General pharmacology. Metabolism (biotransformation) of medicinal substances in the body. Excretion and elimination of drugs in the body Removal of drugs from the body

Metabolism (biotransformation) of medicinal substances in the body. Excretion and elimination of drugs in the body

Biotransformation (metabolism)- changes in the chemical structure of medicinal substances and their physical and chemical properties under the influence of body enzymes. Most medicines undergo biotransformation in the body. Mainly highly hydrophilic ionized compounds are released unchanged. Of the lipophilic substances, the exception is inhalation anesthesia, the main part of which does not enter into chemical reactions in the body. They are excreted by the lungs in the same form in which they were introduced. Many enzymes take part in the biotransformation of drugs, of which the most important role is played by liver microsomal enzymes (located in the endoplasmic reticulum). They metabolize lipophilic compounds (of different structures) that are foreign to the body, turning them into more hydrophilic ones. They do not have substrate specificity. Non-microsomal enzymes of different localization (liver, intestines and other tissues, as well as plasma) are also essential, especially in the case of inactivation of hydrophilic substances.

There are two main types of transformation of drugs: 1 - metabolic transformation and 2 - conjugation.

Metabolic transformation is the transformation of substances through oxidation, reduction and hydrolysis. Many lipophilic compounds undergo oxidation in the liver under the influence of a microsomal enzyme system known as mixed-function oxidases, or monooxygenases. The main components of this system are cytochrome P-450 reductase and cytochrome P-450, a hemoprotein that binds drug molecules and oxygen in its active center. The reaction occurs with the participation of NADPH. As a result, one oxygen atom attaches to the substrate (drug substance) with the formation of a hydroxyl group (hydroxylation reaction).

RH + O 2 + NADPH + H + > ROH + H 2 O + NADP +, where

RH is a drug substance, and ROH is a metabolite.

Mixed-function oxidases have low substrate specificity. There are many isoforms of cytochrome P-450 (Cytochrome P-450, CYP), each of which can metabolize several drugs. Thus, the CYP2C9 iso-form is involved in the metabolism of warfarin, phenytoin, ibuprofen, CYP2D6 metabolizes imipramine, haloperidol, propranolol, and CYP3A4 metabolizes carbamazepine, cyclosporine, erythromycin, nifedipine, verapamil and some other substances. The oxidation of some drugs occurs under the influence of non-microsomal enzymes, which are localized in the cytosol or mitochondria. These enzymes are characterized by substrate specificity, for example, monoamine oxidase A metabolizes norepinephrine, adrenaline, serotonin, alcohol dehydrogenase metabolizes ethyl alcohol to acetaldehyde.

Reduction of medicinal substances can occur with the participation of microsomal (chloramphenicol) and non-microsomal enzymes (chloral hydrate, naloxone).

Hydrolysis of drugs is carried out mainly by non-microsomal enzymes (esterases, amidases, phosphatases) in blood plasma and tissues. In this case, due to the addition of water, ester, amide and phosphate bonds in the molecules of medicinal substances are broken. Esters undergo hydrolysis - acetylcholine, suxamethonium (hydrolyzed with the participation of cholinesterases), amides (procainamide), acetylsalicylic acid.

Metabolites that are formed as a result of non-synthetic reactions may, in some cases, have higher activity than the parent compounds. An example of increasing the activity of drugs during metabolism is the use of drug precursors (prodrugs). Prodrugs are pharmacologically inactive, but they are converted into active substances in the body. For example, salazopyridazine, a drug for the treatment of ulcerative colitis, is converted by the intestinal azoreductase enzyme into sulfapyridazine and 5-aminosalicylic acid, which have antibacterial and anti-inflammatory effects. Many antihypertensive drugs, such as angiotensin-converting enzyme inhibitors (enalapril), are hydrolyzed in the body to form active compounds. Prodrugs have a number of advantages. Very often, with their help, problems with the delivery of a medicinal substance to the site of its action are solved. For example, levodopa is a precursor of dopamine, but unlike dopamine, it penetrates the blood-brain barrier into the central nervous system, where, under the action of DOPA decarboxylase, it is converted into the active substance - dopamine.

Sometimes the products of metabolic transformation are more toxic than the parent compounds. Thus, the toxic effects of drugs containing nitro groups (metronidazole, nitrofurantoin) are determined by intermediate products of the metabolic reduction of NO 2 groups.

Conjugation is a biosynthetic process accompanied by the addition of a number of chemical groups or molecules of biogenic compounds to a drug substance or its metabolites. In the process of biosynthetic reactions (conjugation), residues of endogenous compounds (glucuronic acid, glutathione, glycine, sulfates, etc.) or highly polar chemical groups (acetyl, methyl groups) are added to the functional groups of molecules of medicinal substances or their metabolites. These reactions occur with the participation of enzymes (mainly transferases) of the liver, as well as enzymes of other tissues (lungs, kidneys). Enzymes are localized in microsomes or in the cytosolic fraction.

The most common reaction is conjugation with glucuronic acid. The addition of glucuronic acid residues (formation of glucuronides) occurs with the participation of the microsomal enzyme UDP-glucuronyltransferase, which has low substrate specificity, as a result of which many drugs (as well as some exogenous compounds, such as corticosteroids and bilirubin) enter into a conjugation reaction with glucuronic acid. During the process of conjugation, highly polar hydrophilic compounds are formed, which are quickly excreted by the kidneys (many metabolites also undergo conjugation). Conjugates are generally less active and toxic than the parent drugs.

The rate of biotransformation of drugs depends on many factors. In particular, the activity of enzymes that metabolize drugs depends on gender, age, body condition, and the simultaneous administration of other drugs. In men, the activity of microsomal enzymes is higher than in women, since the synthesis of these enzymes is stimulated by male sex hormones. Therefore, some substances are metabolized faster in men than in women.

In the embryonic period, most enzymes of drug metabolism are absent; in newborns, in the first month of life, the activity of these enzymes is reduced and reaches a sufficient level only after 1 - 6 months. Therefore, in the first weeks of life, it is not recommended to prescribe drugs such as chloramphenicol (due to insufficient enzyme activity, its conjugation processes are slowed down and toxic effects appear).

The activity of liver enzymes decreases in old age, as a result of which the rate of metabolism of many drugs decreases (for people over 60 years of age, such drugs are prescribed in lower doses). In liver diseases, the activity of microsomal enzymes decreases, the biotransformation of certain drugs slows down, and their action increases and prolongs. In tired and weakened patients, the neutralization of drugs occurs more slowly.

Under the influence of certain drugs (phenobarbital, rifampicin, carbamazepine, griseofulvin), induction (increase in the rate of synthesis) of microsomal liver enzymes can occur. As a result, when other drugs (for example, glucocorticoids, oral contraceptives) are prescribed simultaneously with inducers of microsomal enzymes, the metabolic rate of the latter increases and their effect decreases. In some cases, the metabolic rate of the inducer itself may increase, resulting in a decrease in its pharmacological effects (carbamazepine).

Some drugs (cimetidine, chloramphenicol, ketoconazole, ethanol) reduce the activity of metabolizing enzymes. For example, cimetidine is an inhibitor of microsomal oxidation and, by slowing down the metabolism of warfarin, can increase its anticoagulant effect and provoke bleeding. Substances (furanocoumarins) contained in grapefruit juice are known to inhibit the metabolism of drugs such as cyclosporine, midazolam, alprazolam and, therefore, enhance their effect. When using drugs simultaneously with inducers or inhibitors of metabolism, it is necessary to adjust the prescribed doses of these substances.

The rate of metabolism of some drugs is determined by genetic factors. A section of pharmacology appeared - pharmacogenetics, one of the tasks of which is to study the pathology of drug metabolism enzymes. Changes in enzyme activity are often the result of a mutation in the gene that controls the synthesis of the enzyme. Violation of the structure and function of the enzyme is called enzymopathy (enzymopathy). With enzymopathies, enzyme activity can be increased, in which case the process of metabolism of medicinal substances is accelerated and their effect is reduced. Conversely, the activity of enzymes can be reduced, as a result of which the destruction of medicinal substances will occur more slowly and their effect will increase until toxic effects appear.

Elimination (excretion) Excretion of drugs and their transformation products from the body occurs in various ways: through the gastrointestinal tract, lungs, mammary and other glands, and skin. However, the main route of elimination for most drugs is the kidneys. Therefore, kidney disease can lead to the retention of drugs in the body and cause a stronger and longer-lasting effect, even leading to the development of poisoning. For kidney disease, the use of certain medications is contraindicated. By enhancing the excretory function of the kidneys with diuretics, it is possible to accelerate the removal of drugs from the body (for example, in case of poisoning - forced diuresis). The excretion of drugs by the kidneys is influenced to a certain extent by urine pH. Thus, with an acidic urine reaction, the excretion of alkaline compounds (for example, alkaloids) improves and the excretion of acidic drugs (for example, barbiturates, sulfonamides, etc.) becomes more difficult. By administering ammonium chloride, you can “acidify” the urine and thereby accelerate the excretion of bases in the urine, and sodium bicarbonate or other compounds that change the reaction of urine to alkaline will promote the release of acidic substances from the body.

Such control of urine reaction is often resorted to in cases of poisoning. If, due to poisoning, kidney function is severely impaired and life is threatened, then in such cases a special device (an “artificial kidney”) is connected to the person’s circulatory system, with the help of which toxic substances are removed from the blood.

Some medications that are poorly absorbed from the gastrointestinal tract may be excreted in the feces. In addition, the mucous membrane of the gastrointestinal tract can secrete some drugs even after parenteral administration to the body (for example, morphine). Therefore, gastric lavage in such cases is completely justified, although the poison was not ingested. Partial release of drugs can occur through the sweat, salivary and lacrimal glands. The lungs emit mainly volatile substances (ether, fluorotane, ethyl alcohol, etc.).

Particular attention should be paid to the possibility of the release of medicinal substances by the mammary glands during lactation and their entry into the child’s body with mother’s milk. In this regard, it is strictly contraindicated to prescribe drugs of the morphine group to a breastfeeding woman, to which children are very sensitive.

It should be noted that some medications, when administered for a long time, can irritate the tissues of the excretory organs, causing inflammation and even damage. Thus, mercury preparations damage the kidneys, bromine preparations can cause inflammation of the sweat glands, etc.

Elimination Drug metabolism is the total result of inactivation of drugs in body tissues and their excretion through various routes. Most likely, water-soluble, ionized substances not bound to plasma proteins are eliminated. Fat-soluble substances bound to blood proteins are eliminated more slowly. For most drugs, the rate of elimination depends on the concentration of the substance (the lower the concentration of the substance, the lower the rate of elimination). In this case, the curve of changes in the concentration of a substance over time has an exponential character. Such elimination corresponds to 1st order kinetics (a certain part of the substance is eliminated per unit time).

The main parameters characterizing the elimination process are the elimination rate constant (k el , k e) and the half-life period (t 1/2).

The 1st order elimination rate constant shows what part of the substance is eliminated from the body per unit time (dimension min -1, h -1). For example, if k el of a substance administered intravenously at a dose of 100 mg is 0.1 h -1, then after 1 hour the amount of the substance in the blood will be 90 mg, and after 2 hours - 81 mg, etc. .

Few drugs (ethanol, phenytoin) are eliminated according to zero-order kinetics. The rate of such elimination does not depend on the concentration of the substance and is a constant value, i.e. a certain amount of a substance is eliminated per unit time (for example, 10 g of pure ethanol is eliminated in 1 hour). This is due to the fact that at therapeutic concentrations of these substances in the blood, the enzymes that metabolize these substances become saturated. Therefore, as the concentration of such substances in the blood increases, the rate of their elimination does not increase.

Half-elimination period (t 1/2, half-life) is the time during which the concentration of a substance in the blood plasma decreases by 50%. For most medicinal substances (for those whose elimination obeys first-order kinetics), the half-life of elimination is a constant value within certain limits and does not depend on the dose of the medicinal substance. Therefore, if in one half-elimination period 50% of an intravenously administered drug substance is removed from the blood plasma, then in 2 periods - 75%, and in 3.3 periods - 90% (this parameter is used to select the intervals between administrations of the substance necessary to maintain it constant concentration in the blood).

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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I. Absorption (absorption)- the process of drug entry from the site of its administration into the systemic circulation during intravascular administration.

The rate of absorption depends on:

1. Dosage form of the drug.

2. On the degree of solubility in fats or water.

3. On dose or concentration.

4. From the route of administration.

5. On the intensity of blood supply to organs and tissues.

The rate of absorption when administered per os depends on:

1. pH of the environment in various parts of the gastrointestinal tract.

2. The nature and volume of stomach contents.

3. From microbial contamination.

4. Activity of food enzymes.

5. Conditions of gastrointestinal motility.

6. The interval between taking the medicine and food.

The absorption process is characterized by the following pharmacokinetic parameters:

1. Bioavailability(f) – the relative amount of the drug that enters the blood from the injection site (%).

2. Suction rate constant ( K 01) is a parameter that characterizes the rate of entry of drugs from the injection site into the blood (h -1, min -1).

3. Half-absorption period(t ½ α) – time required for absorption of ½ of the administered dose from the injection site into the blood (h, min).

4. Time to reach maximum concentration ( t max) is the time during which the maximum concentration in the blood is reached (h, min).

Absorption processes in children reach the level of drug absorption of adults only by the age of three. Up to three years, the absorption of drugs is reduced mainly due to a lack of intestinal colonization, as well as due to a lack of bile formation. People over 55 also have reduced absorption capacity. They need to dose medications based on their age.

II. Biotransport – after the drugs are absorbed into the blood, they enter into a reverse interaction with the so-called. transport proteins, which include blood serum proteins.

The overwhelming majority of the drug (90%) enters into reversible interactions with human serum albumin. It also interacts with globulins, lipoproteins, and glycoproteins. The concentration of the protein-bound fraction corresponds to the free fraction, i.e.: [C bound] = [C free].

Only the free fraction, not bound to protein, has pharmacological activity, and the bound fraction is a kind of reserve of the drug in the blood.

The bound part of the drug by the transport protein determines:

1. The strength of the pharmacological action of the drug.

2. Duration of its action.

Protein binding sites are common to many substances.

The process of reversible interaction of drugs with transport proteins is characterized by the following pharmacokinetic parameters:

1. Kass (drug + protein) – characterizes the degree of affinity or strength of the reversible interaction of the drug with blood serum protein (mol -1).

2. N is an indicator that indicates the number of fixation sites on a protein molecule for a particular drug molecule.

III. Distribution of drugs in the body.

As a rule, drugs in the body are distributed unevenly among organs and tissues, taking into account their tropism (affinity).

The distribution of drugs in the body is influenced by the following factors:

1. Degree of solubility in lipids.

2. The intensity of regional or local blood supply.

3. Degree of affinity for transport proteins.

4. State of biological barriers (capillary walls, biomembranes, blood-brain and placental).

The main places of distribution of drugs in the body are:

1. Extracellular fluid.

2. Intracellular fluid.

3. Adipose tissue.

Options:

1. Volume of distribution (Vd) - the degree of drug uptake by tissues from the blood (l, ml).

IV . Biotransformation.

One of the central stages of pharmacokinetics and the main route of detoxification (neutralization) of drugs in the body.

The following take part in biotransformation:

5. Placenta

Biotransformation occurs in 2 phases.

Phase 1 reactions:

Hydroxylation, redox reactions, deamination, dealkylation, etc. During the reactions of this phase, the structure of the drug molecule changes so that it becomes more hydrophilic. This allows for easier excretion from the body through urine.

Phase I reactions are carried out with the help of enzymes of the endoplasmic reticulum (microsomal or enzymes of the monooxygenase system, the main of which is cytochrome P450). Medicines can either increase or decrease the activity of this enzyme. Drugs that have passed phase I are structurally prepared for phase II reactions.

During phase II reactions, conjugates or paired compounds of the drug with one of the endogenous substances (for example, glucuronic acid, glutathione, glycine) are formed. The formation of conjugates occurs during the catalytic activity of one of the enzymes of the same name, for example (drug + glucuronic acid - formed using glucuronide transferase). The resulting conjugates are pharmacologically inactive substances and are easily excreted from the body with one of the excrements. However, not all of the administered drug dose undergoes biotransformation; part of it is excreted unchanged.

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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, nutritional habits, disease and its severity, environmental factors, as well as the 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. In case of liver cirrhosis, 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.

Pharmacokinetics is a branch of pharmacology (Greek pharmakon - medicine and kinētikos - related to movement), studying the patterns of absorption, distribution, transformation (biotransformation) and excretion (elimination) of medicinal substances in the body of humans and animals.

Absorption– absorption of the drug. The injected medicine passes from the injection site (for example, the gastrointestinal tract, muscle) into the blood, which carries it throughout the body and delivers it to various tissues of organs and systems. The speed and completeness of absorption characterize bioavailability drug (pharmacokinetic parameter indicating how much of the drug reaches the systemic circulation). Naturally, with intravenous and intra-arterial administration, the drug enters the bloodstream immediately and completely, and its bioavailability is 100%.

When absorbed, the medicine must pass through cell membranes skin, mucous membranes, walls capillaries, cellular and subcellular structures.

Depending on the properties of the drug and the barriers through which it penetrates, as well as the method of administration, all absorption mechanisms can be divided into four main types: diffusion (penetration of molecules due to thermal movement), filtration (the passage of molecules through pores under the influence of pressure), active transport (transfer with energy expenditure) and osmosis, in which the drug molecule is, as it were, pressed through the membrane shell. These same membrane transport mechanisms are involved in the distribution of drugs in the body and their elimination.

Distribution– penetration of the drug into various organs, tissues and body fluids. The distribution of the drug in the body determines the speed of onset of the pharmacological effect, its intensity and duration. In order to begin to act, the drug must be concentrated in the right place in sufficient quantity and remain there for a long time.

In most cases, the drug is distributed unevenly in the body; in different tissues its concentrations differ by 10 or more times. The uneven distribution of the drug in tissues is due to differences in the permeability of biological barriers and the intensity of blood supply to tissues and organs. Cell membranes are the main obstacle to the path of drug molecules to the site of action. Different human tissues have a set of membranes with different “throughput”. The easiest way to overcome the walls of capillaries, the most difficult to overcome barriers between blood and brain tissue - blood-brain barrier and between the blood of the mother and the fetus - placental barrier.

In the vascular bed, the drug binds to plasma proteins to a greater or lesser extent. “Protein + drug” complexes are not able to “squeeze” through the capillary wall. As a rule, binding to plasma proteins is reversible and leads to a slower onset of effect and an increase in the duration of action of the drugs.

Uneven distribution of the drug in the body often causes side effects. It is necessary to learn how to control the distribution of drugs in the human body. Find drugs that can selectively accumulate in certain tissues. Create dosage forms that release the drug where its action is needed.

Metabolism– biotransformation of a drug with the formation of one or more metabolites.

Some drugs act in the body and are excreted unchanged, while some undergo biotransformation in the body. Various organs and tissues take part in the biotransformation of medicinal substances in the human and animal body - liver, lungs, skin, kidneys, placenta. The most active processes of drug biotransformation occur in the liver, which is associated with the performance of detoxification, barrier and excretory functions by this organ.

Two main directions of biotransformation of medicinal substances can be distinguished: metabolic transformation and conjugation.

Metabolic transformation is understood as the oxidation, reduction or hydrolysis of an incoming drug substance by microsomal oxidases of the liver or other organs.

Conjugation is a biochemical process accompanied by the addition of various chemical groups or molecules of endogenous compounds to a drug or its metabolites.

During the processes described, drugs entering the body are converted into more water-soluble compounds. This, on the one hand, can lead to a change in activity, and on the other, to the removal of these substances from the body.

As a result of metabolic transformation and conjugation, drugs usually change or completely lose their pharmacological activity.

Metabolism or biotransformation of a drug often leads to the transformation of fat-soluble substances into polar and finally water-soluble substances. These metabolites are less biologically active, and biotransformation facilitates their excretion in urine or bile.

Excretion - the removal of drugs from the body after they are partially or completely converted into water-soluble metabolites (some drugs are excreted unchanged); excretion of drugs is carried out with urine, bile, exhaled air, sweat, milk, feces, and saliva.

Intestinal drug excretion– excretion of drugs first with bile and then with feces.

Pulmonary drug excretion– elimination of drugs through the lungs, mainly drugs for inhalation anesthesia.

Excretion of drugs by kidney– the main route of drug excretion; depends on the magnitude of renal clearance, the concentration of the drug in the blood, and the degree of binding of the drug to proteins.

Excretion of drugs in breast milk- excretion of drugs during lactation with milk (hypnotics, analgesics, phenylin, amiodorone, acetylsalicylic acid, sotalol, ethyl alcohol).

Most drugs or water-soluble metabolites of fat-soluble substances are excreted by the kidneys. Water-soluble substances in the blood can be excreted in the urine by passive glomerular filtration, active tubular secretion, or by blockade of active, or more often passive, tubular reabsorption.

Filtration is the main mechanism of renal excretion of drugs not bound to plasma proteins. In this regard, in pharmacokinetics, the elimination function of the kidneys is assessed by the speed of this particular process.

Filtration of drugs in the glomeruli occurs passively. The molecular weight of substances should not be more than 5-10 thousand, they should not be associated with blood plasma proteins.

Secretion is an active process (with energy consumption with the participation of special transport systems), independent of the binding of drugs to blood plasma proteins. Reabsorption of glucose, amino acids, cations and anions occurs actively, and fat-soluble substances - passively.

The ability of the kidneys to eliminate drugs by filtration is tested by the excretion of endogenous creatinine, since both processes occur in parallel at the same rate.

In case of renal failure, the dosage regimen is adjusted by calculating the clearance of endogenous creatinine (C/cr). Clearance is the hypothetical volume of blood plasma that is completely cleared of a drug per unit of time. Normal clearance of endogenous creatinine is 80-120 ml/min. In addition, special nomograms exist to determine endogenous creatinine clearance. They are compiled taking into account the level of creatinine in the blood serum, body weight and height of the patient.

The elimination of a xenobiotic can also be quantitatively assessed using the elimination coefficient. It reflects that part (in percentage) of the drug substance by which its concentration in the body decreases per unit of time (usually per day).

The relationship between the volume of distribution and clearance of a substance is expressed by its half-life (T1/2). The half-life of a substance is the time during which its concentration in the blood plasma is reduced by half.

The main goal of pharmacokinetics is to identify the relationship between the concentration of a drug or its metabolite(s) in biological fluids and tissues and the pharmacological effect.

All quantitative and qualitative processes are included in the concept of a primary pharmacological reaction. Usually it occurs latently and manifests itself in the form of clinically diagnosable reactions of the body or, as they are commonly called, pharmacological effects, caused by the physiological properties of cells, organs and systems. Each drug effect, as a rule, can be divided in time into a latent period, the time of maximum therapeutic effect and its duration. Each stage is determined by a number of biological processes. Thus, the latent period is determined mainly by the route of administration, the rate of absorption and distribution of the substance across organs and tissues, and to a lesser extent - by its rate of biotransformation and excretion. The duration of the effect is determined primarily by the rate of inactivation and release. The redistribution of the active agent between the sites of action and deposition, pharmacological reactions and the development of tolerance are of particular importance. In most cases, as the dose of the drug increases, the latent period decreases, the effect and its duration increase. It is convenient and practically important to express the duration of the therapeutic effect by the half-period of the decrease in the effect. If the half-life coincides with the concentration of the substance in plasma, an objective criterion is obtained for monitoring and targeted regulation of therapeutic activity.

The pharmacodynamics and pharmacokinetics of drugs become more complicated in various pathological conditions. Each disease models the pharmacological effect in its own way; in the case of several diseases, the picture becomes even more complicated.

Of course, with liver damage, the biotransformation of drugs is predominantly impaired; Kidney diseases are usually accompanied by a slowdown in xenobiotic excretion. However, such unambiguous pharmacokinetic modulations are rarely observed; more often, pharmacokinetic shifts are intertwined with complex pharmacodynamic changes. Then, not only with one disease does the effect of the medicine increase or decrease, but during the course of the disease there are significant fluctuations, due both to the dynamics of the pathological process itself and to the drugs used in the treatment process.

GLOSSARY

Absorption - absorption, the process of entry of a medicinal substance from the site of administration into the general bloodstream

Abstinence is a painful condition that occurs when the use of narcotic and other addictive substances is abruptly stopped, accompanied by mental and neurological disorders.

Avitaminosis is a vitamin deficiency.

An agonist is a substance that, when interacting with a receptor, causes a mediator effect.

Accommodation is an adaptation.

Active transport is the transfer of drugs into or out of the cell, which occurs with the expenditure of energy.

Anaphylaxis is an immediate allergic reaction accompanied by bronchospasm and laryngeal edema.

Anemia – anemia.

Anorexigenic drugs are drugs that reduce appetite.

An antagonist is a drug that weakens the effect of another drug.

Antacids are medications used for diseases of the digestive system to neutralize the hydrochloric acid contained in the stomach.

Antiplatelet agents are agents that prevent the adhesion of blood cells.

Antianginal drugs are medications used to relieve and prevent angina attacks.

Anticoagulants are drugs that inhibit blood clotting.

Bioavailability is a pharmacokinetic parameter that shows how much of the drug enters the general bloodstream.

Biotransformation is the process of converting medicinal substances in the body into other chemical compounds.

Bronchodilators - Drugs that cause relaxation of the smooth muscles of the bronchi, expanding their lumen and eliminating spasm.

Vitamins are low-molecular compounds involved in various biochemical processes in the body.

Ganglioblockers are agents that prevent the transmission of excitation in the ganglia of the autonomic nervous system.

Gastroprotectors are agents that protect the gastric mucosa from damaging effects.

The blood-brain barrier is a barrier that prevents the exchange of substances between the blood and nervous tissue (brain).

Hematopoiesis is the process of formation, development and maturation of blood cells.

Hepatoprotectors are agents that increase the liver’s resistance to various influences.

Hyperglycemia is an increased level of glucose in the blood.

Hypoxia is an insufficient supply of oxygen to cells.

Homeostasis is the constancy of the internal environment of the body.

Disinfectants are antimicrobial agents designed to kill microbes in the environment.

Dysbacteriosis is a change in the ratio and composition of the natural human microbial flora.

Dyspepsia is a digestive disorder.

Dose is the amount of a drug introduced into the body.

Dopamine is a neurotransmitter of the nervous system.

Choleretic agents are agents that enhance bile formation.

Idiosyncrasy is an unusual effect of a drug that is not associated with an allergy.

Immunosuppressants are drugs that inhibit immune processes.

Immunomodulators are drugs that change immune responses.

Immunostimulants are agents that stimulate immune processes.

Proton pump inhibitors are agents that prevent the release of hydrogen ions from the cells of the gastric mucosa and, as a result, the formation of hydrochloric acid.

Clearance – cleansing, is determined by the body’s ability to eliminate drugs per unit of time.

Coagulants are agents that stimulate blood clotting and stop bleeding.

Contraceptives are means to prevent pregnancy.

Cumulation is the accumulation of biologically active substances during repeated exposure.

A mediator is a biologically active substance formed by cells or nerve endings that carry out intercellular contacts.

Metabolites are intermediate products of metabolism.

Mydriasis is dilation of the pupil.

Miosis is a constriction of the pupil.

Mineralocorticoids are a group of steroid hormones that primarily affect water-salt metabolism.

Muscle relaxants are drugs that reduce the tone of skeletal muscles with a decrease in motor activity up to complete immobility.

Diuretics (diuretics) are drugs that increase urination and promote the removal of salts and water from the body.

Mucolytics are agents that help thin sputum.

Narcotic analgesics (opioids) are drugs that selectively suppress pain sensitivity due to interaction with specific opioid receptors, causing the development of mental and physical dependence.

Neuroleptics (antipsychotics) are drugs that have an inhibitory effect on the functions of the central nervous system and eliminate the manifestations of psychosis.

Non-narcotic analgesics (NSAIDs) are drugs that relieve or eliminate pain, mainly of an inflammatory nature.

Nootropic drugs are drugs that stimulate metabolism in nerve cells and protect against hypoxia, contribute to the normalization of mental processes (thinking, memory, learning).

Expectorants are drugs that make it easier to cough up and remove sputum.

Parenteral route of administration - introduction into the body, bypassing the digestive tract.

Premedication is the use of medications to prepare a patient for general or local anesthesia.

Distribution is the process of drug penetration from the bloodstream into tissues.

Resorptive effect is the effect of a drug substance after absorption into the blood.

Selective action is selective action.

Synergism is the mutually reinforcing effect of drugs when used together.

Sublingual - under the tongue.

Teratogenicity is the toxicity of drugs, characterized by the ability to have a damaging effect on the fetus.

Toxicity is the effect of drugs that harms the body.

Tolerance is the ability to resist the effects of drugs in large doses without manifestations of its damaging factor.

Pharmacodynamics is a branch of pharmacology that studies the effect of drugs on the body, the mechanism of action, the nature, strength and duration of effects.

Pharmacokinetics is a branch of pharmacology that studies the processes of absorption, distribution, metabolism and excretion of drugs in the body.

Pharmacology is a medical and biological science about the effect of medicinal substances on the human body.

Fibrinolytics are agents that help dissolve a fibrin clot.

Chemotherapeutic agents are agents that selectively act to suppress the vital activity of microorganisms or tumor cells.

Anticholinergics (anticholinergics) are drugs that prevent the interaction of acetycholine with cholinergic receptors.

Cholinomimetics are drugs that excite and promote the excitation of cholinergic receptors.

Excretion - excretion.

Enteral drug administration is the administration of drugs through the gastrointestinal tract.

Test questions for Part I of the Lecture Notes

1. What does pharmacology study?

2. How the science of medicines developed in ancient times

3. Pharmacology in Russia

4. The path of a drug from chemical synthesis to introduction into production

5. Basic concepts of pharmacology: medicinal substance, pharmaceutical substance, medicinal product, dosage form.

6. Classification of dosage forms

7. Name solid dosage forms

8. Routes of administration of solid dosage forms

9. Which dosage forms are considered mild

10. Features of the use of soft dosage forms

11. What dosage forms are liquid?

12. Solutions for internal use

13. Solutions for injections

14. Define pharmacodynamics

15. Mechanism of action of drugs

16. Pharmacological effects

17. Define pharmacokinetics

18. Drug absorption

19. Distribution of medicines

20. Biotransformation of drugs

21. Excretion of drugs