico-chemical interaction of drugs in the environment of the body.

Ii. Pharmaceutical interaction.

Combinations of various drugs are often used to enhance or combine effects that are useful for medical practice. However, when the combination of substances can occur and adverse interaction, which is designated as the incompatibility of drugs. The incompatibility is manifested by a weakening, complete loss or change in the nature of the pharmacotherapeutic effect or an increase in the side effect or toxic effect. ( pharmacological incompatibility). Incompatibility is also possible in the manufacture and storage of combined drugs (pharmaceutical incompatibility).

Pharmacological interaction

Pharmacological interaction is associated with the fact that one substance changes the pharmacokinetics and / or pharmacodynamics of another component of the mixture. The pharmacokinetic type of interaction may be associated with impaired absorption, biotransformation, transport, deposition and removal of one of the substances. The pharmacodynamic type of interaction is the result of direct or indirect interaction of substances at the level of receptors, cells, enzymes, organs or physiological systems. In this case, the main effect can be changed quantitatively (strengthen, weaken) or qualitatively.

Pharmaceutical Interaction

There are cases of pharmaceutical incompatibility, in which in the process of making preparations and (or) their storage, as well as when mixing with a water syringe, the components of the mixture interact and such changes occur, as a result of which the preparation becomes unsuitable for practical use. At the same time, the previously existing pharmacotherapeutic activity of the initial components decreases or disappears. In some cases, new, sometimes unfavorable (toxic) properties appear.

THE IMPORTANCE OF INDIVIDUAL PECULIARITIES OF THE ORGANISM AND ITS CONDITION FOR THE MANIFESTATION OF THE ACTION OF MEDICINES

A) AGE

Drug sensitivity varies with age. In this connection, the so-called perinatal pharmacology was distinguished, exploring the peculiarities of the effect of drugs on the fetus from 24 weeks before delivery and on the newborn (up to 4 weeks of life). In terms of sensitivity to medicinal substances, the fetus in the last trimester and newborns in the first month of life differ significantly from adults. This is due to the failure of many enzymes, kidney function, increased permeability of the blood-brain barrier, and underdevelopment of the central nervous system. Receptors during this period of life also have a different sensitivity to drugs. For example, newborns are more sensitive to certain substances that affect the central nervous system (in particular, to morphine). Levmetsetin is very toxic for them, which can even cause death. Young children should not prescribe substances that increase the secretion of glands (bronchial, nasal mucosa, etc.), as this can disrupt the process of respiration and cause respiratory pathology.

In the elderly and senile age, the absorption of drugs is slowed down, their metabolism proceeds less efficiently, the rate of excretion of drugs by the kidneys is lowered. In general, sensitivity to most drugs in the elderly and senile age is increased, and therefore their dose should be reduced.

B) FLOOR

In an experiment on animals, it was shown that males are less sensitive to a number of substances (nicotine, strychnine) than females. Thus, the clearance of paracetamol occurs in men faster than in women. In women in menopause, calcium absorption in the intestine is delayed. Diazepam oxidation occurs faster in women. Antiarrhythmic substances often cause an arrhythmogenic effect (the so-called “pirouettes”) in women. To relieve postoperative pain, men require larger doses of morphine than women.

C) GENETIC FACTORS

Susceptibility to drugs may be genetically determined. This is manifested both quantitatively and qualitatively. For example, in the case of genetic insufficiency of blood plasma cholinesterase, the duration of action of muscle relaxant ditilin increases dramatically and can reach 6–8 hours or more (under normal conditions, ditilin is effective for 5–7 minutes).

There are examples of atypical reactions to substances (idiosyncrasy). For example, antimalarials from the group of 8-aminoquinoline (primaquine and others) in individuals with genetic enzymopathy can cause hemolysis (deficiency of the enzyme glucose-6-phosphate dehydrogenase leads to the formation of quinone, which has a hemolytic effect).

D) CONDITION OF ORGANISM

The effect of drugs may depend on the state of the body, in particular on the pathology at which they are prescribed. So, antipyretic drugs reduce body temperature only during fever (they do not work with normothermia). The effect of cardiac glycosides on the blood circulation is manifested only against the background of heart failure.

Changes pharmacokinetics of drugs during pregnancy, with obesity.

D) THE VALUE OF THE DAY RHYTHMS

Diurnal rhythms are important for physiological functions. It is well known that the alternation of wakefulness and sleep affects significantly the activity of the nervous system and the endocrine glands and, accordingly, on the state of other organs and systems. In turn, this is reflected in the sensitivity of the organism to various substances. The study of the dependence of the pharmacological effect on daily periodism is one of the main tasks of the new trend, called chronopharmacology. The latter includes both hronofarmakodinamu and hronofarmakokinutiku1.

Depending on the time of day, the effect of substances can change not only quantitatively, but sometimes and qualitatively. In most cases, their most pronounced effect is observed during the period of maximum activity (in humans in the daytime, in night animals - in the dark time of day). So, in humans, the painkiller morphine is more active at the beginning of the second half of the day than in the early morning or at night. Daily fluctuations were also found in the production of endogenous peptides with analgesic activity (enkephalins and endorphins). With angina, nitroglycerin is more effective in the morning than in the afternoon.

Depending on the daily periodism, the toxicity of substances varies significantly. Thus, in experiments on animals at different times of day, the lethal effect of phenobarbital in a toxic dose ranges from 0 to 100%.

Pharmacokinetic parameters also depend on circadian rhythms. In particular, the greatest absorption of the human antifungal drug griseofulvin occurs approximately at 12 o'clock in the afternoon. The function of the kidneys and their ability to excrete pharmacological agents vary significantly depending on the time of day. When administered orally, lithium preparations are released at night in smaller amounts than during the daytime.

Thus, the pharmacodynamics and pharmacokinetics of substances depend on daily periodism. To this it should be added that the drugs themselves can influence the phases and amplitude of the diurnal rhythm. It should also be borne in mind that the result of their interaction with the body at different times of the day may change under various pathological conditions and diseases.

It is known that seasonal rhythms are also of some importance for physiological functions, which obviously affects the effects of pharmacological substances.