Metabolism (biotransformation) of drugs is understood as a complex of their transformations in the body, as a result of which polar water-soluble substances are formed - metabolites. In most cases, metabolites are less active and less toxic than the parent compounds. But there are exceptions to the rule, when metabolites are more active than the parent compounds.
The metabolism of drugs in the body is determined by genetic factors, gender, age, dietary habits, disease and its severity, environmental factors, and also by route of entry into the body.
When taken orally, the drug is first of all absorbed by the mucous membrane of the digestive canal, and here it begins to undergo metabolic changes. Some drugs are metabolized not only by digestive enzymes, but also by intestinal bacteria.
Due to their entry into the systemic circulation through the liver, drugs taken orally are divided into two types, respectively, with high and low hepatic clearance. The first type is characterized by a high degree of extraction by hepatocytes from the blood, which largely depends on the speed of intrahepatic blood flow. Hepatic clearance of drugs of the second type is determined not by the speed of blood flow, but by the capacity of the enzymatic systems of the liver and the rate of their binding to liver proteins. The liver has an exceptional place in the metabolism of drugs, so it is always necessary to pay exceptional attention to its functional state. In liver diseases, the metabolism of drugs is always impaired and usually slows down. With cirrhosis of the liver, their bioavailability increases due to the development of portocaval anastomoses and the entry of some into the systemic circulation, bypassing the liver. In such cases, their toxic effect on the brain may increase.
The metabolism of a drug when taken orally before entering the systemic circulation is called the “first pass effect.” The smaller the dose of the drug, the larger part of it is metabolized before entering the systemic circulation, and vice versa. From a certain dose, the enzymatic systems involved in the metabolism of the drug are saturated, and its bioavailability increases.
There are non-synthetic (oxidation, reduction, hydrolysis) and synthetic types and/or stages of metabolic reactions. The non-synthetic type (stage I) is divided into reactions catalyzed by microsomal (endoplasmic reticulum) enzymes and non-microsomal enzymes. The synthetic (stage II) type of reactions is based on the conjugation of drugs with endogenous substrates (glucuronic acid, sulfates, glycine, glutathione, methyl groups and water) through hydroxyl, carboxyl, amine and epoxy functional groups. After the reaction is completed, the drug molecule becomes more polar and is easier to remove from the body.
Microsomal metabolism primarily affects fat-soluble drugs that easily penetrate cell membranes into the endoplasmic reticulum, where they bind to one of the cytochromes of the P446-P455 system, which are the primary components of the oxidative enzyme system. The metabolic rate is determined by the concentration of cytochromes, the ratio of their forms, affinity for the substrate, the concentration of cytochrome c reductase and the rate of recovery of the drug-cytochrome P450 complex. It is also influenced by the competition of endogenous and exogenous substrates. Further oxidation occurs under the influence of oxidase and reductase with the participation of NADP and molecular oxygen. Oxidases catalyze the deamination of primary and secondary amines, hydroxylation of side chains and aromatic rings of heterocyclic compounds, as well as the formation of sulfoxides and dealkylations. Microsomal enzymes also control the conjugation of drugs with glucuronic acid. In this way, estrogens, glucocorticoids, progesterone, narcotic analgesics, salicylates, barbiturates, antibiotics, etc. are removed from the body.
The activity of microsomal enzymes can be activated or inhibited by various substances. The activity of cytochromes decreases under the influence of xycaine, sovcaine, bencaine, inderal, visken, eraldine, etc., and increases under the influence of barbiturates, phenylbutazone, caffeine, ethanol, nicotine, butadione, neuroleptics, amidopyrine, chlorcyclizine, diphenhydramine, meprobamate, tricyclic antidepressants, benzonal , quinine, cordiamine, etc.
A small number of drugs, such as acetylsalicylic acid and sulfonamides, undergo non-microsomal metabolism.
With a non-synthetic type of metabolism, some xenobiotics can form active reactive substances, including epoxides and nitrogen-containing oxides. The latter, in case of deficiency of epoxide hydrases and glutathione peroxidases, interact with structural and enzymatic proteins and damage them. Damage gives them the properties of autoantigens and, as a result, autoimmune reactions are triggered with possible carcinogenesis, mutagenesis, teratogenesis, etc.
As for the synthetic type of metabolism with anabolic reactions and the formation of conjugates with residues of various acids or other compounds, sulfation is formed at the time of birth, methylation - after a month of life, glucuronidation - after two months, connection with cysteine ​​and glutathione - after three months, and with glycine - after six months. In this case, the insufficiency of one of the pathways for the formation of paired compounds can be partially compensated by others.

History of development

The fundamentals of pharmacokinetics were created by scientists of different specialties in different countries.

In 1913, German biochemists L. Michaelis and M. Menten proposed an equation for the kinetics of enzymatic processes, which is widely used in modern pharmacokinetics to describe the metabolism of drugs.

When ingesting a medicinal substance of a basic nature (amines), they are usually absorbed in the small intestine (sublingual dosage forms are absorbed from the oral cavity, rectal dosage forms are absorbed from the rectum), medicinal substances of a neutral or acidic nature begin to be absorbed already in the stomach.

Absorption is characterized by the rate and extent of absorption (called bioavailability). The degree of absorption is the amount of a drug substance (in percentage or fraction) that enters the bloodstream through various routes of administration. The rate and extent of absorption depends on the dosage form, as well as other factors. When taken orally, many medicinal substances during absorption under the action of liver enzymes (or gastric acid) are biotransformed into metabolites, as a result of which only a portion of the medicinal substances reaches the bloodstream. The degree of absorption of a drug from the gastrointestinal tract, as a rule, decreases when taking the drug after meals.

Distribution by organs and tissues

To quantify the distribution, the dose of the drug is divided by its initial concentration in the blood (plasma, serum), extrapolated to the time of administration, or the method of statistical moments is used. The conditional value of the volume of distribution is obtained (the volume of liquid in which the dose must be dissolved in order to obtain a concentration equal to the apparent initial concentration). For some water-soluble drugs, the volume of distribution can take on real values ​​corresponding to the volume of blood, extracellular fluid or the entire aqueous phase of the body. For fat-soluble drugs, these estimates can exceed the actual volume of the body by 1-2 orders of magnitude due to the selective cumulation of the drug substance in adipose and other tissues.

Metabolism

Drugs are excreted from the body either unchanged or in the form of products of their biochemical transformations (metabolites). During metabolism, the most common processes are oxidation, reduction, hydrolysis, as well as compounds with residues of glucuronic, sulfuric, acetic acids, and glutathione. Metabolites tend to be more polar and more water soluble compared to the parent drug and are therefore more quickly excreted in the urine. Metabolism can occur spontaneously, but is most often catalyzed by enzymes (for example, cytochromes) localized in the membranes of cells and cellular organelles of the liver, kidneys, lungs, skin, brain and others; some enzymes are localized in the cytoplasm. The biological significance of metabolic transformations is the preparation of liposoluble drugs for excretion from the body.

Excretion

Medicinal substances are excreted from the body through urine, feces, sweat, saliva, milk, and exhaled air. Excretion depends on the rate of delivery of the drug to the excretory organ with the blood and on the activity of the excretory systems themselves. Water-soluble drugs are usually excreted through the kidneys. This process is determined by the algebraic sum of three main processes: glomerular (glomerular) filtration, tubular secretion and reabsorption. The filtration rate is directly proportional to the concentration of free drug in the blood plasma; tubular secretion is realized by saturable transport systems in the nephron and is characteristic of some organic anions, cations and amphoteric compounds; Neutral forms of drugs can be reabsorbed. Polar drugs with a molecular weight of more than 300 are excreted primarily in bile and then in feces: the rate of excretion is directly proportional to the flow of bile and the ratio of drug concentrations in the blood and bile.

The remaining routes of excretion are less intense, but can be studied in pharmacokinetic studies. In particular, the content of medicinal substances in saliva is often analyzed, since the concentration in saliva for many drugs is proportional to their concentration in the blood; the concentration of medicinal substances in breast milk is also examined, which is important for assessing the safety of breastfeeding.

Literature

• Soloviev V.N., Firsov A.A., Filov V.A., Pharmacokinetics, M., 1980.
• Lakin K. M., Krylov Yu. Pharmacokinetics. Biotransformation of medicinal substances, M., 1981.
• Kholodov L.E., Yakovlev V.P., Clinical pharmacokinetics. M., 1985.
• Wagner J.G., Fundamentals of clinical pharma-cokinetics, Hamilton, 1975.

see also

Links

• General issues of clinical pharmacology. Chapter 6. Basic issues of pharmacokinetics
• Distribution of drugs in the body. Biological barriers. Deposit (Lectures, in Russian)
• Software for data analysis of pharmacokinetic/pharmacodynamic studies
• Conducting qualitative studies of the bioequivalence of medicines. // Guidelines of the Ministry of Health and Social Development of the Russian Federation dated August 10, 2004.
• Laboratory of clinical (applied) pharmacokinetics: standardization, accreditation and licensing

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Pharmacokinetics... Spelling dictionary-reference book

- (from the Greek pharmakon medicine and kinetikos setting in motion), a section of pharmacology that studies the speed of the processes of entry, distribution, biotransformation and excretion of medicinal substances from the body. Pharmacokinetics of toxic substances... ... Ecological dictionary

Noun, number of synonyms: 1 pharmacy (5) ASIS Dictionary of Synonyms. V.N. Trishin. 2013… Synonym dictionary

pharmacokinetics- - a section of pharmaceutical chemistry, the task of which is to study the patterns of absorption, distribution and release of drugs from the body... A brief dictionary of biochemical terms

pharmacokinetics- A branch of pharmacology related to the study of the concentration and rate of passage of a drug in the body. Topics of biotechnology EN pharmacokinetics ... Technical Translator's Guide

I Pharmacokinetics (Greek pharmakon medicine kinētikos related to movement) is a branch of pharmacology that studies the patterns of absorption, distribution, metabolism and excretion of drugs. The study of these patterns is based on... ... Medical encyclopedia

- (pharmaco + Greek kinetikos related to movement) a section of pharmacology that studies the routes of entry, distribution and metabolism of medicinal substances in the body, as well as their excretion... Large medical dictionary

- (from the Greek pharmakon medicine and kinetikos setting in motion), studies kinetic. patterns of processes occurring with lek. Wed vom in the body. Basic pharmacokinetic processes: absorption, distribution, metabolism and excretion (removal).... ... Chemical encyclopedia

In modern pharmacotherapy, particularly great importance is attached to the study of the pharmacokinetics of drugs, including determination of the rate and completeness of absorption of the drug through different routes of administration, including oral administration, binding to plasma proteins (for all routes of administration), onset of action, time to reach maximum concentration in blood plasma, half-life (T 1/2), time of complete elimination (after cessation of drug administration), routes of elimination and the amount of drug (in percent) excreted in different ways (unchanged or in the form of metabolites). Determining these parameters and comparing them with the dynamics of the therapeutic effect makes it possible to establish the optimal dose and regimen (frequency, duration) of drug use, evaluate (by comparing doses and effectiveness) the advantages of different drugs, select the most appropriate one, and adjust dosages in cases of internal dysfunction. organs, etc.

A full study of pharmacokinetic parameters for each patient in everyday practice is almost impossible due to the complexity of the study and, sometimes, the lack of necessary equipment - chromatographs, mass spectrometers, etc. These studies are carried out mainly in clinical and pharmacological medical institutions and in experimental laboratories. However, knowledge of the available data on the pharmacokinetic parameters of the drugs used is necessary for every modern doctor.

Pharmacokinetic studies include the study of drug metabolism. Once in the body, most drugs undergo metabolic transformations (fragmentation of molecules, hydroxylation, reduction, demethylation, etc.). Only certain drugs are excreted from the body unchanged. The resulting metabolites (and their number for different compounds ranges from units to dozens) can be active, inactive, inactive, and in some cases toxic. Often the main pharmacological and therapeutic effect is determined by active metabolism, that is, it is not the drug itself that acts, but the product of its metabolic transformation. In these cases, the drug used is considered a "prodrug".

The first prodrugs were long-known “old” drugs. Hexamethylenetetramine (urotropine) acts by releasing formaldehyde in the body (in an acidic environment). Phenyl salicylate (salol) is metabolized to form phenol and salicylic acid, and the first sulfonamide antibacterial drug prontosil (“red” streptocide) is an active metabolite of sulfonamide (“white” streptocide), which completely replaced the prodrug as a medicine.

Prodrugs are various modern drugs. Salazosulfapyridine, used to treat ulcerative colitis, is metabolized to form active sulfonamide and salicylic components. Imipramine has an active metabolite, desipramine, used as an independent antidepressant. The active substance of the ACE inhibitor enalapril is its metabolite enalaprilat. The angiotensin II receptor blocker losartan forms an active metabolite that specifically binds to AT1 receptors, etc.

Metabolism of drugs is carried out under the influence of various enzyme systems of the body. A particularly important role is played by microsomal and other liver enzymes, under the influence of which inactivation (detoxification) of drugs occurs. If liver function is impaired, its detoxification ability may change. There are a number of drugs that are both “inducers” and “inhibitors” of liver enzymes, which respectively enhance or inhibit the metabolism and detoxification of other drugs. The most well-known “inducers” include barbiturates, as well as diphenin, carbamazepine, and rifampicin. For the first time, “induction” of enzymes attracted attention in connection with the development of dangerous bleeding when barbiturates were used simultaneously with indirect (oral) anticoagulants (dicoumarin, etc.). Anticoagulants were prescribed to patients in doses necessary to create an anticoagulant effect, but they were higher than usual, since the activity of anticoagulants was reduced under the influence of barbiturates. When the latter were discontinued and the use of the anticoagulant continued at the previous doses, severe hemorrhagic complications developed (including death).

The anticoagulants themselves (coumarin derivatives), as well as cimetidine, isoniazid, chloramphenicol, teturam and a number of other drugs are inhibitors of liver enzymes (in particular, they enhance the effect of oral hypoglycemic drugs, theophylline, diphenine, β-blockers and some other drugs). Studying the effect of new drugs on the activity of liver enzymes has become one of the important elements of pharmacokinetic research. Taking these features into account plays an important role in the combined use (interaction) of different drugs.

Suction(absorption) - is the overcoming of barriers separating the site of drug administration and the bloodstream.

For each medicinal substance, a special indicator is determined - bioavailability . It is expressed as a percentage and characterizes the rate and extent of drug absorption from the site of administration into the systemic circulation and accumulation in the blood in a therapeutic concentration.

There are four main stages in the pharmacokinetics of drugs.

Stage - suction.

Absorption is based on the following basic mechanisms:

1. Passive diffusion molecules, which mainly follows a concentration gradient. The intensity and completeness of absorption are directly proportional to lipophilicity, that is, the greater the lipophilicity, the higher the ability of the substance to be absorbed.

2. Filtration through the pores of cell membranes. This mechanism is involved only in the absorption of low-molecular compounds, the size of which does not exceed the size of cell pores (water, many cations). Depends on hydrostatic pressure.

3. Active transport Usually carried out using special transport systems, it occurs with the expenditure of energy, against a concentration gradient.

4. Pinocytosis characteristic only of high-molecular compounds (polymers, polypeptides). Occurs with the formation and passage of vesicles through cell membranes.

Absorption of drugs can be carried out by these mechanisms through various routes of administration (enteral and parenteral), except intravenous, in which the drug immediately enters the bloodstream. In addition, the listed mechanisms are involved in the distribution and excretion of drugs.

Stage - distribution.

After the drug enters the bloodstream, it spreads throughout the body and is distributed in accordance with its physicochemical and biological properties.

The body has certain barriers that regulate the penetration of substances into organs and tissues: hematoencephalic (BBB), hematoplacental (HPB), hemato-ophthalmological (GOB) barriers.

Stage 3 - metabolism(transformation). There are two main pathways for drug metabolism:

ü biotransformation , occurs under the action of enzymes - oxidation, reduction, hydrolysis.

ü conjugation , in which residues of other molecules are added to a molecule of a substance, forming an inactive complex that is easily excreted from the body in urine or feces.

These processes entail the inactivation or destruction of medicinal substances (detoxification), the formation of less active compounds, hydrophilic and easily excreted from the body.

In some cases, the drug becomes active only after metabolic reactions in the body, that is, it is prodrug , which turns into medicine only in the body.

The main role in biotransformation belongs to liver microsomal enzymes.

Stage 4 - elimination (excretion). Medicinal substances are eliminated from the body unchanged or in the form of metabolites after a certain time.

Hydrophilic substances excreted by the kidneys. Most drugs are isolated in this way.

Many lipophilic drugs excreted through the liver as part of bile entering the intestines. Drugs and their metabolites released into the intestines with bile can be excreted in feces, reabsorbed into the blood and again released through the liver into the intestines with bile (enterohepatic circulation).

Drugs may be excreted through sweat and sebaceous glands(iodine, bromine, salicylates). Volatile drugs are released through the lungs with exhaled air. Mammary gland secrete various compounds in milk (hypnotics, alcohol, antibiotics, sulfonamides), which should be taken into account when prescribing the drug to nursing women.

Elimination- the process of releasing the body from a drug substance as a result of inactivation and excretion.

General drug clearance(from the English clearance - cleaning ) – the volume of blood plasma cleared of drugs per unit of time (ml/min) due to excretion by the kidneys, liver and other routes.

Half-life (T 0.5)– the time during which the concentration of the active drug substance in the blood decreases by half.

Pharmacodynamics

studies the localization, mechanisms of action of drugs, as well as changes in the activity of organs and systems of the body under the influence of a medicinal substance, i.e. pharmacological effects.

Mechanisms of action of drugs

Pharmacological effect- the effect of a medicinal substance on the body, causing changes in the activity of certain organs, tissues and systems (increased heart function, elimination of bronchospasm, decreased or increased blood pressure, etc.).

The ways in which drugs produce pharmacological effects are defined as mechanisms of action medicinal substances.

Medicinal substances interact with specific receptors of cell membranes, through which the activity of organs and systems is regulated. Receptors – these are active sites of macromolecules with which mediators or hormones specifically interact.

To characterize the binding of a substance to a receptor, the term is used affinity.

Affinity is defined as the ability of a substance to bind to a receptor, resulting in the formation of a substance-receptor complex.

Medicinal substances that stimulate (stimulate) these receptors and cause such effects as endogenous substances (mediators) are called mimetics, stimulants or agonists. Agonists, due to their similarity to natural mediators, stimulate receptors, but act longer due to their greater resistance to destruction.

Substances that bind to receptors and interfere with the action of endogenous substances (neurotransmitters, hormones) are called blockers, inhibitors or antagonists.

In many cases, the effect of drugs is associated with their effects on enzyme systems or individual enzymes;

Sometimes drugs inhibit the transport of ions across cell membranes or stabilize cell membranes.

A number of substances affect metabolic processes inside the cell and also exhibit other mechanisms of action.

Pharmacological activity of drugs– the ability of a substance or a combination of several substances to change the state and functions of a living organism.

Drug effectiveness– characterization of the degree of positive effect of drugs on the course or duration of the disease, prevention of pregnancy, rehabilitation of patients through internal or external use.

10. Pharmacokinetics and pharmacodynamics - definition, sections. Main indicators of pharmacokinetics.

Pharmacokinetics- this is a section of pharmacology about the absorption, distribution in the body, deposition, metabolism and excretion of substances.

Pharmacokinetics provisions

I.Routes of administration of medicinal substances – enteral (oral, sublingual, rectal), parenteral without violating the integrity of the skin (inhalation, vaginal) and all types of injections (subcutaneous, intramuscular, intravenous, intraarterial, intracavitary, with introduction into the spinal canal, etc.). II.Absorption of drugs funds with different routes of administration, it mainly occurs due to passive diffusion through cell membranes, by filtration through membrane pores and pinocytosis). Factors affecting absorption: solubility of the substance in water and lipids, polarity of the molecule, size of the molecule, pH of the medium, dosage form; bioavailability (the amount of unchanged substance in the blood plasma relative to the initial dose of the drug), taking into account the loss of the substance during absorption from the gastrointestinal tract and during the first passage through the hepatic barrier (bioavailability after intravenous administration is taken as 100%). Distribution of medicinal substances in the body in most cases it turns out to be uneven and depends on the state of biological barriers - capillary walls, cell membranes, placental and blood-brain barriers. The difficulties in overcoming the latter are due to its structural features: the endothelium of the brain capillaries does not have pores, they lack pinocytosis, they are covered with glial elements that act as an additional lipid membrane (lipophilic molecules easily penetrate into the brain tissue). The distribution of medicinal substances also depends on the affinity of the latter for different tissues and on the intensity of tissue blood supply; reversible binding of drugs with plasma (mainly albumin) and tissue proteins, nucleoproteins and phospholipids contributes to their deposition. III. Biotransformation (transformation) of medicinal substances in the body (metabolic transformation, conjugation or metabolic transformation) - transformation of medicinal substances by oxidation (using microsomal liver enzymes with the participation of NADP, O 2 and cytochrome P-450), conjugation - attachment to a medicinal substance or its metabolite chemical groups and molecules of endogenous compounds (glucuronic and sulfuric acids, amino acids, glutathione, acetyl and methyl groups); the result of biotransformation is the formation of more polar and water-soluble compounds that are easily removed from the body. During the process of biotransformation, the activity of the substance is usually lost, which limits the time of its action, and in case of liver diseases or blockade of metabolizing enzymes, the duration of action increases (the concept of inducers and inhibitors of microsomal enzymes). IV . Removal of drugs the body is mainly excreted through urine and bile: substances are removed from the urine through filtration and active calcium secretion; the rate of their elimination depends on the rate of reabsorption in the tubules due to simple diffusion. For reabsorption processes, the pH of urine is important (in an alkaline environment, weak acids are eliminated faster, in an acidic environment, weak bases are eliminated); the rate of excretion by the kidneys characterizes renal clearance (an indicator of the purification of a certain volume of blood plasma per unit of time). When excreted in bile, drugs leave the body in excrement and can be reabsorbed in the intestines (enterohepatic circulation). Other glands also take part in the removal of medicinal substances, including the mammary glands during lactation (the possibility of drugs entering the infant’s body); One of the accepted pharmacokinetic parameters is the half-life of the substance (half-life T1/2), reflecting the time during which the content of the substance in the plasma decreases by 50%.

Main indicators of pharmacokinetics

medicines

– Absorption rate constant (Ka), characterizing the rate of their entry into the body.

– Elimination rate constant (Kel), characterizing the rate of their biotransformation in the body.

– Excretion rate constant (Kex), characterizing the rate of their elimination from the body (through the lungs, skin, digestive and urinary tract).

– Half-absorption period (T 1/2, a) as the time required for the absorption of their half dose from the injection site into the blood (T 1/2, a = 0.693/Ka).

– Half-distribution period (T 1/2, a) as the time during which their concentration in the blood reaches 50% of the equilibrium between the blood and tissues.

– Half-life (T 1/2) as the time during which their concentration in the blood decreases by half (T 1/2 = 0.693/Kel).

– The apparent initial concentration (C0), which would be achieved in the blood plasma when administered intravenously and immediately distributed in organs and tissues.

– Equilibrium concentration (Css), established in the blood plasma (serum) when they enter the body at a constant rate (with intermittent administration (reception) at equal intervals of time in equal doses, the maximum (Css max) and minimum (Css min) equilibrium concentrations are released ).

– Volume of distribution (Vd) as a conditional volume of liquid in which it is necessary to dissolve the dose entering the body (D) to obtain a concentration equal to the apparent initial one (C0).

– General (Clt), renal (Clr) and extrarenal (Cler) clearances, characterizing the rate of release of them from the body and, accordingly, their excretion in the urine and other routes (primarily bile) (Clt = Clr + Cler).

– The area under the concentration-time curve (AUC), related to their other pharmacokinetic characteristics (volume of distribution, total clearance), with their linear kinetics in the body, the AUC value is proportional to the dose entering the systemic circulation.

– Absolute bioavailability (f) as the fraction of dose reaching the systemic circulation after extravascular administration (%).

An indicator of drug elimination is clearance (ml/min). There are general, renal and hepatic clearance. Total clearance is the sum of renal and hepatic clearances and is defined as the volume of blood plasma that is cleared of a drug per unit time. Clearance is used to calculate the dose of a drug required to maintain its equilibrium concentration (maintenance dose) in the blood. Equilibrium concentration is established when the amount of drug absorbed and the amount of drug administered are equal to each other.

Mathematical modeling plays an important role in the study of drug pharmacokinetics.

There are many mathematical methods and models, from the simplest one-dimensional ones to multidimensional ones of varying levels of complexity.

The use of mathematical modeling allows us to study in detail the pharmacokinetics of drugs, both in time and space (organs and tissues), with the derivation of characteristic constants.

Pharmacodynamics- a section that studies the biological effects of substances, their localization and mechanism of action.

Basic Principles of Pharmacodynamics

I. Types of pharmacological action medications(local, resorptive, direct and indirect, reflex, reversible, irreversible, preferential, selective, specific action). In all cases, the drug interacts with certain biochemical substrates; active groups of macromolecular substrates that interact with substances are called receptors, and receptors, interaction with which ensures the main effect of a substance, are called specific. The affinity of a substance for a receptor, leading to the formation of a complex with it, is designated by the term “affinity”; the ability of a substance, when interacting with a receptor, to cause one or another effect is called internal activity; a substance that, when interacting with a receptor, causes a biological effect is called an agonist (they are internally active); agonism can be complete (the substance causes the maximum effect) and partial (partial). Substances that, when interacting with the receptor, do not cause an effect, but eliminate the effect of the agonist, are called antagonists. II.Typical mechanisms of action of drugs (mimetic, lytic, allosteric, change in membrane permeability, release of metabolite from protein binding, etc.). III.Pharmacological effects – direct and indirect. IV.Types of pharmacotherapeutic action (etiotropic, pathogenetic, symptomatic, main and secondary).

Mechanisms of action of drugs.

The vast majority of drugs have a therapeutic effect by changing the activity of the physiological systems of cells that were produced in the body during the process of evolution. Under the influence of a medicinal substance in the body, as a rule, a new type of cell activity does not arise, only the speed of various natural processes changes. Inhibition or stimulation of physiological processes leads to a decrease or increase in the corresponding functions of body tissues.

Drugs can act on specific receptors, enzymes, cell membranes, or directly interact with cell substances. The mechanisms of action of medicinal substances are studied in detail in the course of general or experimental pharmacology. Below we provide just a few examples of the main mechanisms of action of drugs.

Action on specific receptors. Receptors are macromolecular structures that are selectively sensitive to certain chemical compounds. The interaction of chemicals with the receptor leads to biochemical and physiological changes in the body, which are expressed in one or another clinical effect.

Drugs that directly excite or increase the functional activity of receptors are called agonists, and substances that interfere with the action of specific agonists are called antagonists. Antagonism can be competitive or non-competitive. In the first case, the drug competes with a natural regulator (mediator) for binding sites in specific receptors. Receptor blockade caused by a competitive antagonist can be reversed by large doses of an agonist or natural mediator.

Various receptors are divided according to their sensitivity to natural mediators and their antagonists. For example, receptors sensitive to acetylcholine are called cholinergic, and those sensitive to adrenaline are called adrenergic. Based on their sensitivity to muscarine and nicotine, cholinergic receptors are divided into muscarine-sensitive (m-cholinergic receptors) and nicotine-sensitive (n-cholinergic receptors). N-cholinergic receptors are heterogeneous. It has been established that their difference lies in sensitivity to various substances. There are n-cholinergic receptors located in the ganglia of the autonomic nervous system and n-cholinergic receptors in striated muscles. Various subtypes of adrenergic receptors are known, designated by the Greek letters α 1, α 2, β 1, β 2.

There are also H 1 - and H 2 -histamine, dopamine, serotonin, opioid and other receptors.

Effect on enzyme activity. Some drugs increase or inhibit the activity of specific enzymes. For example, physostigmine and neostigmine reduce the activity of cholinesterase, which destroys acetylcholine, and produce effects characteristic of excitation of the parasympathetic nervous system. Monoamine oxidase inhibitors (iprazide, nialamide), which prevent the destruction of adrenaline, increase the activity of the sympathetic nervous system. Phenobarbital and zixorine, by increasing the activity of liver glucuronyltransferase, reduce the level of bilirubin in the blood.

Physicochemical effect on cell membranes. The activity of cells of the nervous and muscular systems depends on ion flows that determine the transmembrane electrical potential. Some drugs alter ion transport.

This is how antiarrhythmic, anticonvulsant drugs, and general anesthesia work.

Direct chemical interaction. Drugs can directly interact with small molecules or ions inside cells. For example, ethylenediaminetetraacetic acid (EDTA) strongly binds lead ions. The principle of direct chemical interaction underlies the use of many antidotes for poisoning by chemical substances. Another example is the neutralization of hydrochloric acid with antacids.

Dose-effect relationship

It is an important pharmacodynamic indicator. Typically, this indicator is not a simple arithmetic relation and can be expressed graphically in different ways: linearly, a curve curved up or down, or a sigmoidal line.

Each medicine has a number of desirable and undesirable properties. Most often, when the dose of a drug is increased to a certain limit, the desired effect increases, but undesirable effects may occur. A drug may have more than one dose-response curve for its different aspects of action. The ratio of doses of a drug that produces an undesired or desired effect is used to characterize the safety margin or therapeutic index of the drug. The therapeutic index of a drug can be calculated by the ratio of its concentrations in the blood plasma that cause undesirable (side) effects and concentrations that have a therapeutic effect, which can more accurately characterize the ratio of the effectiveness and risk of using a given drug.

Methods for studying pharmacodynamics must have a number of important properties:

A) high sensitivity- the ability to identify most of the deviations from the initial state that they are trying to influence, as well as evaluate positive changes in the body.

b) high specificity- the ability to relatively rarely give “false positive” results.

V) high reproducibility- the ability of this method to consistently display the characteristics of the condition of patients during repeated studies under the same conditions in the same patients in the absence of any dynamics in the condition of these patients according to other clinical data.