Pharmacokinetics of drugs! Ways of introducing drugs into the human body Algorithm for the pharmacokinetics of drugs in the body.

Pharmacokinetics(“Man is a drug”) - studies the influence of the body on the medicinal substance, the ways of its intake, distribution, biotransformation and excretion of drugs from the body. The physiological systems of the body, depending on their innate and acquired properties, as well as methods and routes of drug administration, will change the fate of the drug substance to varying degrees. The pharmacokinetics of the drug depends on gender, age and nature of the disease.

The main integral indicator for judging the fate of medicinal substances in the body is the definition concentrations of these substances and their metabolites in fluids, tissues, cells and cell organelles.

The duration of action of drugs depends on its pharmacokinetic properties. Half-life- the time required for the purification of blood plasma from the medicinal substance by 50%.

Stages (phases) of pharmacokinetics. The movement of a medicinal substance and the change in its molecule in the body is a series of sequential processes. absorption, distribution, metabolism and excretion (excretion)medicines. For all these processes necessary condition their penetration through cell membranes.

The passage of drugs through cell membranes.

Penetration of drugs through cell membranes regulated natural processes diffusion, filtration and active transport.

Diffusion is based on the natural tendency of any substance to move from an area of ​​high concentration towards an area of ​​lower concentration.

Filtration. Water channels in places of close connection of adjacent epithelial cells miss through the pores only some water-soluble substances. Neutral or uncharged (i.e., non-polar) molecules penetrate faster because the pores are electrically charged.

Active transport - this mechanism regulates the movement of certain drugs into or out of cells against a concentration gradient. This process requires energy to implement and is faster than the transfer of substances by diffusion. Molecules with a similar structure compete for carrier molecules. The mechanism of active transport is highly specific for certain substances.

Some organ features of cell membranes.

Brain and cerebrospinal fluid. Capillaries in the brain differ from most capillaries elsewhere in the body in that their endothelial cells do not have spaces through which substances can enter the extracellular fluid. Closely adjacent capillary endothelial cells connected to the basement membrane, as well as a thin layer of astrocyte processes, prevent blood from contacting the brain tissue. This blood-brain barrier prevents the penetration of certain substances from the blood into the brain and cerebrospinal fluid (CSF). Fat insoluble substances do not pass through this barrier. Against, fat-soluble substances easily cross the blood-brain barrier.

Placenta. Chorionic villi, consisting of a layer of trophoblasts, i.e. cells surrounding the fetal capillaries are immersed in maternal blood. The blood flow of the pregnant woman and the fetus are separated by a barrier, the features of which are the same as those of all lipid membranes of the body, i.e. it is only permeable to fat-soluble substances and impermeable to water-soluble substances (especially if their relative molecular weight (RMM) exceeds 600). In addition, the placenta contains monoamine oxidase, cholinesterase, and a microsomal enzyme system (similar to that in the liver) capable of metabolizing drugs and responsive to drugs taken by the pregnant woman.

Suction - the process of drug entry from the injection site into the bloodstream. Regardless of the route of administration suction rate The drug is determined by three factors: a) dosage form (tablets, suppositories, aerosols); b) solubility in tissues; c) blood flow at the injection site.

There are a number of successive absorption steps medicines through biological barriers:

1) passive diffusion. In this way, drugs that are highly soluble in lipids penetrate. The rate of absorption is determined by the difference between its concentration and external and inside membranes;

2) active transport. In this case, the movement of substances through the membranes occurs with the help of transport systems contained in the membranes themselves;

3) Filtration. Due to filtration, drugs penetrate through the pores present in the membranes (water, some ions and small hydrophilic molecules of drugs). Filtration intensity depends on hydrostatic and osmotic pressure;

4) Pinocytosis. The transport process is carried out through the formation of special vesicles from the structures of cell membranes, in which the particles of the medicinal substance are enclosed. The bubbles move to the opposite side of the membrane and release their contents.

Distribution. After introduction into the bloodstream, the medicinal substance is distributed throughout all tissues of the body. The distribution of a medicinal substance is determined by its lipid solubility, the quality of its association with blood plasma proteins, the intensity of regional blood flow, and other factors.

A significant part of the drug in the first time after absorption enters those organs and tissues that are most active blood supply(heart, liver, lungs, kidneys).

Many naturally occurring substances circulate in the plasma, partly free and partly bound to plasma proteins. Drugs also circulate in both bound and free states. It is important that only the free, unbound fraction of the drug is pharmacologically active, while the protein-bound fraction is a biologically inactive compound. Connection and disintegration of the complex of the drug with the plasma protein usually occur quickly.

Metabolism (biotransformation) is a complex of physicochemical and biochemical transformations that medicinal substances undergo in the body. As a result metabolites are formed(water-soluble substances), which are easily excreted from the body.

As a result of biotransformation, substances acquire a large charge (become more polar) and, as a result, greater hydrophilicity, i.e., solubility in water. Such a change in the chemical structure entails a change in the pharmacological properties (as a rule, a decrease in activity), the rate of excretion from the body.

It happens in two main directions: a) a decrease in the solubility of drugs in fats and b) a decrease in their biological activity.

Stages of metabolism : Hydroxylation. Dimethylation. Oxidation. The formation of sulfoxides.

Allocate two types of metabolism drugs in the body

Non-synthetic reactions drug metabolism by enzymes. Non-synthetic reactions include oxidation, reduction and hydrolysis. They are divided into enzyme-catalyzed cell lysosomes (microsomal) and catalyzed by enzymes of other localization (non-microsomal).

Synthetic reactions which are realized with the help of endogenous substrates. These reactions are based on conjugation medicines with endogenous substrates (glucuronic acid, glycine, sulfates, water, etc.).

Biotransformation of drugs occurs mainly in the liver, however, it is also carried out in blood plasma and in other tissues. Intensive and numerous metabolic reactions are already taking place in the intestinal wall.

Biotransformation is affected by liver disease, diet, gender, age and a number of other factors. With liver damage, the toxic effect of many drugs on the central nervous system and the incidence of encephalopathy increases sharply. Depending on the severity of the liver disease, some drugs are used with caution or are contraindicated altogether (barbiturates, narcotic analgesics, phenothiazines, androgenic steroids, etc.).

Clinical observations have shown that the efficacy and tolerability of the same medicinal substances in different patients is not the same. These differences are defined genetic factors determining the processes of metabolism, reception, immune response, etc. The study of the genetic basis of the sensitivity of the human body to medicinal substances is the subject pharmacogenetics. This is manifested most often by a deficiency of enzymes that catalyze the biotransformation of drugs. Atypical reactions can also occur with hereditary metabolic disorders.

The synthesis of enzymes is under strict genetic control. When the corresponding genes are mutated, hereditary violations of the structure and properties of enzymes occur - fermentopathy. Depending on the nature of the gene mutation, the rate of enzyme synthesis changes or an atypical enzyme is synthesized.

Among the hereditary defects of enzyme systems, deficiency is often found. glucose-6-phosphate dehydrogenesis(G-6-FDG). It is manifested by massive destruction of red blood cells (hemolytic crises) with the use of sulfonamides, furazolidone and other drugs. In addition, people with G-6-FDR deficiency are sensitive to foods containing fava beans, gooseberries, and red currants. There are patients with deficiency acetyltransferase, catalase and other enzymes in the body. Atypical reactions to drugs in hereditary metabolic disorders occur with congenital methemoglobinemia, porphyria, hereditary non-hemolytic jaundice.

Elimination . There are several routes of excretion) drugs and their metabolites from the body: with feces, urine, exhaled air, salivary, sweat, lacrimal and mammary glands.

Elimination by the kidneys . The excretion of drugs and their metabolites by the kidneys occurs with the participation of several physiological processes:

Glomerular filtration. The rate at which a substance passes into the glomerular filtrate depends on its plasma concentration, OMM, and charge. Substances with an OMM of more than 50,000 do not enter the glomerular filtrate, and those with an OMM of less than 10,000 (i.e., almost the majority of medicinal substances) are filtered in the renal glomeruli.

Excretion in the renal tubules. The ability of the cells of the proximal renal tubules to actively transfer charged (cations and anions) molecules from the plasma to the tubular fluid is one of the important mechanisms of the excretory function of the kidneys.

renal tubular reabsorption. In the glomerular filtrate, the concentration of drugs is the same as in plasma, but as it moves along the nephron, it concentrates with an increase in the concentration gradient, so the concentration of the drug in the filtrate exceeds its concentration in the blood passing through the nephron.

Elimination through the gut.

After taking the drug inside for systemic action, part of it, without being absorbed may be excreted in feces. Sometimes drugs are taken orally that are not specifically designed for absorption in the intestine (eg, neomycin). Under the influence of enzymes and bacterial microflora of the gastrointestinal tract, drugs can be converted into other compounds that can again be delivered to the liver, where a new cycle takes place.

To the most important mechanisms that contribute to active drug transport to the intestines biliary excretion(cookie). From the liver, with the help of active transport systems, medicinal substances in the form of metabolites or, without changing, enter the bile, then into the intestine, where they are excreted. with feces.

The degree of excretion of drugs by the liver should be taken into account in the treatment of patients suffering from liver diseases and inflammatory diseases bile ducts.

Elimination through the lungs . The lungs serve as the main route of administration and elimination of volatile anesthetics. In other cases drug therapy their role in elimination is small.

Elimination of drugs breast milk . Medicinal substances contained in the plasma of lactating women are excreted in milk; their amounts in it are too small to significantly affect their elimination. However, sometimes drugs that enter the body baby, can have a significant effect on it (hypnotics, analgesics, etc.).

Clearance allows you to determine the excretion of the drug from the body. The term " renal creatinine clearance» determine the excretion of endogenous creatinine from plasma. Most drugs are eliminated either through the kidneys or the liver. In this regard, the total clearance in the body is the sum of hepatic and renal clearance, and hepatic clearance calculated by subtracting the value of renal clearance from the total body clearance (hypnotics, analgesics, etc.).