Inhibitors and inducers of microsomal liver enzymes. Substance that causes the induction of microsomal liver enzymes

Hepatologist → About the liver → Changes in liver enzymes in various pathologies, their diagnostic value

A group of protein substances that increase the activity of various metabolic processes is called enzymes.

The successful course of biological reactions requires special conditions - elevated temperature, a certain pressure, or the presence of certain metals.

Enzymes help speed up chemical reactions without these conditions being met.

What are liver enzymes

Based on their function, enzymes are located inside the cell, on the cell membrane, are part of various cellular structures and participate in reactions within it. According to the function performed, the following groups are distinguished:

hydrolases - break down the molecules of substances; synthetases - participate in molecular synthesis; transferases - transport sections of molecules; oxidoreductases - affect redox reactions in the cell; isomerases - change the configuration of molecules; lyases - form additional molecular bonds.

The work of many enzymes requires the presence of additional co-factors. Their role is performed by all vitamins, microelements.

What are liver enzymes

Each cell organelle has its own set of substances that determine its function in the life of the cell. Enzymes of energy metabolism are located on mitochondria, granular endoplasmic reticulum is tied to protein synthesis, smooth reticulum is involved in lipid and carbohydrate metabolism, lysosomes contain hydrolysis enzymes.

Enzymes that can be found in blood plasma are conventionally divided into three groups:

Secretory. They are synthesized in the liver and released into the blood. An example is blood coagulation enzymes, cholinesterase. Indicator, or cellular (LDH, glutamate dehydrogenase, acid phosphatase, ALT, AST). Normally, only their traces are found in the serum, tk. their location is intracellular. Tissue damage causes the release of these enzymes into the blood, by their number one can judge the depth of the lesion. Excretory enzymes are synthesized and excreted along with bile (alkaline phosphatase). Violation of these processes leads to an increase in their indicators in the blood.

What enzymes are used in diagnosis

Pathological processes are accompanied by the appearance of cholestasis and cytolysis syndromes. Each of them is characterized by its own changes in the biochemical parameters of serum enzymes.

Cholestatic syndrome is a violation of bile secretion. It is determined by the change in the activity of the following indicators:

an increase in excretory enzymes (alkaline phosphatase, GGTP, 5-nucleotidase, glucuronidase); an increase in bilirubin, phospholipids, bile acids, cholesterol.

Cytolytic syndrome indicates the destruction of hepatocytes, an increase in the permeability of cell membranes. The condition develops with viral, toxic damage. A change in indicator enzymes is characteristic - ALT, AST, aldolase, LDH.

Alkaline phosphatase can be of both hepatic and bone origin. A parallel rise in GGTP speaks of cholestasis. Activity increases with liver tumors (jaundice may not appear). If there is no parallel increase in bilirubin, one can assume the development of amyloidosis, liver abscess, leukemia or granuloma.

GGTP rises simultaneously with an increase in alkaline phosphatase and indicates the development of cholestasis. An isolated increase in GGTP can occur with alcohol abuse, when there are no gross changes in the liver tissue yet. If fibrosis, cirrhosis or alcoholic hepatitis has developed, the level of other liver enzymes also increases.

Transaminases are represented by ALT and AST fractions. Aspartate aminotransferase is found in the mitochondria of the liver, heart, kidneys, and skeletal muscles. Damage to their cells is accompanied by the release a large number enzyme into the blood. Alanine aminotransferase is a cytoplasmic enzyme. Its absolute amount is small, but the content in hepatocytes is the highest, compared with the myocardium and muscles. Therefore, an increase in ALT is more specific for damage to liver cells.

The change in the ratio of AST / ALT matters. If it is 2 or more, then this indicates hepatitis or cirrhosis. Especially high enzymes are observed in hepatitis with active inflammation.

Lactate dehydrogenase is a cytolysis enzyme, but is not specific to the liver. May increase in pregnant women, newborns, after severe physical activity. Significantly increases LDH after myocardial infarction, pulmonary embolism, extensive injuries with muscle relaxation, with hemolytic and megaloblastic anemia. The level of LDH is based on the differential diagnosis of Gilbert's disease - cholestasis syndrome is accompanied by normal LDH. In other jaundices, at the beginning, LDH remains unchanged, and then rises.

Analysis for liver enzymes

Preparation for analysis begins the day before. It is necessary to completely exclude alcohol, in the evening do not eat fatty and fried foods. Do not smoke one hour before the test.

Perform venous blood sampling on an empty stomach in the morning.

The hepatic profile includes the definition of the following indicators:

ALT; AST; alkaline phosphatase; GGTP; bilirubin and its fractions.

Also pay attention to the total protein, separately the level of albumin, fibrinogen, glucose, 5-nucleotidase, ceruloplasmin, alpha-1-antitrypsin.

Diagnostics and norms

Normal biochemical indicators, characterizing the work of the liver, are reflected in the table

liver enzymes during pregnancy

Most of the laboratory parameters during pregnancy remain within the normal range. If there are slight fluctuations in enzymes, then they disappear soon after childbirth. In the third trimester, a significant rise in alkaline phosphatase is possible, but not more than 4 norms. This is due to the release of the enzyme by the placenta.

An increase in other liver enzymes, especially in the first half of gestation, should be associated with the development of liver pathology. This may be liver damage caused by pregnancy - intrahepatic cholestasis, fatty hepatosis. Also, a change in the analyzes will appear with severe preeclampsia.

Cirrhosis and changes in biochemistry

Pathology of the liver associated with tissue restructuring causes changes in all functions of the organ. There is an increase in nonspecific and specific enzymes. A high level of the latter is characteristic of cirrhosis. These are the enzymes:

arginase; fructose-1-phosphate aldolase; nucleotidase.

AT biochemical analysis You can see changes in other indicators as well. Albumin decreases to less than 40 g/l, globulins may increase. Cholesterol becomes less than 2 mmol/l, urea below 2.5 mmol/l. An increase in haptoglobin is possible.

Significantly increases bilirubin due to the growth of direct and bound forms.

microsomal enzymes

The endoplasmic reticulum of hepatocytes produces cavity formations - microsomes containing a group of microsomal enzymes on their membranes. Their purpose is to neutralize xenobiotics and endogenous compounds by oxidation. The system includes several enzymes, among them cytochrome P450, cytochrome b5 and others. These enzymes neutralize drugs, alcohol, toxins.

Oxidizing medicinal substances, the microsomal system accelerates their excretion and reduces the time of action on the body. Some substances are able to increase the activity of cytochrome, then they speak of the induction of microsomal enzymes. This is manifested by the acceleration of the disintegration of the drug. Alcohol, rifampicin, phenytoin, carbamazepine can act as inducers.

Other drugs inhibit myrosomal enzymes, which is manifested by lengthening the life of the drug and increasing its concentration. Fluconazole, cyclosporine, diltiazem, verapamil, erythromycin can act as inhibitors.

Attention! Given the possibility of inhibition or induction of microsomal reactions, only a doctor can correctly prescribe several drugs at the same time without harm to the patient.

The role of microsomal oxidation in the life of the organism is difficult to overestimate or overlook. Inactivation of xenobiotics (toxic substances), the breakdown and formation of adrenal hormones, participation in protein metabolism and the preservation of genetic information are just a small part of the known problems that are solved due to microsomal oxidation. This is an autonomous process in the body that starts after the hit of a trigger substance and ends with its elimination.

Definition

Microsomal oxidation is a cascade of reactions included in the first phase of xenobiotic transformation. The essence of the process is the hydroxylation of substances using oxygen atoms and the formation of water. Due to this, the structure of the original substance changes, and its properties can both be suppressed and enhanced.

Microsomal oxidation allows you to proceed to the conjugation reaction. This is the second phase of the transformation of xenobiotics, at the end of which molecules produced inside the body will join the already existing functional group. Sometimes intermediate substances are formed that cause damage to liver cells, necrosis and oncological degeneration of tissues.

Oxidase type oxidation

Microsomal oxidation reactions occur outside the mitochondria, so they consume about ten percent of all oxygen that enters the body. The main enzymes in this process are oxidases. Their structure contains atoms of metals with variable valence, such as iron, molybdenum, copper and others, which means that they are able to accept electrons. In the cell, oxidases are located in special vesicles (peroxisomes) that are located on the outer membranes of mitochondria and in the ER (granular endoplasmic reticulum). The substrate, getting on peroxisomes, loses hydrogen molecules, which attach to a water molecule and form peroxide.

There are only five oxidases:

Monoamine oxygenase (MAO) - helps to oxidize adrenaline and other biogenic amines formed in the adrenal glands;

Diaminooxygenase (DAO) - is involved in the oxidation of histamine (a mediator of inflammation and allergies), polyamines and diamines;

Oxidase of L-amino acids (that is, left-handed molecules);

Oxidase of D-amino acids (right-rotating molecules);

Xanthine oxidase - oxidize adenine and guanine (nitrogenous bases included in the DNA molecule).

The significance of microsomal oxidation according to the oxidase type is the elimination of xenobiotics and the inactivation of biologically active substances. The formation of peroxide, which has a bactericidal effect and mechanical cleansing at the site of damage, is side effect, which occupies an important place among other effects.

Oxygenase type oxidation

Reactions of the oxygenase type in the cell also occur on the granular endoplasmic reticulum and on the outer shells of mitochondria. This requires specific enzymes - oxygenases, which mobilize an oxygen molecule from the substrate and introduce it into the oxidized substance. If one oxygen atom is introduced, then the enzyme is called monooxygenase or hydroxylase. In the case of the introduction of two atoms (that is, a whole molecule of oxygen), the enzyme is called dioxygenase.

Oxygenase-type oxidation reactions are included in a three-component multienzyme complex, which is involved in the transfer of electrons and protons from the substrate, followed by oxygen activation. This whole process occurs with the participation of cytochrome P450, which will be discussed in more detail later.

Examples of oxygenase-type reactions

As mentioned above, monooxygenases use only one of the two available oxygen atoms for oxidation. The second they attach to two hydrogen molecules and form water. One example of such a reaction is the formation of collagen. In this case, vitamin C acts as an oxygen donor. Proline hydroxylase takes an oxygen molecule from it and gives it to proline, which, in turn, is included in the procollagen molecule. This process gives strength and elasticity to the connective tissue. When the body is deficient in vitamin C, gout develops. It is manifested by weakness of the connective tissue, bleeding, bruising, tooth loss, that is, the quality of collagen in the body becomes lower.

Another example is hydroxylases, which convert cholesterol molecules. This is one of the stages in the formation of steroid hormones, including sex hormones.

Less specific hydroxylases

These are hydrolases necessary for the oxidation of foreign substances such as xenobiotics. The meaning of the reactions is to make such substances more tractable for excretion, more soluble. This process is called detoxification, and it happens mostly in the liver.

Due to the inclusion of a whole molecule of oxygen in xenobiotics, the cycle of reactions is broken and one complex substance breaks down into several simpler and more accessible metabolic processes.

reactive oxygen species

Oxygen is a potentially dangerous substance, since, in fact, oxidation is a combustion process. As an O2 molecule or water, it is stable and chemically inert because its electrical levels are full and no new electrons can attach. But compounds in which oxygen does not have a pair of all electrons are highly reactive. That is why they are called active.

These oxygen compounds are:

In monoxide reactions, superoxide is formed, which is separated from cytochrome P450. In oxidase reactions, peroxide anion (hydrogen peroxide) is formed. During reoxygenation of tissues that have undergone ischemia.

The strongest oxidizing agent is the hydroxyl radical, it exists in its free form for only a millionth of a second, but during this time it has time to undergo many oxidative reactions. Its peculiarity is that the hydroxyl radical acts on substances only in the place where it was formed, since it cannot penetrate tissues.

Superoxidanion and hydrogen peroxide

These substances are active not only at the site of formation, but also at some distance from them, as they can penetrate cell membranes.

The hydroxyl group causes the oxidation of amino acid residues: histidine, cysteine ​​and tryptophan. This leads to inactivation of enzyme systems, as well as disruption of transport proteins. In addition, microsomal oxidation of amino acids leads to the destruction of the structure of nucleic nitrogenous bases and, as a result, the genetic apparatus of the cell suffers. The fatty acids that make up the bilipid layer of cell membranes are also oxidized. This affects their permeability, the operation of membrane electrolyte pumps, and the location of receptors.

Microsomal oxidation inhibitors are antioxidants. They are found in food and are produced within the body. The best known antioxidant is vitamin E. These substances can inhibit microsomal oxidation. Biochemistry describes the interaction between them according to the feedback principle. That is, the more oxidases, the stronger they are suppressed, and vice versa. This helps to maintain a balance between systems and the constancy of the internal environment.

Electric transport chain

The microsomal oxidation system has no components soluble in the cytoplasm, so all its enzymes are collected on the surface of the endoplasmic reticulum. This system includes several proteins that form the electrotransport chain:

NADP-P450 reductase and cytochrome P450;

NAD-cytochrome B5 reductase and cytochrome B5;

Steatoryl-CoA desaturase.

The electron donor in the vast majority of cases is NADP (nicotinamide adenine dinucleotide phosphate). It is oxidized by NADP-P450 reductase, which contains two coenzymes (FAD and FMN), to accept electrons. At the end of the chain, FMN is oxidized with P450.

Cytochrome P450

It is an enzyme of microsomal oxidation, a heme-containing protein. Binds oxygen and substrate (as a rule, it is a xenobiotic). Its name is associated with the absorption of light from a wavelength of 450 nm. Biologists have found it in all living organisms. At the moment, more than eleven thousand proteins that are part of the cytochrome P450 system have been described. In bacteria, this substance is dissolved in the cytoplasm, and it is believed that this form is the most evolutionarily ancient than in humans. In our country, cytochrome P450 is a parietal protein fixed on the endoplasmic membrane.

Enzymes of this group are involved in the metabolism of steroids, bile and fatty acids, phenols, neutralization of medicinal substances, poisons or drugs.

Properties of microsomal oxidation

The processes of microsomal oxidation have a wide substrate specificity, and this, in turn, makes it possible to neutralize various substances. Eleven thousand cytochrome P450 proteins can be folded into more than one hundred and fifty isoforms of this enzyme. Each of them has a large number of substrates. This enables the body to get rid of almost all harmful substances that are formed inside it or come from outside. Being produced in the liver, enzymes of microsomal oxidation can act both locally and at a considerable distance from this organ.

Regulation of microsomal oxidation activity

Microsomal oxidation in the liver is regulated at the level of messenger RNA, or rather its function - transcription. All variants of cytochrome P450, for example, are recorded on the DNA molecule, and in order for it to appear on the EPR, it is necessary to “rewrite” part of the information from DNA to messenger RNA. The mRNA is then sent to the ribosomes, where protein molecules are formed. The number of these molecules is regulated from the outside and depends on the amount of substances that need to be deactivated, as well as on the presence of the necessary amino acids.

At the moment, more than two hundred and fifty chemical compounds have been described that activate microsomal oxidation in the body. These include barbiturates, aromatic carbohydrates, alcohols, ketones, and hormones. Despite such apparent diversity, all these substances are lipophilic (fat-soluble), and therefore susceptible to cytochrome P450.

Biotransformation is a change in the chemical structure and f-x properties Drugs under the action of body enzymes. Purpose: removal of xenobiotics by converting non-polar lipophilic compounds into polar hydrophilic ones (not reabsorbed in the kidney canal)

Enzymes:

Microsomal - associated with small subcellular fragments of smooth ER - microsomes, which are formed during the homogenization of the liver tissue or intestines, kidneys, lungs, GM (less);

Non-microsomal - localized in the cytosol, mitochondria of the tissue of the liver, intestines, kidneys, GM, skin, CO;

Drug metabolism is divided into: metabolic transformation and biosynthetic (conjugation)

1) Metabolic transformation: oxidation, reduction, hydrolysis

Oxidation: under the action of the microsomal system of enzymes (oxidases of mixed functions, the main component is cytochrome P450 (hemoprotein with oxygen in the center)). The reaction proceeds with the participation of cytochrome reductase and NADPH;

RH + O(2) + NADPH + H+ =>ROH + H(2)O + NADP+

There are various cytochrome isoenzymes, they are grouped into families and subfamilies and are designated CYP1A1 ... some are strictly specific, some are not; the largest amount of drugs is metabolized in the liver with the participation of CYP3A4;

under the action of non-microsomal enzymes:

MAO-A: deamination of catecholamines

alcohol dehydrogenase: ethanol -> acetaldehyde

xanthine oxidase: hydroxylation of purine bases

Recovery: addition to the drug molecule H + or removal of O-

microsomal enzymes (reduction of chloramphenicol

non-microsomal (reduction of chloral hydrate, intestinal mesalazine reductases)

Hydrolysis: leads to rupture of ester, amide and phosphate bonds

most non-microsomal enzymes (esterases, amidases, phosphatases - procaine, benzocaine)

microsomal enzymes (amidases - procainamide)

The result of metabolic transformation: a decrease in the toxicity of the starting substances, the formation of active metabolites from prodrugs (enalapril, valaciclovir), there may be the formation of toxic compounds (paracetamol, inactivation - glutathione)

2) Biosynthetic transformation: residues of endogenous compounds (glucuronic, sulfuric acid, glutathione, glycine) or highly polar chemical groups (acetyl, methyl) are attached to the functional groups of drug molecules or their metabolites. The reactions take place with the participation of microsomal and non-microsomal enzymes of the liver and other tissues (intestine ...), mainly transferases.

glucuronic acid: uridine-di-phosphate-glucuronyl-t-f has a low substrate specificity (many drugs, bilirubin, thyroid hormones), conjugates are excreted in the bile into the intestine.

sulfuric acid: sulfo-t-f mainly phenolic compounds, catecholamines, steroid hormones, thyroid hormones;

glutathione: glutathione-SH-S-t-ph in the cytosol, reaction with epoxides, quinones, toxic metabolite of paracetamol.

The result of biosynthetic transformation: a decrease in the activity and toxicity of drugs (excl: minoxidil, morphine)

Factors affecting biotransformation:

Gender (the synthesis of microsomal enzymes is regulated by androgens => in men their activity is higher, ethanol, estrogens, benzodiazepines are metabolized faster)

Age (the activity of microsomal enzymes reaches the normal level by 1-6 months of age, in the elderly it decreases)

Body condition (liver disease, heart failure, diabetes, hyper or hypothyroidism)

Taking other drugs (microsomal oxidation inducers: phenobarbital and rifampicin cause a decrease in the therapeutic effect of COCs, chronic alcohol intake, isoniazid cause an increase in paracetamol toxicity; inhibitors: cimetidine, macrolides, azoles, ciprofloxacin cause a decrease in warfarin oxidation, azoles cause an increase in the nephrotoxic effect of cyclosporine, omeprazole causes decrease in the effectiveness of clopidogrel, inducers are also furanocoumarins of grapefruit juice, St. John's wort)

Genetic factors (genetic polymorphism of the genes of cytochrome p450 isoenzymes, deficiency of acetyl-t-p causes an increase in side effects when taking sulfonamides, isoniazid, insufficiency of g6-fdg of erythrocytes when taking sulfonamides, chloramphenicol causes hemolytic anemia inhabitants of the tropics, subtropics)

IX. Bioavailability of drugs- part of the administered dose of the drug that reached the systemic circulation, expressed as a percentage; when administered parenterally, it is taken as 100%; when administered internally, it usually decreases, the reasons:

influence of hydrochloric acid, gastrointestinal enzymes

hydrophilicity and polarity of compounds (beta-lactam antibiotics)

metabolization in the intestinal wall (levodopa is converted to dopamine under the action of DOPA-decarboxylase, digoxin is metabolized by intestinal microflora)

excretion of P-glycoprotein substrates (digoxin)

Elimination when passing through the liver (nitroglycerin is eliminated by 90%)

Incomplete release from tablet dosage form

NB! Pharmaceutically equivalent drugs manufactured under different conditions may differ in bioavailability, absorption rates => drugs must be bioequivalent (same bioavailability, same rate of reaching maximum blood concentration)

The interaction of a number of medicinal substances in the process of their distribution in the body can be considered as one of the important pharmacokinetic stages that characterizes their biotransformation, leading in most cases to the formation of metabolites.

Metabolism (biotransformation) - the process of chemical modification of medicinal substances in the body.

Metabolic reactions are divided into non-synthetic(when medicinal substances undergo chemical transformations, undergoing oxidation, reduction and hydrolytic cleavage or several of these transformations) - I phase of metabolism and synthetic(conjugation reaction, etc.) - II phase. Usually, non-synthetic reactions are only the initial stages of biotransformation, and the resulting products can participate in synthetic reactions and then be eliminated.

Products of non-synthetic reactions may have pharmacological activity. If the activity is possessed not by the substance itself introduced into the body, but by some metabolite, then it is called a prodrug.

Non-synthetic metabolic reactions of medicinal substances are catalyzed by microsomal enzyme systems of the endoplasmic reticulum of the liver or non-microsomal enzyme systems. These substances include: amphetamine, warfarin, imipramine, meprobamate, procainamide, phenacetin, phenytoin, phenobarbital, quinidine.

In synthetic reactions (conjugation reactions), a drug or metabolite is a product of a non-synthetic reaction, combining with an endogenous substrate (glucuronic, sulfuric acids, glycine, glutamine) to form conjugates. As a rule, they do not have biological activity and, being highly polar compounds, they are well filtered, but poorly reabsorbed in the kidneys, which contributes to their rapid excretion from the body.

The most common conjugation reactions are: acetylation (the main pathway of metabolism of sulfonamides, as well as hydralazine, isoniazid and procainamide); sulfation (reaction between substances with phenolic or alcohol groups and inorganic sulfate. The source of the latter can be sulfur-containing acids, such as cysteine); methylation (some catecholamines, niacinamide, thiouracil are inactivated). Examples of various types of reactions of metabolites of medicinal substances are given in the table.

The transformation of some drugs taken orally depends significantly on the activity of enzymes produced by the intestinal microflora, where unstable cardiac glycosides are hydrolyzed, which significantly reduces their cardiac effect. Enzymes produced by resistant microorganisms catalyze hydrolysis and acetylation reactions, due to which antimicrobial agents lose their activity.

There are examples when the enzymatic activity of the microflora contributes to the formation of medicinal substances that exhibit their activity. So, phthalazole (phthalylsulfathiazole) outside the body practically does not show antimicrobial activity, but under the influence of enzymes of the intestinal microflora it is hydrolyzed with the formation of norsulfazole and phthalic acid, which have an antimicrobial effect. With the participation of enzymes of the intestinal mucosa, reserpine and acetylsalicylic acid are hydrolyzed.

However, the main organ where the biotransformation of medicinal substances is carried out is the liver. After absorption in the intestine, they enter the liver through the portal vein, where they undergo chemical transformations.

Drugs and their metabolites enter the systemic circulation through the hepatic vein. The combination of these processes is called the "first pass effect", or presystemic elimination, as a result of which the amount and effectiveness of a substance entering the general circulation may change.

It should be borne in mind that when drugs are taken orally, their bioavailability is individual for each patient and varies for each drug. Substances that undergo significant metabolic transformations during the first passage in the liver may not have a pharmacological effect, for example, lidocaine, nitroglycerin. In addition, first pass metabolism can be carried out not only in the liver, but also in other internal organs. For example, chlorpromazine is more extensively metabolized in the intestine than in the liver.

The course of presystemic elimination of one substance is often influenced by other medicinal substances. For example, chlorpromazine reduces the “first pass effect” of propranolol, as a result, the concentration of β-blocker in the blood increases.

Absorption and presystemic elimination determine the bioavailability and, to a large extent, the effectiveness of drugs.

The leading role in the biotransformation of medicinal substances is played by enzymes of the endoplasmic reticulum of liver cells, which are often called microsomal enzymes. More than 300 drugs are known that can change the activity of microsomal enzymes.. Substances that increase their activity are called inductors.

Liver enzyme inducers are: sleeping pills(barbiturates, chloral hydrate), tranquilizers(diazepam, chlordiazepoxide, meprobamate), antipsychotics(chlorpromazine, trifluoperazine), anticonvulsants(phenytoin) anti-inflammatory(phenylbutazone), some antibiotics(rifampicin), diuretics(spironolactone), etc.

Active inducers of liver enzyme systems are also considered nutritional supplements, low doses of alcohol, coffee, chlorinated insecticides (dichlorodiphenyltrichloroethane (DDT), hexachloran). In small doses, some drugs, such as phenobarbital, phenylbutazone, nitrates, can stimulate their own metabolism (autoinduction).

With the joint appointment of two medicinal substances, one of which induces liver enzymes, and the second is metabolized in the liver, the dose of the latter must be increased, and when the inducer is canceled, reduced. A classic example of such an interaction is the combination of indirect anticoagulants and phenobarbital. Special studies have shown that in 14% of cases, the cause of bleeding in the treatment of anticoagulants is the abolition of drugs that induce microsomal liver enzymes.

The antibiotic rifampicin has a very high inducing activity of microsomal liver enzymes, and somewhat less - phenytoin and meprobamate.

Phenobarbital and other inducers of liver enzymes are not recommended for use in combination with paracetamol and other drugs whose biotransformation products are more toxic than the parent compounds. Sometimes liver enzyme inducers are used to accelerate the biotransformation of compounds (metabolites) that are foreign to the body. So phenobarbital, which promotes the formation of glucuronides, can be used to treat jaundice with impaired conjugation of bilirubin with glucuronic acid.

The induction of microsomal enzymes often has to be considered as an undesirable phenomenon, since the acceleration of drug biotransformation leads to the formation of inactive or less active compounds and reduce the therapeutic effect. For example, rifampicin can reduce the effectiveness of glucocorticosteroid treatment, which leads to an increase in the dose of a hormonal drug.

Much less frequently, as a result of the biotransformation of the medicinal substance, more active compounds are formed. In particular, during treatment with furazolidone, dihydroxyethylhydrazine accumulates in the body for 4-5 days, which blocks monoamine oxidase (MAO) and aldehyde dehydrogenase, which catalyzes the oxidation of aldehydes into acids. Therefore, patients taking furazolidone should not drink alcohol, since the blood concentration of acetaldehyde, which is formed from ethyl alcohol, can reach a level at which a pronounced toxic effect of this metabolite (acetaldehyde syndrome) develops.

Medicinal substances that reduce or completely block the activity of liver enzymes are called inhibitors.

Drugs that inhibit the activity of liver enzymes include narcotic analgesics, some antibiotics (actinomycin), antidepressants, cimetidine, etc. As a result of the use of a combination of drugs, one of which inhibits liver enzymes, the rate of metabolism of another drug slows down, its concentration in the blood and the risk of side effects increase. Thus, the histamine H2 receptor antagonist cimetidine dose-dependently inhibits the activity of liver enzymes and slows down the metabolism of indirect anticoagulants, which increases the likelihood of bleeding, as well as β-blockers, which leads to severe bradycardia and arterial hypotension. Possible inhibition of the metabolism of anticoagulants of indirect action by quinidine. The side effects that develop with this interaction can be severe. Chloramphenicol inhibits the metabolism of tolbutamide, diphenylhydantoin and neodicumarin (ethyl biscumacetate). The development of hypoglycemic coma in combination therapy with chloramphenicol and tolbutamide has been described. Fatal cases are known with the simultaneous appointment of patients with azathioprine or mercaptopurine and allopurinol, which inhibits xanthine oxidase and slows down the metabolism of immunosuppressive drugs.

The ability of some substances to disrupt the metabolism of others is sometimes specially used in medical practice. For example, disulfiram is used in the treatment of alcoholism. This drug blocks the metabolism of ethyl alcohol at the stage of acetaldehyde, the accumulation of which causes discomfort. Metronidazole and antidiabetic agents from the group of sulfonylurea derivatives also act in a similar way.

A kind of blockade of enzyme activity is used in case of poisoning with methyl alcohol, the toxicity of which is determined by formaldehyde formed in the body under the influence of the alcohol dehydrogenase enzyme. It also catalyzes the conversion of ethyl alcohol to acetaldehyde, and the affinity of the enzyme for ethyl alcohol is higher than for methyl alcohol. Therefore, if both alcohols are in the medium, the enzyme catalyzes mainly the biotransformation of ethanol, and formaldehyde, which has a much higher toxicity than acetaldehyde, is formed in a smaller amount. Thus, ethyl alcohol can be used as an antidote (antidote) for methyl alcohol poisoning.

Ethyl alcohol changes the biotransformation of many medicinal substances. Its single use blocks the inactivation of various drugs and can enhance their action. In the initial stage of alcoholism, the activity of microsomal liver enzymes may increase, which leads to a weakening of the action of drugs due to the acceleration of their biotransformation. On the contrary, in the later stages of alcoholism, when many liver functions are impaired, it should be borne in mind that the effect of drugs whose biotransformation is impaired in the liver may noticeably increase.

The interaction of drugs at the level of metabolism can be realized through a change in hepatic blood flow. It is known that the factors limiting the metabolism of drugs with a pronounced effect of primary elimination (propranolol, verapamil, etc.) are the amount of hepatic blood flow and, to a much lesser extent, the activity of hepatocytes. In this regard, any medicinal substances that reduce regional hepatic circulation, reduce the intensity of metabolism of this group of drugs and increase their content in blood plasma.

Interactions that reduce the concentration of drugs include:

Decreased absorption in the gastrointestinal tract.

induction of hepatic enzymes.

Decreased cellular uptake.

I. Decreased absorption in the gastrointestinal tract.

The anion-exchange resin cholestyramine binds thyroid hormone preparations and cardiac glycosides in the gastrointestinal tract, thereby preventing their absorption. It is possible that this remedy interacts with other drugs, so it is desirable that at least 2 hours pass between taking cholestyramine and other drugs.

Aluminum ions contained in antacids form insoluble complexes with tetracyclines, also preventing their absorption.

Divalent iron ions also inhibit the absorption of tetracyclines.

Kaolin/pectin in suspension binds digoxin, reducing its absorption by 2 times. However, this effect does not appear if kaolin/pectin is taken no earlier than 2 hours after digoxin.

Ketoconazole is a weak base that only dissociates in an acidic environment. Therefore, H2-blockers (ranitidine, famotidine, etc.), which reduce the acidity of gastric contents, prevent the dissociation and absorption of ketoconazole.

Decreased acidity of gastric contents does not affect the absorption of fluconazole.

Aminosalicylic acid, when taken orally, by an unclear mechanism, reduces the absorption of rifampicin.

II. Induction of liver enzymes.

If the main route of elimination of the drug is metabolism, then the acceleration of metabolism leads to a decrease in the concentration of the drug in target organs. Most of the drugs are metabolized in the liver - an organ with a large cell mass, high blood flow and enzyme content. The first reaction in the metabolism of many drugs is catalyzed by microsomal liver enzymes associated with cytochrome P450 and contained in the endoplasmic reticulum. These enzymes oxidize drug molecules through various mechanisms - aromatic ring hydroxylation, N-demethylation, O-demethylation, and sulfoxidation. The molecules of the products of these reactions are usually more polar than the molecules of their precursors, and therefore are more easily removed by the kidneys.

The expression of some isoenzymes of cytochrome P450 is regulated, and their content in the liver may increase under the influence of certain drugs.

A typical substance that causes the induction of microsomal liver enzymes is phenobarbital. Other barbiturates work the same way. The inducing effect of phenobarbital is already manifested at a dose of 60 mg / day.

The induction of microsomal liver enzymes is also caused by rifampicin, carbamazepine, phenytoin, glutethimide; it occurs in smokers, exposure to chlorine-containing insecticides such as DDT, and chronic alcohol consumption.

Phenobarbital, rifampicin and other inducers of microsomal liver enzymes cause a decrease in the serum concentration of many drugs, including warfarin, quinidine, mexiletine, verapamil, ketoconazole, itraconazole, cyclosporine, dexamethasone, methylprednisolone, prednisolone (the active metabolite of prednisone), steroid oral contraceptives , methadone, metronidazole and metyrapone. These interactions are of great clinical importance. So, if a patient, against the background of indirect anticoagulants, achieves the proper level of blood clotting, but at the same time he takes any inducer of microsomal liver enzymes, then when the latter is canceled (for example, at discharge), the serum concentration of the anticoagulant will increase. As a result, bleeding may occur.

There are significant individual differences in the inducibility of drug metabolizing enzymes. In some patients, phenobarbital sharply increases this metabolism, in others it has almost no effect.

Phenobarbital not only induces the induction of certain cytochrome P450 isoenzymes, but also enhances hepatic blood flow, stimulates bile secretion and transport of organic anions in hepatocytes.

Some medicinal substances can also enhance the conjugation of other substances with bilirubin.

III. Decreased cellular uptake.

Guanidine derivatives used to treat arterial hypertension (guanethidine and guanadrel) are transferred to adrenergic neurons due to the active transport of biogenic amines. The physiological role of this transport is the reuptake of adrenergic mediators, but with its help many other compounds similar in structure, including guanidine derivatives, can be transported against the concentration gradient.

Norepinephrine reuptake inhibitors prevent these drugs from being taken up by adrenergic neurons, thereby blocking their action. Tricyclic antidepressants are powerful norepinephrine reuptake inhibitors. In this regard, while taking tricyclic antidepressants (desipramine, imipramine, protriptyline, nortriptyline and amitriptyline) and guanethidine or guanadrel, the hypotensive effect of the latter is almost completely suppressed. Doxepin and chlorpromazine block the reuptake of norepinephrine to a lesser extent, but they also have a dose-dependent antagonistic effect on guanidine derivatives. So does ephedrine. In patients with severe arterial hypertension such drug interactions can lead to treatment failure, hypertensive crisis and stroke.

The hypotensive effect of clonidine is also partially suppressed by tricyclic antidepressants. Clonidine acts on the cardiovascular center medulla oblongata causing a decrease in sympathetic tone. It is here that its effect is blocked by tricyclic antidepressants.

See also:

DRUG INTERACTIONS

The listed mechanisms of absorption (absorption) "work", as a rule, in parallel, but the predominant contribution is usually made by one of them (passive diffusion, filtration, active transport, pinocytosis). Yes, in oral cavity and in the stomach, passive diffusion is mainly realized, to a lesser extent - filtration. Other mechanisms are practically not involved.

AT small intestine there are no obstacles to the implementation of all absorption mechanisms; which one dominates depends on medicinal product.

Passive diffusion and filtration processes predominate in the large intestine and rectum. They are also the main mechanisms of drug absorption through the skin.

The use of any drug for therapeutic or prophylactic purposes begins with its introduction into the body or application to the surface of the body. The rate of development of the effect, its severity and duration depend on the routes of administration. Existing routes of administration are usually divided into ENTERAL (that is, through the digestive tract: administration through the mouth, under the tongue, into the 12 duodenum, into the rectum or rectally), and PARENTERAL (that is, bypassing the digestive tract: in / venous administration, in / arterial, intramuscular, subcutaneous, inhalations - aerosols, gases, powders); intrathecal or subarachnoid administration; finally, local application of drugs: intrauterine, vaginal, bladder, intraperitoneal, etc.).

The route of administration of the drug largely determines whether it can get to the site of action (into the biophase) (for example, in the focus of inflammation) and have a therapeutic effect.

II. DISTRIBUTION OF DRUGS IN THE BODY. BIOLOGICAL BARRIERS. DEPOSIT

After absorption, medicinal substances enter, as a rule, into the blood, and then they are carried to different organs and tissues. The nature of the distribution of the drug is determined by many factors, depending on which the drug will be distributed in the body evenly or unevenly. It should be said that most drugs are distributed unevenly and only a small part is relatively evenly distributed (inhalation drugs for anesthesia). The most important factors influencing the distribution pattern of a drug are: 1) lipid solubility,

2) the degree of binding to plasma proteins, 3) the intensity of regional blood flow.

The lipid solubility of a drug determines its ability to cross biological barriers. This is, first of all, the wall of capillaries and cell membranes, which are the main structures of various histohematic barriers, in particular, such as the blood-brain and placental barriers. Non-ionized fat-soluble drugs easily penetrate cell membranes and are distributed in all body fluids. The distribution of drugs that do not penetrate well through cell membranes (ionized drugs) is not so uniform.

The permeability of the BBB increases with an increase in the osmotic pressure of the blood plasma. Various diseases can change the distribution of drugs in the body. Thus, the development of acidosis can contribute to the penetration of drugs into tissues - weak acids, which are less dissociated under such conditions.

Sometimes the distribution of a medicinal substance depends on the affinity of the drug for certain tissues, which leads to their accumulation in individual organs and tissues. An example is the formation of a tissue depot in the case of using preparations containing iodine (J) in tissues. thyroid gland. When using tetracyclines, the latter can selectively accumulate in bone tissue, in particular, teeth. Teeth in this case, especially in children, may acquire a yellow color.

Such selectivity of action is due to the affinity of tetracyclines for biological substrates of bone tissue, namely the formation of tetracycline-calcium complexes by the type of chelates (hela - cancer claw). These facts are important to remember, especially for pediatricians and obstetrician-gynecologists.

Some drugs can accumulate in large quantities inside the cells, forming cellular depots (Acrichin). This happens due to the binding of the drug substance to intracellular proteins, nucleoproteins, phospholipids.

Some anesthetics, due to their lipophilicity, can form fat depots, which should also be taken into account.

Drugs are deposited, as a rule, due to reversible bonds, which, in principle, determines the duration of their stay in tissue depots. However, if persistent complexes are formed with blood proteins (sulfadimethoxine) or tissues (heavy metal salts), then the presence of these funds in the depot is significantly prolonged.

It should also be borne in mind that after absorption into the systemic circulation, most of the drug substance in the first minutes enters those organs and tissues that are most actively perfused by blood (heart, liver, kidneys). The saturation of the muscles, mucous membranes, skin and adipose tissue with the drug occurs more slowly. To achieve therapeutic concentrations of drugs in these tissues takes time from several minutes to several hours.

The influence of the state of hemodynamics on the distribution of drugs is most clearly seen in pathological conditions. The fact is that hemodynamic disturbances can significantly change the distribution kinetics. Thus, in hemorrhagic shock or congestive heart failure, perfusion of most organs decreases. Violation of the rate of glomerular filtration and hepatic blood flow lead to a decrease in renal and hepatic clearance, respectively, which will immediately affect the increase in the concentration of the drug in the blood plasma. Accordingly, the intensity and duration of the drug will be increased. As an example, one can point to an increase in the duration of action of thiopental in shock.

Many medicinal substances have a strong physicochemical affinity for various plasma proteins. The most important in this regard are albumins and, to a lesser extent, acidic alpha-glycoproteins. Such a drug agent ultimately leads to the fact that, after absorption, it can circulate in the blood not only in free form, but also in protein-bound form. This is the so-called EXTRACELLULAR (extracellular) depot of a medicinal substance, its kind of reservoir in the blood. The plasma protein-bound fraction of the drug is a temporary depot and prevents sharp fluctuations in the concentration of the unbound substance in the blood and body fluids. The binding of drugs to plasma proteins limits their concentration in tissues and at the site of action, since only free (unbound) drug can pass through the membranes. A substance that is in a complex with a protein is devoid of specific activity. Protein binding reduces the diffusion of the drug into the cell and therefore slows down the process of metabolism. Protein binding reduces the amount of drug that can be filtered in the renal glomeruli, resulting in slowing down the process of its excretion (excretion).

It is practically noticeable if the drug substance binds to proteins very actively, that is, more than 90%. The strength of the interaction of blood proteins and drugs is expressed by affinity or affinity. An important conclusion follows from this definition (provision):

If A is a drug,

and O is a protein, then A + B \u003d AO

As can be seen from this equation, the free and bound parts of the medicinal substance are in a state of dynamic equilibrium. Since the drug is active only in the free state, it is inactive in connection with the protein. A somewhat simplified comparison can be assumed that in the free state, the drug acts on the pharmacological receptors of tissues like a key to a lock, but in connection with a protein, this key does not work.

The degree of affinity, that is, the strength of drug binding to protein, depends on:

1) the rate of entry of the drug into the tissue. Since drug activity is determined by the diffusible moiety, drugs with high affinity, high affinity for proteins, such as long-acting sulfonamides (affinity > 90%), act slowly and are found in the interstitial (intercellular) fluid and in tissue cells. in low concentrations.

Another example is the cardiac glycoside (digitoxin), which is 97% protein bound. After taking this drug inside, it begins to act only after 5-6-7 hours.

2) The duration of their action depends on the degree of affinity of drugs with plasma proteins. Digitoxin after a single dose has a pharmacological effect for 2-3 days, and its residual effect is realized even after a few weeks (14-21 days). If in chronic heart failure, the binding of drugs to plasma proteins is reduced, then in chronic pulmonary insufficiency or in postoperative period increased (about 10%). In patients with reduced kidney function, the percentage of protein binding of acidic drugs with acidic properties is reduced.

3) The degree of drug affinity with blood proteins affects the difference in the effects of drugs in people with different pathologies. For example, when a patient with a burn disease develops deep hypoproteinemia, the fraction of free drug substance increases, which in such a situation requires a reduction in therapeutic doses of the drug. A similar situation can develop during starvation, when, if the dose of the drug is not reduced, a toxic effect will develop on its usual dose (similarly with radiation sickness).

4) The simultaneous use of drugs that bind to the same radicals of protein molecules can cause the effect of their competition for binding to proteins. If, then, these drugs have different binding powers, that is, different affinities, there may be a sudden increase in the concentration of one of them, sometimes to dangerous levels. So, if a patient receives an indirect anticoagulant (a drug such as phenylin, neodocoumarin), the coagulation potential of which is corrected, then with the additional introduction (inflammation of the joints) of salicylates or butadione in the blood plasma, the level of the free drug (anticoagulant) can significantly increase due to its displacement by salicylate (butadion ) from a complex with proteins. As a result, there is a risk of bleeding. Schematically, this can be shown as follows:

A + O \u003d AO + B \u003d BO + A, where B is butadione.

These pharmacokinetic data have become known only in recent years.

What is the further fate of drugs in the body? After soaking and dispensing, drugs may:

1) be metabolized under the influence of adequate enzymes;

2) change spontaneously, turning into other substances without the action of enzymes;

3) or can be excreted from the body (or excreted) unchanged.

Some medicinal substances spontaneously change (embichin), turning into other substances with corresponding changes in the acidity of the environment in the body. Thus, in a living organism, medicinal substances undergo certain changes or BIOTRANSFORMATION. Biotransformation (or transformation, or metabolism) is understood as a complex of physicochemical and biochemical transformations of medicinal substances that contribute to their conversion into simpler, ionized, more polar and, therefore, water-soluble components (metabolites), which are more easily excreted from the body. In other words, no matter what structure a xenobiotic has, an adequate enzyme encountered with it transfers it to a state convenient for excretion from the body (as a rule, a xenobiotic becomes less lipophilic) or to a state for use as an energy and plastic material (cocarboxylase, sodium nucleinate) . Although some medicinal substances, when biotransformed, form metabolites that are more active than substances introduced into the body, the vast majority of drugs are inactivated, decomposed, transformed into simpler, pharmacologically less active and less toxic metabolites. Biotransformation of administered drugs occurs predominantly in the liver, but may occur in the kidneys, intestinal wall, lungs, muscles, and other organs. The processes of biotransformation are complex and usually involve a series of successive steps, each of which is mediated by a specific blood enzyme.

There are two (2) types of drug metabolism reactions in the body: NON-SYNTHETIC and SYNTHETIC.

1. Non-synthetic reactions include OXIDATION, REDUCTION and HYDROLYSIS. All non-synthetic reactions of metabolism, also called metabolic transformation of drugs, can also be divided into 2 groups depending on the localization of the 2 main biotransforming systems:

a) the main group of reactions by which most drugs are biotransformed are reactions catalyzed by enzymes of the endoplasmic reticulum of hepatocytes or MICROSOMAL reactions;

b) reactions catalyzed by enzymes of other localization, NON-MICROSOMAL reactions.

That is, if the microsomal biotransforming system is represented by enzymes of the endoplasmic reticulum of liver hepatocytes, then the non-microsomal system is represented by enzymes of a different localization.

Microsomal reactions of oxidation or reduction of drugs, or rather their individual active groups in the structure of the drug molecule, occur with the participation of monooxygenase systems, the main components of which are cytochrome P-450 and phosphorus-reduced nicotine-amidadenine dinucleotide (NADPH).

These cytochromes are the primary components of the oxidative enzyme monooxygenase system. In most cases, the pharmacological activity of such metabolites becomes less than the activity of the parent substance.

Further oxidation of medicinal substances occurs under the influence of other oxidative enzymes, such as OXIDASES and REDUCTASES, with the obligatory participation of NADP and molecular oxygen.

Microsomal enzymes mainly catalyze the oxidation processes of many drugs, then the REDUCTION and HYDROLYSIS reactions of these drugs are associated not only with microsomal, but also with non-microsomal enzymes. Although non-microsomal enzymes are involved in the biotransformation of a small number of drugs, they still play an important role in their metabolism. Non-microsomal biotransformation of drugs also occurs in the liver, but can occur in blood plasma and other tissues (stomach, intestines, lungs). An example is the biotransformation of acetylcholine in blood plasma, carried out by the enzyme ESTERASE, in our case, ACETYLCHOLINESTERASE. According to such reactions, a number of commonly used drugs are biotransformed, for example, aspirin and sulfonamides.

Synthetic reactions are based on the formation of paired esters of drugs with glucuronic, sulfuric, acetic acids, as well as with glycine and glutathione, which helps to create

juice-polar compounds, highly soluble in water, slightly soluble in lipids, poorly penetrating into tissues and, in most cases, pharmacologically inactive. Naturally, these metabolites are well excreted from the body. Thus, synthetic reactions lead to the formation and synthesis of a new metabolite and are carried out using conjugation, acetylation, methylation, etc.

As an example, the biotransformation of drugs by synthetic reactions can be given the following illustration. In the liver of adults, the antibiotic chloramphenicol undergoes conjugation with clucuronic acid by 90%, and only 10% of it is excreted in the urine unchanged. The resulting glucuronides are easily biotransformed and excreted. In the same way, estrogen and glucocorticoid drugs, opium alkaloids, salicylates, barbiturates and other drugs are excreted from the body.

From the point of view of evolution, a more ancient way of biotransformation is the attachment to the xenobiotic (conjugation) of highly polar groups: glucuronic acid, sulfate, glycine, phosphate, acetyl, epoxy group, making xenobiotics more soluble in water. An evolutionarily younger path - redox (oxidation, reduction, hydrolysis reactions) is considered as the initial phase of biotransformation. The products of oxidation or reduction (I phase) are usually then subjected to conjugation (II phase). Thus, it can be said that phase I reactions of drug biotransformation are usually non-synthetic, while phase II reactions are synthetic.

As a rule, only after phase II of biotransformation, inactive or low-active compounds are formed; therefore, it is synthetic reactions that can be considered blue reactions of detoxification of xenobiotics, including drugs.

From a practical point of view, it is important that with the help of a number of means it is possible to actively influence the processes of microsomal transformation of drugs. It has been noted that both INDUCTION (increase in activity) and DEPRESSION of microgomal enzymes can develop under the influence of drugs. There are significantly more substances that stimulate biotransformation by inducing the synthesis of enzymatic proteins in the liver than substances that suppress this synthesis. These inducer substances, which are currently described more than 200, include phenobarbital, barbiturates, hexobarbital, caffeine, ethanol, nicotine, butadione, antipsychotics, diphenhydramine, quinine, cordiamine, many chlorine-containing pesticides and insecticides.

Microsomal glucuronyltranson phase is involved in the activation of liver enzymes by these substances. At the same time, the synthesis of RNA and microsomal proteins increases. It is important to remember that inductors increase not only the metabolism of drugs in the liver, but also their excretion with bile.

All these substances accelerate the processes of liver metabolism by 2-4 times only by inducing the synthesis of microsomal enzymes. At the same time, the metabolism is accelerated not only of drugs administered together with them or against their background, but also of themselves. However, there is also a large group of substances (inhibitors) that suppress and even destroy cytochrome P-450, that is, the main microsomal enzyme. These drugs include the group local anesthetics, antiarrhythmic drugs (anaprilin or inderal, visken, eraldin), as well as cimeticine, chloramphenicol, butadione, anticholinesterase agents, MAO inhibitors. These substances prolong the effects of drugs administered with them. In addition, many of the inhibitors cause the phenomenon of autoinhibition of metabolism (verapamil, propranolol). It follows from the foregoing that it is necessary to take this possibility into account when combining drugs in a patient. For example, the induction of hepatic microsomal enzymes by phenobarbital underlies the use of this drug to eliminate hyperbilirubinemia in newborns with hemolytic disease.

The decrease in the effectiveness of drugs with repeated use is called tolerance. The use of the same phenobarbatal as a sleeping pill leads to the gradual development of addiction, i.e. to tolerance, which dictates the need to increase the dose of the drug. special kind addictive is tachyphylaxis.

TACHYPHILAXIA - very quickly addictive, sometimes after the first injection of the substance. So, the introduction of ephedrine intravenously repeatedly with an interval of 10-20 minutes causes a smaller rise in blood pressure than with the first injection. A similar situation can be traced when ephedrine solutions are instilled into the nose.

Substances-inducers, activating microsomal enzymes, contribute to increased excretion of vitamin D from the body, as a result of which softening of the bones can develop and a pathological fracture occurs. These are all examples of drug interactions.

It must also be remembered that pharmacological agents can be divided into 2 groups according to the rate of inactivation in the liver: the former are oxidized at a low rate, for example, diphenin, carbamazenin; the second - with medium or high speed, for example, imizin, isadrin, lidocaine, anaprilin.

In addition, the metabolism of medicinal substances depends both on the type and kind of animals, the race of the patient, and on age, gender, nutrition (vegetarians have a lower rate of drug biotransformation, if there are a lot of proteins in food, metabolism is enhanced), nervous system, ways of application, from the simultaneous use of other drugs.

Moreover, it is important to remember that each person has his own, genetically determined rate of biotransformation. In this regard, we can refer to the example of alcohol, when there is idiosyncrasy work of alcohol dehydrogenase in an individual. These features of the individual work of enzymes depending on the genotype are studied by pharmacogenetics.

An excellent example of genetic dependence is the inactivation of the anti-tuberculosis drug isoniazid (ftivazid) by acetylation. It has been established that the rate of this process is genetically determined. There are individuals who slowly inactivate isoniazid. At the same time, its concentration in the body decreases more gradually than in people with rapid inactivation of the drug. Among the European population of slow acetylators, according to some authors, 50-58.6% are noted, and fast - up to 30-41.4%. At the same time, if the peoples of the Caucasus and the Swedes are mostly fast acetylators, then the Eskimos, on the contrary, are slow acetylators.

The dependence of individual biotransformation is studied by the science of PHARMACOGENETICS.

Slow acetylators have a higher blood concentration for a certain dose of the drug and therefore may have more side effects. Indeed, isoniazid causes complications in the form of peripheral neuropathy in 20% of patients with tuberculosis, slow acetylators, and in fast acetylators only in 3% of cases.

Liver diseases change the biotransformation of drugs in this organ. For substances that are slowly transformed in the liver, an important role is played by the function of liver cells, the activity level of which decreases with hepatitis, cirrhosis, reducing the inactivation of these substances. Such multifactorial features of drug biotransformation make it necessary to study this problem in each specific case.

The last step in the interaction of drugs with a living organism is their excretion or EXECRETION.

Drugs, with the exception of drugs for inhalation anesthesia, as a rule, are not excreted through the structures in which absorption (absorption) occurred. The main routes of excretion are the kidneys, liver, gastrointestinal tract, lungs, skin, salivary glands, sweat glands, and mother's milk. We are particularly interested in the kidneys clinically.

Excretion of drugs by the kidneys is determined by three processes carried out in the nephron:

1) passive glomerular filtration;

2) passive diffusion through the tubules or REABSORPTION;

3) active tubular secretion.

As you can see, all physiological processes in the nephron are characteristic of drugs. Non-ionized drugs that are well absorbed may be filtered in the renal glomeruli, but from the lumen of the renal tubules they may again diffuse into the cells lining the tubules. Thus, only a very small amount of the drug appears in the urine.

Ionized drugs that are poorly absorbed are excreted almost entirely by glomerular filtration and are not reabsorbed.

Passive diffusion is a bidirectional process, and drugs can diffuse through the wall of the tubules in any direction, depending on their concentration and the pH of the medium (for example, quinacrine, salicylates).

The pH value of the urine affects the excretion of some weak acids and bases. Thus, weak acids are rapidly excreted in alkaline urine, such as barbiturates and salicylates, and weak bases are rapidly excreted in an acidic environment (phenamine). Therefore, in acute poisoning with barbiturates, it is necessary to alkalize the urine, which is achieved by intravenous administration of sodium bicarbonate (soda) solutions, the latter improves the excretion of sleeping pills.

If the pH value of the urine does not correspond to the optimal value for the excretion of the drug, the action of these drugs can be prolonged.

With an alkaline urine reaction, the tubular reabsorption of weak acids is minimal, since the bulk of these substances are in an ionized state in an alkaline environment. The situation is similar for weak bases in acidic urine. The excretion of weak bases and acids can be accelerated if high diuresis is maintained by the administration of mannitol and diuretics (diuretics), and also corrected by the pH value of the urine to the optimum in relation to this drug.

With pathology of the kidneys, their ability to excrete medicinal substances is reduced. As a result, even when using normal doses of drugs, their level in the blood rises and the effect of drugs is prolonged. In this regard, when prescribing drugs such as aminoglycoside antibiotics (streptomycin, gentamicin), coumarin anticoagulants, patients with reduced kidney function ( kidney failure), a special mode of observation is required.

In conclusion of this section, a few words about the term "ELIMINATING". In the literature, the terms "elimination" and "excretion" are often used interchangeably. But it must be remembered that ELIMINATION is a broader term, corresponding to the sum of all metabolic (biotransformation) and excretory processes, as a result of which active substance disappears from the body.

The result of insufficiency of excretion or elimination may be the accumulation or cumulation of the drug in the body, in its tissues. Cumulation - (accumulator - storage) is a consequence of insufficient excretion and elimination, and, as a rule, is associated with pathology of the excretory organ (liver, gastrointestinal tract, etc.) or with increased binding to plasma proteins, which reduces the amount of substance that can be filtered in the glomeruli.

There are three (3) main ways to deal with cumulation:

1) reducing the dose of the medicinal substance;

2) a break in prescribing drugs (2-3-4 days-2 weeks);

3) at the first stage, the introduction of a large dose (dose of saturation), and then the transfer of the patient to a low, maintenance dose. Thus, for example, cardiac glycosides (digitoxin) are used.

Preferanskaya Nina Germanovna
Art. Lecturer, Department of Pharmacology, Faculty of Pharmacy, MMA named after A.I. THEM. Sechenov

Hepatoprotectors prevent the destruction of cell membranes, prevent damage to liver cells by decay products, accelerate reparative processes in cells, stimulate regeneration of hepatocytes, and restore their structure and functions. They are used to treat acute and chronic hepatitis, fatty degeneration of the liver, cirrhosis of the liver, toxic liver damage, including those associated with alcoholism, intoxication with industrial poisons, drugs, heavy metals, fungi and other liver damage.

One of the leading pathogenetic mechanisms damage to hepatocytes is an excessive accumulation of free radicals and products of lipid peroxidation when exposed to toxins of exogenous and endogenous origin, ultimately leading to damage to the lipid layer of cell membranes and destruction of liver cells.

Medicines used to treat liver disease have different pharmacological mechanisms protective action. The hepatoprotective effect of most drugs is associated with the inhibition of enzymatic lipid peroxidation, with their ability to neutralize various free radicals, while providing an antioxidant effect. Other drugs are the building material of the lipid layer of liver cells, have a membrane-stabilizing effect and restore the structure of hepatocyte membranes. Still others induce microsomal liver enzymes, increase the rate of synthesis and activity of these enzymes, enhance the biotransformation of substances, activate metabolic processes, which contributes to the rapid removal of foreign toxic compounds from the body. The fourth drugs have a wide range of biological activity, contain a complex of vitamins and essential amino acids, increase the body's resistance to adverse factors, reduce toxic effects, including after drinking alcohol, etc.

It is very difficult to isolate drugs with a single mechanism of action; as a rule, these drugs have several of the above mechanisms at the same time. Depending on the origin, they are divided into drugs: plant origin, synthetic medicines, animal origin, homeopathic and biologically active additives to food. According to their composition, they are divided into monocomponent and combined (complex) preparations.

Drugs that predominantly inhibit lipid peroxidation

These include preparations and phytopreparations of the fruits of milk thistle (sharp-motley). Plant flavonoid compounds isolated from the fruits and milky juice of milk thistle contain a complex of isomeric polyhydroxyphenol chromanones, the main of which are silibinin, silydianin, silicristin, etc. The properties of milk thistle have been known for over 2000 years, it has been used in Ancient Rome for the treatment of various poisonings. The hepatoprotective effect of bioflavonoids isolated from the fruits of milk thistle is due to its antioxidant, membrane-stabilizing properties and stimulation of reparative processes in the liver cells.

The main active bioflavonoid in milk thistle is silibinin. It has a hepatoprotective and antitoxic effect. Interacts with hepatocyte membranes and stabilizes them, preventing the loss of transaminases; binds free radicals, inhibits the processes of lipid peroxidation, prevents the destruction of cellular structures, while reducing the formation of malondialdehyde and oxygen uptake. Prevents the penetration into the cell of a number of hepatotoxic substances (in particular, the poison of the pale toadstool). By stimulating RNA polymerase, it increases the biosynthesis of proteins and phospholipids, accelerates the regeneration of damaged hepatocytes. With alcoholic liver damage, it blocks the production of acetaldehyde and binds free radicals, preserves glutathione reserves, which promotes detoxification processes in hepatocytes.

Silibinin(Silibinin). Synonyms: Silymarin, Silymarin Sediko instant, Silegon, Karsil, Legalon. It is produced in dragee 0.07 g, capsules 0.14 g and suspension 450 ml. Silymarin is a mixture of isomeric flavonoid compounds (silibinin, silidianin, silychristin) with a predominant content of silibinin. Bioflavonoids activate the synthesis of proteins and enzymes in hepatocytes, affect metabolism in hepatocytes, have a stabilizing effect on the membrane of hepatocytes, inhibit dystrophic and potentiate regenerative processes in the liver. Silymarin prevents the accumulation of lipid hydroperoxides, reduces the degree of damage to liver cells. Significantly reduces elevated level transaminases in the blood serum, reduces the degree of fatty degeneration of the liver. By stabilizing the cell membrane of hepatocytes, it slows down the entry of toxic metabolic products into them. Silymarin activates the metabolism in the cell, resulting in the normalization of protein-synthetic and lipotropic functions of the liver. Improving the immunological reactivity of the body. Silymarin is practically insoluble in water. Due to its slightly acidic properties, it can form salts with alkaline substances. More than 80% of the drug is excreted in the bile in the form of glucuronides and sulfates. As a result of the breakdown by the intestinal microflora of the silymarin excreted in the bile, up to 40% is reabsorbed again, which creates its enterohepatic circulation.

Silibor- a preparation containing the amount of flavonoids from the fruits of milk thistle (Silibbum marianum L). Release form: coated tablets of 0.04 g.

Silimar, a dry purified extract obtained from the fruits of milk thistle (Silybum marianum L), contains flavolignans (silibinin, silidianin, etc.), as well as other substances, mainly flavonoids, 100 mg per tablet. Silimar has a number of properties that determine its protective effect on the liver when exposed to various damaging agents. It exhibits antioxidant and radioprotective properties, enhances the detoxifying and exocrine functions of the liver, has antispasmodic and slight anti-inflammatory effects. In acute and chronic intoxication caused by carbon tetrachloride, Silimar has a pronounced hepatoprotective effect: it inhibits the growth of indicator enzymes, inhibits the processes of cytolysis, and prevents the development of cholestasis. In patients with diffuse liver lesions, including those of alcoholic origin, the drug normalizes the functional and morphological parameters of the hepatobiliary system. Silimar reduces fatty degeneration of liver cells and accelerates their regeneration due to the activation of RNA polymerase.

Hepatofalk plant - complex drug containing extracts from the fruits of milk thistle, celandine and termelik. The pharmacological effect of the combined herbal preparation is determined by the combined action of its components. The drug has a hepatoprotective, antispasmodic, analgesic, choleretic (choleretic and cholekinetic) effect. Stabilizes hepatocyte membranes, increases protein synthesis in the liver; has a distinct antispasmodic effect on smooth muscles; has antioxidant, anti-inflammatory and antibacterial activity. Prevents penetration into the cell of a number of hepatotoxic substances. With alcoholic liver damage, it blocks the production of acetaldehyde and binds free radicals, preserves glutathione reserves, which promotes detoxification processes in hepatocytes. The alkaloid chelidonin contained in celandine has antispasmodic, analgesic and choleretic effects. Curcumin, the active substance of Javanese termelik, has a choleretic (both choleretic and cholekinetic) and anti-inflammatory effect, reduces the saturation of bile with cholesterol, has bactericidal and bacteriostatic activity against Staphylococcus aureus, salmonella and mycobacteria.

Gepabene contains an extract of milk thistle with a standardized amount of flavonoids: 50 mg of silymarin and at least 22 mg of silibinin, as well as an extract of fumes, containing at least 4.13 mg of fumes alkaloids in terms of protopin. The therapeutic properties of Gepabene are determined by the optimal combination of the hepatoprotective effect of the milk thistle extract and the normalizing effect of bile secretion and bile duct motility. Normalizes both too weak and increased bile secretion, relieves spasm of the ODDI sphincter, normalizes motor function bile ducts with their dyskinesia, both in hyperkinetic and hypokinetic types. Effectively restores the drainage function of the biliary tract, preventing the development of bile stasis and the formation of stones in gallbladder. When taking the drug, a laxative effect may occur and diuresis may increase. Available in capsules. Apply inside, during meals, one capsule 3 times a day.

Sibektan, one tablet of which contains: extract from tansy, fruit pulp of milk thistle, St. John's wort, birch 100 mg. The drug has a membrane-stabilizing, regenerating, antioxidant, hepatoprotective and choleretic effect. It normalizes lipid and pigment metabolism, enhances the detoxification function of the liver, inhibits the processes of lipid peroxidation in the liver, stimulates the regeneration of mucous membranes and normalizes intestinal motility. Accepted in 20-40 minutes. before meals, 2 tablets 4 times a day. The course is 20-25 days.

Drugs that predominantly restore the structure of hepatocyte membranes and have a membrane-stabilizing effect Damage to hepatocytes is often accompanied by a violation of the integrity of the membranes, which leads to the entry of enzymes from the damaged cell into the cytoplasm. Along with this, intercellular connections are damaged, the connection between individual cells is weakened. Violated important processes for the body - the absorption of triglycerides necessary for the formation of chylomicrons and micelles, reduced bile formation, protein production, impaired metabolism and the ability of hepatocytes to perform a barrier function. When taking drugs of this subgroup, the regeneration of liver cells is accelerated, the synthesis of proteins and phospholipids, which are the plastic material of hepatocyte membranes, is enhanced, and the exchange of phospholipids of cell membranes is normalized. These drugs exhibit an antioxidant effect, tk. in the liver, they interact with free radicals and convert them into an inactive form, which prevents further destruction of cellular structures. The composition of these drugs includes essential phospholipids, which are a plastic material for damaged liver cells, consisting of 80% of hepatocytes.

Essentiale N and Essentiale forte N. Available in capsules containing 300 mg of "essential phospholipids" for oral administration with meals. The drug provides the liver with a high dose of phospholipids ready for assimilation, which penetrate into the liver cells, penetrate into the membranes of hepatocytes and normalize its functions, including detoxification. The cellular structure of hepatocytes is restored, the formation of connective tissue in the liver is inhibited, all this contributes to the regeneration of liver cells. Daily intake of the drug promotes the activation of phospholipid-dependent enzyme systems of the liver, reduces the level of energy consumption, improves the metabolism of lipids and proteins, converts neutral fats and cholesterol into easily metabolized forms, and stabilizes the physicochemical properties of bile. For acute and severe forms liver lesions (hepatic ancestor and coma, necrosis of liver cells and its toxic lesions, during operations in the hepatobiliary zone, etc.) use a solution for intravenous slow administration in 5 ml dark glass ampoules containing 250 mg of "essential phospholipids". Enter 5-10 ml per day, if necessary, increase the dose to 20 ml / day. Do not mix with other drugs.

Essliver forte- a combined preparation containing essential phospholipids 300 mg and a complex of vitamins: thiamine mononitrate, riboflavin, pyridoxine, tocopherol acetate 6 mg each, nicotinamide 30 mg, cyanocobalamin 6 μg, has a hepatoprotective, hypolipidemic and hypoglycemic effect. Regulates the permeability of biomembranes, the activity of membrane-bound enzymes, ensuring the physiological norm of oxidative phosphorylation processes in cellular metabolism. Restores hepatocyte membranes by structural regeneration and competitive inhibition of peroxide processes. Unsaturated fatty acids, embedding in biomembranes, take on toxicogenic effects instead of liver membrane lipids and normalize liver function, increase its detoxification role.

Phosphogliv- one capsule contains 0.065 g of phosphatidylcholine and 0.038 g of disodium salt of glycerrisic acid. The drug restores the cell membranes of hepatocytes with the help of glycerophospholipids. The phosphatidylcholine molecule combines glycerol, higher fatty acids, phosphoric acid and choline, all the necessary substances for building cell membranes. The molecule of glycyrrhizic acid is similar to the structure of the hormones of the adrenal cortex (for example, cortisone), due to which it has anti-inflammatory and anti-allergic properties, provides emulsification of phosphatidylcholine in the intestine. The glucuronic acid contained in its structure binds and inactivates the resulting toxic products. Apply inside 1-2 capsules 3 times a day for a month. The dose can be increased to 4 capsules at a time and 12 capsules per day.

Livolin forte- a combined preparation, one capsule of which contains 857.13 mg of lecithin (300 mg of phosphatidylcholine) and a complex essential vitamins: E, B1, B6 - 10 mg each, B2 - 6 mg, B12 - 10 mcg and PP - 30 mg. The phospholipids included in the composition are the main elements in the structure of the cell membrane and mitochondria. When using the drug, lipid and carbohydrate metabolism is regulated, the functional state of the liver improves, its most important detoxification function is activated, the structure of hepatocytes is preserved and restored, and the formation of the connective tissue of the liver is inhibited. Incoming vitamins perform the function of coenzymes in the processes of oxidative decarboxylation, respiratory phosphorylation, have an antioxidant effect, protect membranes from the effects of phospholipases, prevent the formation of peroxide compounds and inhibit free radicals. Apply 1-2 capsules 2-3 times a day with meals, the course is 3 months, if necessary, the course is repeated.

Drugs that improve metabolic processes in the body They provide cell detoxification, stimulate cell regeneration by increasing the activity of liver microsomal enzymes, improving microcirculation and cell nutrition, and also improve metabolic processes in hepatocytes.

Means that affect metabolic processes, Thioctic acid (lipoic acid, lipamide, thioctacid). Pharmacological action - hypolipidemic, hepatoprotective, hypocholesterolemic, hypoglycemic. Thioctic acid is involved in the oxidative decarboxylation of pyruvic and a-keto acids. By the nature of the biochemical action, it is close to B vitamins. It participates in the regulation of lipid and carbohydrate metabolism, stimulates cholesterol metabolism, and improves liver function. Applied inside, at an initial dose of 200 mg (1 tablet) 3 times a day, a maintenance dose of 200-400 mg / day. When using the drug, dyspepsia may occur, allergic reactions: urticaria, anaphylactic shock; hypoglycemia (due to improved glucose uptake). In severe forms of diabetic polyneuropathy, 300–600 mg is administered intravenously or intravenously by drip, for 2–4 weeks. In the future, they switch to maintenance therapy with tablet forms - 200-400 mg / day. After intravenous administration, adverse reactions are possible - such as the development of convulsions, diplopia, pinpoint hemorrhages in the mucous membranes and skin, impaired platelet function; with the rapid introduction of a feeling of heaviness in the head, difficulty breathing.

Alpha Lipoic Acid is a coenzyme of oxidative decarboxylation of pyruvic acid and alpha-keto acids, normalizes energy, carbohydrate and lipid metabolism, regulates cholesterol metabolism. Improves liver function, reduces the damaging effects of endogenous and exogenous toxins on it. Apply inside the / m and / in. With an intramuscular injection, the dose administered at one site should not exceed 2 ml. In / in the introduction of drip, after diluting 1-2 ml with 250 ml of 0.9% sodium chloride solution. In severe forms of polyneuropathy - in / in 12-24 ml daily for 2-4 weeks, then they switch to maintenance therapy inside 200-300 mg / day. The drug is photosensitive, so the ampoules should be removed from the package only immediately before use. The solution for infusion is suitable for administration within 6 hours if protected from light.

Espa lipon Available in coated tablets and injection solutions. One tablet contains 200 mg or 600 mg of ethylenediamine salt of alpha-lipoic acid, and 1 ml of its solution contains 300 mg or 600 mg, 12 ml and 24 ml ampoules, respectively. When using the drug, oxidative decarboxylation of pyruvic acid, a-keto acids is stimulated, lipid and carbohydrate metabolism is regulated, liver function improves, and protection from the adverse effects of endo- and exo-factors occurs.

Ademetionine (Heptral) is a precursor of physiological thiol compounds involved in numerous biochemical reactions. This endogenous substance, found in almost all tissues and body fluids, is obtained synthetically, has hepatoprotective, detoxifying, regenerating, antioxidant, antifibrosing and neuroprotective effects. Its molecule is included in most biological reactions, incl. as a donor of the methyl group in methylation reactions, as part of the lipid layer of the cell membrane (transmethylation); as a precursor of endogenous thiol compounds - cysteine, taurine, glutathione, coenzyme A (transsulfation); as a precursor of polyamines - putrescine, which stimulates cell regeneration, proliferation of hepatocytes, spermidine, spermine, which are part of the structure of ribosomes (aminopropylation). Provides a redox mechanism of cellular detoxification, stimulates the detoxification of bile acids - increases the content of conjugated and sulfated bile acids in hepatocytes. Stimulates the synthesis of phosphatidylcholine in them, increases the mobility and polarization of hepatocyte membranes. Heptral is included in the biochemical processes of the body, while stimulating the production of endogenous ademetionine, primarily in the liver and brain. Penetrating through the blood-brain barrier, it exhibits an antidepressant effect, which develops in the first week and stabilizes during the second week of treatment. Heptral therapy is accompanied by the disappearance of asthenic syndrome in 54% of patients and a decrease in its intensity in 46% of patients. Antiasthenic, anticholestatic and hepatoprotective effects persisted for 3 months after discontinuation of treatment. Available in tablets of 0.4 g of lyophilized powder. Maintenance therapy inside 800-1600 mg / day. between meals, swallow without chewing, preferably in the morning. In intensive care in the first 2-3 weeks of treatment, 400-800 mg / day is prescribed intravenously. (very slowly) or / m, the powder is dissolved only in the special solvent supplied (L-lysine solution). The main side effects when taken orally are heartburn, pain or discomfort in the epigastric region, dyspepsia, and allergic reactions are possible.

Ornithine aspartate (Hepa-Merz granules). Pharmacological action - detoxification, hepatoprotective, contributes to the normalization of the KOS of the body. Participates in the ornithine cycle of urea formation (the formation of urea from ammonia), utilizes ammonium groups in the synthesis of urea and reduces the concentration of ammonia in the blood plasma. When taking the drug, the production of insulin and growth hormone is activated. The drug is available in granules for the preparation of solutions for oral administration. 1 sachet contains 3 g of ornithine aspartate. Applied inside, 3-6 g 3 times a day after meals. Concentrate for infusion, in 10 ml ampoules, 1 ml of which contains 500 mg of ornithine aspartate. Enter the / m 2-6 g / day. or in / in a stream of 2-4 g / day; frequency of administration 1-2 times a day. If necessary, intravenously drip: 25-50 g of the drug is diluted in 500-1500 ml of isotonic sodium chloride solution, 5% glucose solution or distilled water. The maximum infusion rate is 40 drops / min. The duration of the course of treatment is determined by the dynamics of the concentration of ammonia in the blood and the patient's condition. The course of treatment can be repeated every 2-3 months.

Gepasol A, combined preparation, 1 liter of solution contains: 28.9 g of L-arginine, 14.26 g of L-malic acid, 1.33 g of L-aspartic acid, 100 mg of nicotinamide, 12 mg of riboflavin and 80 mg of pyridoxine.

The action is based on the influence of L-arginine and L-malic acid on the processes of metabolism and metabolism in the body. L-arginine promotes the conversion of ammonia into urea, binds toxic ammonium ions formed during protein catabolism in the liver. L-malic acid is necessary for the regeneration of L-arginine in this process and as an energy source for the synthesis of urea. Riboflavin (B2) is converted into flavin mononucleotide and flavin adenine dinucleotide. Both metabolites are pharmacologically active and, as part of coenzymes, play an important role in redox reactions. Nicotinamide passes into the depot in the form of pyridine nucleotide, which plays an important role in the oxidative processes of the body. Together with lactoflavin, nicotinamide is involved in intermediate metabolic processes, in the form of triphosphopyridine nucleotide - in protein synthesis. It reduces the level of serum very low density and low density lipoproteins and at the same time increases the level of high density lipoproteins, therefore it is used in the treatment of hyperlipidemia. D-panthenol, as coenzyme A, being the basis of intermediate metabolic processes, is involved in the metabolism of carbohydrates, gluconeogenesis, catabolism of fatty acids, in the synthesis of sterol, steroid hormones and porphyrin. Pyridoxine (B6) is an integral part of the groups of many enzymes and coenzymes, plays a significant role in the metabolism of carbohydrates and fats, is necessary for the formation of porphyrin, as well as the synthesis of Hb and myoglobin. Therapy is set individually, taking into account the initial concentration of ammonia in the blood and is prescribed depending on the dynamics of the patient's condition. Usually prescribed in / in the drip of 500 ml of solution at a rate of 40 drops / min. The introduction of the drug can be repeated every 12 hours and up to 1.5 liters per day.

Arginine is found in hepatoprotective drugs sargenor and Citrargin.

Betaine Citrate Bofur- it contains betaine and citrate (anion of citric acid). Betaine is an amino acid, a derivative of glycine with a methylated amino group, present in the human liver and kidneys, the main lipotropic factor. Helps prevent fatty degeneration of the liver and lowers cholesterol levels in the blood, increases the respiratory processes in the affected cell. Citrate is an important link in the tricarboxylic acid cycle (Krebs cycle). Produced in granules of 250 g for oral administration.

Flumecinol (zixorin) and barbituric acid derivative phenobarbital, which has anticonvulsant and hypnotic effects, also belong to inducers of microsomal liver enzymes.

Animal productsHepatamine, a complex of proteins and nucleoproteins isolated from the liver of cattle; Sirepar - hydrolyzed liver extract; Hepatosan- a drug derived from the liver of a pig.

Preparations of animal origin contain a complex of proteins, nucleotides and other active substances isolated from the liver of cattle. They normalize metabolism in hepatocytes, increase enzymatic activity. They have a lipotropic effect, promote the regeneration of parenchymal liver tissue and have a detoxifying effect.

Herbal raw materials to improve liver function and digestion

Liv-52, containing juices and decoctions of many plants, has a hepatotropic effect, improves liver function, appetite and gas from the intestines.

Tykveol contains fatty oil obtained from ordinary pumpkin seeds, which includes carotenoids, tocopherols, phospholipids, flavonoids; vitamins: B1, B2, C, P, PP; fatty acids: saturated, unsaturated and polyunsaturated - palmitic, stearic, oleic, linoleic, linolenic, arachidonic, etc. The drug has a hepatoprotective, antiatherosclerotic, antiseptic, choleretic effect. Produced in bottles of 100 ml and in plastic dropper bottles of 20 ml. Apply 1 teaspoon for 30 minutes. before meals 3-4 times a day, the course of treatment is 1-3 months.

Bonjigar is available in syrup and hard gelatin capsules, contains a mixture of plant components with anti-inflammatory, hepatoprotective, membrane-stabilizing, detoxifying and lipotropic effects. Prevents damage and normalizes liver function, protects it from the action of damaging factors and the accumulation of toxic metabolic products. Applied inside, after meals, 2 tablespoons of syrup or 1-2 capsules 3 times a day for 3 weeks.

Homeopathic preparations

Gepar compositum- a complex preparation containing phytocomponents: Lycopodium and Carduus marianus, suis-organ preparations of the liver, pancreas and gallbladder, catalysts and sulfur, supports the metabolic functions of the liver.

Hepel- this preparation contains milk thistle, celandine, club moss, hellebore, phosphorus, colocynth, etc. The antihomotoxic drug has antioxidant activity, protects hepatocytes from free radical damage, as well as antiproliferative and hepatoprotective effects. Available in tablets, apply under the tongue 1 tablet 3 times a day.

Complex homeopathic remedy Galstena used in the complex treatment of acute and chronic diseases liver, gallbladder diseases (chronic cholecystitis, postcholecystectomy syndrome) and chronic pancreatitis. Produced in bottles of 20 ml. Assign children under 1 year 1 drop, up to 12 years - 5 drops, adults - 10 drops. In acute cases, it is possible to take it every half an hour or an hour until the condition improves, but not more than 8 times, then take it 3 times a day.

Biologically active food supplements (BAA)Ovesol- a complex preparation containing an extract of milky ripeness oats in combination with choleretic herbs and turmeric oil. It is produced in the form of drops of 50 ml and tablets of 0.25 g. Daily intake of the drug 1 tablet 2 times with meals for a month improves the drainage functions of the biliary tract, eliminates stagnation and normalizes the biochemical composition of bile, prevents the formation of gallstones. The dietary supplement gently cleanses the liver of toxins and toxic products of endogenous and exogenous origin, improves the metabolic function of the liver, and promotes the washing out of sand.

Hepatrin– it contains three main components: milk thistle extract, artichoke extract and essential phospholipids. BAA is used for prophylactic purposes, to protect liver cells from damage when using drugs, alcohol, from the adverse effects of endo-, exotoxins and excessive consumption. fatty foods. Available in capsules of 30 pieces.

Essential oil– high quality fish fat, obtained from Greenland salmon by cold processing and stabilized against oxidation with vitamin E. One capsule contains: unsaturated fatty acids (omega-3): 180 mg of eixapentaenoic acid, 120 mg of docosahexaenoic acid and 1 mg of D-alpha-tocopherol. As a dietary supplement, adults take 1-3 capsules per day with meals. The course of admission is 1 month.

Hepavit Life formula contains a complex of vitamins of group B and fat-soluble vitamins A, E, K, a phospholipid complex that activates liver functions, active ingredients vegetable raw materials with antioxidant, choleretic, detoxifying effect. Available in capsules (tablets), apply 1 caps. (Table) 1-2 times a day.

Tykvinol - dietary supplement, made on the basis of edible oils of marine and vegetable origin - eikonol and tykveol, obtained according to domestic technologies using sparing modes of processing raw materials. Tykvinol contains a complex of biologically active substances: saturated and polyunsaturated fatty acids - eicosapentaenoic, docosahexaenoic, linolenic, linoleic, palmitic, stearic, arachidonic, etc., carotenoids, tocopherols, phospholipids, sterols, phosphatides, flavonoids, vitamins A, D, E, F , B1, B2, C, P, PP. Due to the combination of active compounds of marine and vegetable origin, it helps to cleanse the body of fatty and lime deposits, improve blood circulation, increase the elasticity of blood vessels, strengthen the heart muscle, prevent myocardial infarction, improve vision, noise in the head disappears, and also has hepatoprotective, choleretic, antiulcer, antiseptic action; inhibits the excessive development of prostate cells; contributes to the reduction inflammatory processes and acceleration of tissue regeneration in diseases of the mucosa of the gastrointestinal tract, oral mucosa, biliary tract, genitourinary system and skin. When taking dietary supplements, the composition of bile improves, the impaired functional state of the gallbladder normalizes, and the risk of cholelithiasis and cholecystitis decreases. Normalizes the secretory and motor evacuation functions of the stomach and improves metabolism. For therapeutic use, it is necessary to reduce the content of vegetable oil in the daily diet by 10 g. For prophylactic purposes, Tykveinol is recommended to be taken in courses of 2 g per day for at least 1 month twice a year, in the autumn-winter and spring periods of the year. Tykveinol is especially necessary for people prone to mental and physical overload, students and schoolchildren to increase learning ability and tolerance to stress. At a dose of 1 g per day, Tykvanol is useful for everyone healthy people for prevention.

Leaver Wright contains liver extract 300 mg, choline bitartrate 80 mg, milk thistle extract 50 mg, inositol 20 mg; cysteine ​​15 mg; vitamin B12 6 mcg. Prevents the hepatotoxic effect of acetaldehyde, a product of alcohol metabolism, restores cellular endoplasmic membranes, consisting of phosphoglycerides synthesized on the basis of inositol and choline, reduces the level of lactic acid in the blood by improving metabolism with the participation of cysteine, promotes the accumulation of glutathione as a result of the action of cysteine, which prevents peroxide lipid oxidation, improves mic

This action of the drug at the site of its application + can lead to a reflex response + can be a side effect - this is a kind of resorptive action

It's always side effect-determined by the dose of the substance +determined by the concentration of the substance

The action of the substancedeveloping after its entry into the systemic circulationcalled:

Resorptive - reflex - etiotropic - local + general

Factorsaffecting the drug in the stomach:

Pepsin - pancreatic enzymes + acidic environment - moderately alkaline environment - insulinase enzyme

The amount of drug that entered the systemic circulation - the ratio between the prescribed dose and the weight of the person + the estimated volume of body fluid necessary for uniform distribution of the administered dose of the drug substance + the ratio between the dose taken and the concentration of the substance in the blood

The volume of blood in which the drug is dissolved

Any direct action + action undesirable in the course of treatment - any reflex

Synergistic - antagonistic + idiosyncratic + allergic action

Transport of drugs across the membrane from the low side

concentration into a space with a higher concentration is carried out:

Passive diffusion - facilitated diffusion - pinocytosis + active transport

Transport with energy costs - phagocytosis + transport with the participation of carriers

Biological meaning of biotransformation reactions involving cytochromes P-450:

Oxidize the drug molecule

Acetylation of a drug means:

Attachment of an acetic acid residue with the participation of acetyl-CoA - attachment of glucuronic acid - a synonym for microsomal oxidation - the same as hydrolysis - addition of hydroxyl groups + type of conjugation

Type of chemical transformation that occurs in the liver

Faster detoxified by the liver + less detoxified by the liver + have different bioavailability indicators + are not destroyed by gastrointestinal enzymes

Easier to cross the blood-brain barrier

To the concept« polypharmacy» related to the following phenomenon:

Sensitization - tolerance

Unreasonable prescribing of a large number of drugs - withdrawal - idiosyncrasy

The processes of microsomal oxidation of substances in the liver are characterized by the following features:

Ability to induce + possibility of inhibition + non-specificity of the substrate

Strict chemical specificity of the substrate - addition of methyl radicals - addition of an acetic acid residue

Term« addictive» corresponds:

Strengthening the effect of the drug with repeated administration - the concept of "drug dependence" + the concept of "tolerance"

Weakening of the effect of the drug with repeated use - the concept of "withdrawal"

Choose an answerwhich corresponds to the fastest removal of the drug by the kidneys:

The substance is poorly filtered and poorly reabsorbed - the substance is well filtered and well reabsorbed

The substance is well filtered and secreted by the tubules, but not

reabsorbed - the substance is well filtered, well reabsorbed and secreted by the tubules

Drug addiction may result from:

Induction of microsomal liver enzymes - suppression of cytochromes P-450 - increased sensitivity of receptors

Decreased sensitivity of target organ receptors - reduced metabolism of a given drug substance

If what- This substance inhibits the liver microsomal oxidation systemthen you can expect:

Reducing the rate of drug metabolism + prolonging the effect of drugs + possible cumulation of substances - shortening the elimination period

Decreased effectiveness of drugs

Induction of microsomal liver enzymes can:

Require a decrease in the dose of certain substances +require an increase in the dose of certain substances

Promote the penetration of substances through the hemato-

brain barrier + promote the removal of foreign substances from the body

Prevent the removal of foreign substances from the body

The drug enters the bloodstreambypassing the liver barrierwhen applied as:

Capsule + tablets under the tongue

Intravenous injections - infusions inside + inhalations

Acceleration of the excretion of the drug in the urine is achieved with:

Increased filtration in the glomeruli - increased tubular reabsorption - the use of aldosterone and vasopressin + activation of tubular secretion in the kidneys

Increasing the degree of drug binding to proteins

concept« pharmacokinetics» includes:

Absorption of a substance + distribution of a substance in the body + biotransformation of a substance - interaction with receptors - effects of action - mechanism of action + excretion of a substance + half-life of a substance

The mechanism of side effects of the substance

When administering acetylsalicylic acid along with

anti-inflammatory action may cause stomach ulcers. This effect can be described as:

Symptomatic effect + side effect - carcinogenicity - embryotoxicity + ulcerogenic effect

concept« histohematic barriers» includes:

Blood-ophthalmic barrier - lysosome membranes + placental barrier + blood-brain barrier

Presystemic drug elimination– this is:

The process of removal of a substance from the blood by the kidneys + removal of the drug before it enters the general circulation - secretion of the substance by the glands of the stomach

Biotransformation of the substance in the liver after absorption into the blood

Prolongation of the effects of drugs is achieved with:

Creation of a depot in adipose tissue - malabsorption in the intestine + increased binding to plasma proteins

Increased glomerular filtration in the kidneys - increased biotransformation in the liver

Secondary intracellular messengers in the action of drugs can be:

Cyclic nucleotides (cAMP, cGMP) - ion channel activators + calcium ions - adenylate cyclase

The process of metabolic transformation of drugs includes:

Oxidation-methylation

Reduction + hydrolysis -acetylation

The drug conjugation reaction is:

Oxidation + interaction with glucuronic acid

Interaction with glutathione + acetylation - interaction with hydrochloric acid - hydrolysis

concept« affinity» implies:

The ability to form complexes with cytoreceptors - a type of combined action of drugs + the affinity of a substance for a receptor

The ability of a substance to cause sensitization of the body

To secondary transmitters(« messengers») relate:

Cyclic nucleotides (cAMP, cGMP) -adenylate cyclase + diacylglycerol (DAG)

Membrane receptor ligands + ionized calcium + inositol 1,4,5-triphosphate (NF3)

To drugs- generics include:

Original drugs that first appeared on the pharmaceutical market + generic drugs

The most expensive drugs from this pharmacological group drugs classified according to their chemical structure

Drugs are converted in the liver through several processes catalyzed by enzymes. All of these enzymes are collectively referred to as the microsomal enzyme system and are present in the endoplasmic reticulum of hepatocytes.

microsomal enzymes

Microsomal enzymes are mainly found in the endoplasmic reticulum of liver cells. Microsomes are part of the endoplasmic reticulum and the ribosomes attached to them are isolated together by centrifugation of homogenized cells.

There are several microsomal enzymes, which are represented by monooxygenases, cytochrome P450, NADP cytochrome c reductase, glucoronyl transferases, glutathione-c-transferases, epoxide hydrolases, etc. Cytochrome P450 and NADP cytochrome c reductase are the two main microsomal enzymes in this system. Cytochrome P450 binds to oxygen while reductase binds electrons between NADP and cytochrome P450. Phospholipids are involved in this process.

Cytochrome P450

The cytochrome P450 enzyme belongs to a family of enzymes containing a heme complex that is non-covalently attached to a polypeptide chain or hemoproteins. The enzyme was named as such because the hemoprotein can form a complex that maximally absorbs light at a wavelength of 450 nm. This enzyme is involved in the metabolism of endogenous substances, such as the synthesis of steroids, the metabolism of retinoic and fatty acids, etc.

Induction of microsomal liver enzymes

Liver microsomal enzymes can be activated by a drug that binds to a receptor in the cytoplasm or nucleus of a cell. This coupled receptor can move into the cell nucleus, form a heterodimer, bind to promoter regions of P450 genes, and increase gene expression. Such inducers include omeprozole, phenobarbital, rifampicin, etc.

Induction of the enzyme system can increase its metabolic level by 2-4 times. This increase in the rate of enzyme synthesis will continue as long as the inducer agent is present. The enzyme system can return to its original values ​​within one to three weeks.

Examples of factors that may cause clinically significant interactions: cigarette smoking, chronic alcoholism, rifampicin and certain anticonvulsant drugs (barbiturates, phenytoin, carbamazepine). The rate of development and reversibility of enzyme induction depends on the inductor and the rate of synthesis of new enzymes. This adaptation process is relatively slow and can take anywhere from a few days to several months. It can also accelerate the metabolism of the inductor itself - this is auto-induction.

Two drugs - inducers are widely used in the practice of the intensive care unit - this is rifampicin and phenobarbital. Unlike phenobarbital, which takes at least several weeks to develop as an inducer, rifampicin as an inducer acts quickly and such an effect can be detected already after 2-4 days and reach its maximum after 6-10 days. Enzyme induction caused by rifampicin can lead to more pronounced interactions with warfarin, cyclosporine, glucocorticoids, ketoconazole, theophylline, quinidine, digitoxin and verapamil, which requires close monitoring of the patient and frequent dose adjustment of the drug - the object. Cytochrome can also be induced by anticonvulsants, rifampicin, glucocorticoids, and some macrolide antibiotics. It can also lead to drug interactions.

INHIBITION OF MICROSOMAL LIVER ENZYMES

Inhibition of cytochrome enzymes is the most common mechanism responsible for the occurrence of drug interactions in the practice of intensive care units. If a substance inhibits cytochrome, then it also changes the metabolism of the drug - the object. This effect consists in lengthening the half-life of the drug-object and, accordingly, increasing its concentration. Some inhibitors affect several isoforms of enzymes at once, for example, the macrolide antibiotic erythromycin. Large inhibitor concentrations may be required to inhibit several enzyme isoforms at once. Fluconazole inhibits the activity of cytochrome 2-9 at a dose of 100 mg per day, but if the dose is increased to 400 mg, the activity of cytochrome 3-4 will be inhibited. The higher the dose of the inhibitor, the faster its action occurs and the more pronounced it is. Inhibition generally develops faster than induction, usually it can be registered as early as 24 hours from the moment the inhibitors were prescribed. The time of development of maximum inhibition of enzyme activity depends both on the inhibitor itself and on the drug - the object. Since enzyme isoforms differ by gene, the effects environment, the age of a person, existing diseases under the influence of the same inhibitor, the degree of inhibition of enzyme activity in different patients may vary. Approximately 5% of all US residents have a genetic deficiency of the cytochrome 2-6 isoform, which is involved in the metabolism of beta-blockers, antipsychotics and antidepressants. In these patients, there is no inhibition of this form of the enzyme by quinidine, which is observed in the rest of the population. Inhibition of the 3A isoform is common and is caused by a large number of drugs commonly used in intensive care unit practice. These may include: ketoconazole, fluconazole, cyclosporine, ritonavir, diltiazem, nifedipine, nicardipine, fluoxetine, quinidine, verapamil, and erythromycin. These are rapidly reversible inhibitors. The route of administration of the drug affects the rate of development and the severity of inhibition of enzyme activity. For example, if the drug is administered intravenously, then the interaction will develop faster.

Highly polar substances or water-soluble metabolites of fat-soluble substances are excreted by the kidneys, but we must not forget that they are excreted to a lesser extent by the liver, with sweat and breast milk. Water-soluble substances in the blood can be excreted in the urine by passive glomerular filtration, active tubular secretion, or by blocking active, or more often passive, tubular reabsorption.

Drugs that reduce the glomerular filtration rate (GFR) usually reduce filtration pressure either due to a decrease in intravascular volume or a decrease in blood pressure or vascular tone of the renal arteries. A decrease in GFR by a drug-target, such as furosemide, may in turn limit passive filtration of the drug-target, such as aminoglycosides, resulting in increased blood concentrations. At the same time, nephrotoxic drugs, such as aminoglycosides, can reduce the number of functioning nephrons and reduce GFR, which leads to the accumulation in the body of other drugs, such as digoxin, which are excreted almost exclusively by the kidneys. Although this is an indirect interaction, it is of great importance for ICU patients and can be avoided by careful titration of drug doses.

Many water-soluble organic acids are actively secreted primarily in the proximal tubule. Active energy-dependent transport of organic anions and cations is a unique system. Inhibition of these specific systems by drugs can lead to accumulation of the target drug. Competition for transport systems with endogenous (eg, uric acid) and exogenous substances (penicillins, probenecid, non-steroidal anti-inflammatory drugs, methotrexate, sulfonamides, and cephalosporins) can lead to the development of clinically significant drug interactions. An example of such an interaction can be seen in the example of quinidine and digoxin. As mentioned earlier, changes in the metabolism of digoxin in organs and tissues can occur with the simultaneous administration of these two drugs. There is a relative change in the volume of distribution of the drug and, at the same time, an interaction of another kind - competition for transport systems in the kidneys. Decreased excretion of digoxin by the kidneys and a simultaneous change in the metabolism of the drug can lead to a doubling of the concentration of the drug in the blood. This type of drug interaction has been used therapeutically in the past. The drug probenecid was used to increase the concentration of penicillin in the body. Reabsorption of filtered and excreted drugs occurs in the distal tubule and in the collecting ducts. This process is influenced by changes in the concentration of drugs, the volumetric rate of diuresis, and the pH of the urine compared to that of the blood serum. When the pH of urine changes in the distal part of the tubules, the transport of organic bases and acids changes. These ionized substances do not directly pass through the membrane of the tubules of the kidneys, which increases the rate of their excretion. An important and clinically significant example of such interactions is the use of sodium bicarbonate to alkalinize the urine and accelerate the elimination of aspirin or salicylates in case of poisoning with these substances. Since pH changes in a logarithmic relationship, with an increase in this indicator by one unit, it leads to a tenfold acceleration in renal excretion. The uricosuric effect of probenecid is associated with the drug blocking the active reabsorption of endogenous uric acid from the proximal part of the renal tubules.

Aspirin also inhibits the reabsorption of uric acid, but when used in conjunction with probenecid, aspirin eliminates the uricosuric effect of the latter. Indirect drug interactions can affect both excretion and reabsorption mechanisms. Lithium is reabsorbed in the kidneys along with sodium, by the same mechanism. With a decrease in intravascular volume, for example, when using thiazide diuretics, the reabsorption of sodium and lithium in the proximal tubules increases compensatory, which in some situations can lead to the accumulation of toxic amounts of lithium in the body.

What are liver enzymes, their diagnostic value and normal values?

Liver enzymes, mainly alanine aminotransferase (ALT) and aspartate aminotransferase (AST), provide a detailed assessment of the functioning of the organ in normal and pathological conditions.

Enzymes (liver enzymes) are produced in large quantities and enter the bloodstream. When the functions of this organ are disturbed, certain enzymes increase or decrease in the blood and this indicates a disease.

Enzymes - what is it?

Metabolic processes are carried out thanks to enzymes that are contained in the hepatobiliary system. Microsomal liver enzymes in dynamic constancy determine the normal functioning of this organ.

So, mitochondria contain enzymes for the liver of energy metabolism. Most enzymes are amenable to proteolysis (cleavage), some enzymes are excreted in the bile.

By using laboratory diagnostics one or another liver enzyme can be determined. An enzyme liver analysis can be done at any time, there are express tests to determine the necessary indicators. Today, the analysis and objective evaluation of enzyme tests for clinical practice is important.

Enzymatic inducers of cytolysis and inducers of cellular damage, cholestasis, and impairment of the synthetic function of the organ are discussed.

What are the different groups?

Liver enzymes are divided into several groups:

• Secretory (prothrombinase, cholinesterase). They affect the process of blood coagulation, if the functions of the hepatobiliary system are impaired, these enzymes are reduced;
• Indicator (AST, ALT, LDH). They are inside the cells, when the organ is affected, they are washed out of the cells and their level rises in the blood;
• Excretory (alkaline phosphatase). They are synthesized and excreted in the bile. When the outflow of bile is disturbed, this liver enzyme rises.

What enzymes are of diagnostic value?

Most often, for the diagnosis of diseases of the hepatobiliary system, the determination of indicators of AST, ALT, gamma-lutamyl transpeptidase (GGT), lactate dehydrogenase (LDH) and alkaline phosphatase (AP) is used.

Liver enzyme GGT and LDH can be measured during pregnancy. The liver enzyme alkaline phosphatase is necessary for accurate differentiation of diseases of the hepatobiliary system.

Having done the analysis, the patient will be able to go to the doctor with the data, and he will evaluate the functions of the affected organ. During pregnancy, it is especially important to do a biochemical analysis to control the woman and the fetus in order to identify pathology in the early stages.

Each laboratory has its own norm, presumably the indicators are measured in U / l, mol / l, μmol / l.

The ratio of AST and ALT

The ratio of aminotransferases is pathognomonic for diseases of the hepatobiliary system. By itself, the liver enzyme AST is also found in the myocardium, skeletal muscles, and kidneys. The liver enzyme ALT is found only in this organ.

ALT norm -U/l, AST norm -U/l.

An ALT:AST ratio of 1 (alanine aminotransferase greater than or equal to aspartate aminotransferase) indicates acute hepatitis. If ALT:AST is higher than 2:1, then this ratio indicates an alcoholic disease. An AST:ALT ratio greater than 1 (AST greater than ALT) indicates cirrhosis.

An increase in the activity of AST and ALT occurs with necrosis of hepatocytes of any etiology, obstructive jaundice, and fatty degeneration. A decrease in activity is characteristic of extensive necrosis, cirrhosis.

In addition, these enzymes for the liver play an important role in determining the hepatotoxicity of drugs. Thus, AST and ALT increase during long-term use of anticoagulants, barbiturates, hormonal contraceptives, antiepileptic drugs, ascorbic acid, codeine, morphine, erythromycin, gentamicin, lincomycin. A decrease in activity is observed during pregnancy.

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What other liver tests are there?

In addition to the main AST and ALT, the level of GGT, alkaline phosphatase, LDH is determined.

GGT norm - up to 40 U / l. GGT is found in large quantities in addition to the main organ, in the kidneys, pancreas, and walls of the bile ducts. Determination of GGT is a particularly sensitive test during pregnancy and in children. An increase in GGT activity is observed in hepatitis, cirrhosis, tumors, cholestasis, alcohol intoxication, obstructive jaundice, cholangitis.

Dynamics of ALT, AST, GGT, alkaline phosphatase depending on age

Decreased GGT activity - in decompensated cirrhosis. GGT is a highly sensitive indicator, especially for toxic effects. If you do an analysis and the levels of aminotransferases are normal, then the GGT indicators will be increased.

An increase in the rate occurs with cholestasis, obstructive jaundice, biliary cirrhosis, and hepatitis. Increase during pregnancy (in the third trimester), with the use of hepatotoxic drugs. If you do an analysis, and the level of alkaline phosphatase is low, then this indicates the use of glucocorticosteroids.

The norm of lactate dehydrogenase is up to 250 U / l. There are several LDHs, so LDH 1-2 is found in the myocardium and erythrocytes, LDH 5 is in the liver, LDH 4-5 is in the skeletal muscles. With dysfunction of the hepatobiliary system, an analysis is made for LDH 5. An increase in activity is observed in acute hepatitis, obstructive jaundice, and tumors. There is also an increase in activity during pregnancy, massive physical exercise.

Conclusion

The most indicative in the disease of the hepatobiliary zone are aminotransferases, but in biochemical analysis it is also important to determine alkaline phosphatase, lactate dehydrogenase, gamma-glutamyl transpeptidase.

Changes in indicators should be monitored during pregnancy. The norm in this case will indicate an increased result, since some indicators are decreasing. During pregnancy, a woman needs to be examined several times a trimester.

To recognize pathology, you need to know what is the norm in a particular enzyme. This is of great diagnostic value.

Biotransformation of medicinal substances. Reactions of stages I and II of metabolism. Inducers and inhibitors of microsomal enzymes (examples)

Biotransformation (metabolism) - a change in the chemical structure of medicinal substances and their physicochemical properties under the action of body enzymes. The main focus of this process is the conversion of lipophilic substances that are easily reabsorbed in the renal tubules into hydrophilic polar compounds that are rapidly excreted by the kidneys (not reabsorbed in the renal tubules). In the process of biotransformation, as a rule, there is a decrease in the activity (toxicity) of the starting substances.

Biotransformation of lipophilic drugs mainly occurs under the influence of liver enzymes localized in the membrane of the endoplasmic reticulum of hepatocytes. These enzymes are called microsomal because

they are associated with small subcellular fragments of the smooth endoplasmic reticulum (microsomes), which are formed during homogenization of the liver tissue or tissues of other organs and can be isolated by centrifugation (precipitated in the so-called "microsomal" fraction).

In blood plasma, as well as in the liver, intestines, lungs, skin, mucous membranes and other tissues, there are non-microsomal enzymes localized in the cytosol or mitochondria. These enzymes may be involved in the metabolism of hydrophilic substances.

There are two main types of drug metabolism (stages):

Non-synthetic reactions (metabolic transformation);

Synthetic reactions (conjugation).

biotransformation (metabolic reactions of the 1st phase), occurs under the action of enzymes - oxidation, reduction, hydrolysis.

conjugation (metabolic reactions of the 2nd phase), in which residues of other molecules (glucuronic, sulfuric acids, alkyl radicals) are attached to the molecule of the substance, with the formation of an inactive complex that is easily excreted from the body with urine or feces.

Medicinal substances can undergo either metabolic biotransformation (where substances called metabolites are formed) or conjugation (conjugates are formed). But most drugs are first metabolized with the participation of non-synthetic reactions with the formation of reactive metabolites, which then enter into conjugation reactions.

Metabolic transformation includes the following reactions: oxidation, reduction, hydrolysis. Many lipophilic compounds are oxidized in the liver by a microsomal system of enzymes known as mixed function oxidases, or monooxygenases. The main components of this system are cytochrome P450 reductase and cytochrome P450 hemoprotein, which binds drug molecules and oxygen in its active center. The reaction proceeds with the participation of NADPH. As a result, one oxygen atom is attached to the substrate (drug) with the formation of a hydroxyl group (hydroxylation reaction).

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, while prescribing other drugs (for example, glucocorticoids, oral contraceptives) with inducers of microsomal enzymes, the metabolic rate of the latter increases and their effect decreases. In some cases, the metabolic rate of the inductor itself may increase, as a result of which its pharmacological effects (carbamazepine) decrease.

Some medicinal substances (cimetidine, chloramphenicol, ketoconazole, ethanol) reduce the activity (inhibitors) of metabolizing enzymes. For example, cimetidine is an inhibitor of microsomal oxidation and, by slowing down the metabolism of warfarin, may increase its anticoagulant effect and provoke bleeding. Known substances (furanocoumarins) contained in grapefruit juice that inhibit the metabolism of drugs such as cyclosporine, midazolam, alprazolam and, therefore, increase their action. With the simultaneous use of medicinal substances with inducers or inhibitors of metabolism, it is necessary to adjust the prescribed doses of these substances.

12. Ways of excretion of medicinal substances from the body, meaning, the concept of elimination quota, half-life (T 1/2) and total plasma clearance. The dependence of the action of medicinal substances on the route of excretion, examples.

Excretion of unchanged drug or its metabolites is carried out by all excretory organs (kidneys, intestines, lungs, mammary, salivary, sweat glands, etc.).

The kidneys are the main organ for removing drugs from the body. Excretion of drugs by the kidneys occurs by filtration and by active or passive transport. Lipid-soluble substances are easily filtered in the glomeruli, but are passively reabsorbed in the tubules. Drugs that are poorly soluble in lipoids are more rapidly excreted in the urine because they are poorly reabsorbed in the renal tubules. The acidic reaction of urine promotes the excretion of alkaline compounds and makes it difficult to excrete acidic ones. Therefore, in case of intoxication with acidic drugs (for example, barbiturates), sodium bicarbonate or other alkaline compounds are used, and in case of intoxication with alkaline alkaloids, ammonium chloride is used. It is also possible to accelerate the excretion of drugs from the body by the appointment of potent diuretics, for example, osmotic diuretics or furosemide, against the background of the introduction of a large amount of fluid into the body (forced diuresis). Bases and acids are excreted from the body by active transport. This process takes place with the expenditure of energy and with the help of certain enzymatic carrier systems. By creating competition for the carrier with some substance, it is possible to slow down the excretion of the drug (for example, etamide and penicillin are secreted using the same enzyme systems, so etamide slows down the excretion of penicillin).

Drugs that are poorly absorbed from the gastrointestinal tract are excreted by the intestines and are used for gastritis, enteritis and colitis (for example, astringents, some antibiotics used in intestinal infections). In addition, from the liver cells, drugs and their metabolites enter the bile and enter the intestine with it, from where they are either reabsorbed, delivered to the liver, and then with bile to the intestine (enterohepatic circulation), or excreted from the body with feces. Direct secretion of a number of drugs and their metabolites by the intestinal wall is not excluded.

Volatile substances and gases (ether, nitrous oxide, camphor, etc.) are excreted through the lungs. To accelerate their release, it is necessary to increase the volume of pulmonary ventilation.

Many drugs can be excreted in milk, especially weak bases and non-electrolytes, which should be taken into account when treating nursing mothers.

Some medicinal substances are partially excreted by the glands of the oral mucosa, exerting a local (for example, irritating) effect on the excretion pathways. So, heavy metals (mercury, lead, iron, bismuth), standing out salivary glands, cause irritation of the oral mucosa, stomatitis and gingivitis occur. In addition, they cause the appearance of a dark border along the gingival margin, especially in the area of ​​carious teeth, which is due to the interaction of heavy metals with hydrogen sulfide in the oral cavity and the formation of practically insoluble sulfides. Such a "border" is a diagnostic sign of chronic heavy metal poisoning.

With prolonged use of diphenin and sodium valproate (anticonvulsants), irritation of the gingival mucosa can cause hypertrophic gingivitis ("diphenin gingivitis"). The level of elimination of any drug substance is assessed using two main tests:

• firstly, the time is determined during which half of the administered dose of the chemotherapy drug is eliminated, that is, the half-life of the latter is found (T 1/2);
• secondly, the percentage of that part of a single dose of the drug that is eliminated during the day is calculated (the coefficient, or quota, of elimination).

These two criteria for the elimination of any drug substance are not stable, because they depend on a set of conditions. Among the latter, a significant role is given to the properties of the drug itself and the state of the body. They depend on the rate of drug metabolism in tissues and body fluids, the intensity of its excretion, the functional state of the liver and kidneys, the route of administration of the chemotherapy drug, the duration and storage conditions, lipid solubility, chemical structure, etc.

The elimination of fat-soluble, ionized drugs associated with proteins is slower than that of water-soluble, ionized, non-protein-bound drugs. With the introduction of high doses of drugs, their elimination is prolonged, which is due to the intensification of all processes involved in the transport, distribution, metabolism and release of chemotherapy drugs.

Elimination of most drugs in children is significantly lower than in adults. It is especially slowed down in premature babies of the first months of life. Sharply prolong the elimination of congenital and acquired enzymopathies (insufficiency of glucose-6-phosphate dehydrogenase, N-acetyltransferase, etc.), diseases of the liver and kidneys, occurring with insufficiency of their functions.

Other factors also influence the rate of elimination: the patient's gender, body temperature, physiological biorhythms, the child's stay in bed, etc. Data on the half-life of drugs allows the doctor to more reasonably prescribe a single and daily dose of a particular drug, the frequency of its administration .

Microsomal oxidation increases the reactivity of molecules

Microsomal oxidation is a sequence of reactions involving oxygenases and NADPH, leading to the introduction of an oxygen atom into the composition of a non-polar molecule and the appearance of hydrophilicity in it and increases its reactivity.

Microsomal oxidation reactions are carried out by several enzymes located on the membranes of the endoplasmic reticulum (in the case of in vitro they are called microsomal membranes). Enzymes organize a short chain that ends with cytochrome P 450 . Cytochrome P 450 interacts with molecular oxygen and includes one oxygen atom in the substrate molecule, contributing to the appearance (strengthening) of its hydrophilicity, and the other - in the water molecule.

Microsomal oxidation reactions are phase 1 reactions and are designed to impart polar properties to a hydrophobic molecule and/or to increase its hydrophilicity, enhance the reactivity of molecules to participate in phase 2 reactions. In oxidation reactions, the formation or release of hydroxyl, carboxyl, thiol and amino groups occurs, which are hydrophilic.

Microsomal oxidation enzymes are located in the smooth endoplasmic reticulum and are mixed-function oxidases (monooxygenases).

The main protein of this process is a hemoprotein - cytochrome P 450. In nature, there are up to 150 isoforms of this protein, oxidizing about 3000 different substrates. The ratio of different isoforms of cytochrome P 450 differs due to genetic characteristics. It is believed that some isoforms are involved in the biotransformation of xenobiotics, while others metabolize endogenous compounds (steroid hormones, prostaglandins, fatty acids, etc.).

The main reactions carried out by cytochrome P 450 are:

• oxidative dealkylation, accompanied by the oxidation of an alkyl group (at N, O or S atoms) to an aldehyde group and its elimination,
• oxidation (hydroxylation) of non-polar compounds with aliphatic or aromatic rings,
• oxidation of alcohols to the corresponding aldehydes.

The work of cytochrome P 450 is provided by two enzymes:

Scheme of mutual arrangement of enzymes of microsomal oxidation and their functions

Both oxidoreductases receive electrons from their respective reduced equivalents and donate them to cytochrome P 450 . This protein, having previously attached a reduced substrate molecule, binds to an oxygen molecule. Having received one more electron, cytochrome P 450 incorporates the first oxygen atom into the composition of the hydrophobic substrate (oxidation of the substrate). At the same time, the second oxygen atom is reduced to water.

The sequence of substrate hydroxylation reactions involving cytochrome P 450

An essential feature of microsomal oxidation is the ability to induce or inhibit, i.e. to change the power of the process.

Inductors are substances that activate the synthesis of cytochrome P 450 and the transcription of the corresponding mRNA. They are

1. Broad spectrum of action, which have the ability to stimulate the synthesis of cytochrome P450 and NADPH-cytochrome P-450 oxidoreductase, glucuronyl transferase. The classic representative is barbituric acid derivatives - barbiturates, also diazepam, carbamazepine, rifampicin, etc.

2. Narrow spectrum of action, i.e. stimulate one of the forms of cytochrome P450 - aromatic polycyclic hydrocarbons (methylcholanthrene, spironolactone and many others)

Inhibitors of microsomal oxidation bind to the protein part of the cytochrome or to the heme iron. They are divided into:

• direct action - carbon monoxide(CO), antioxidants,
• indirect action, i.e. affect through the intermediate products of their metabolism, which form complexes with cytochrome P-450 - erythromycin.

Assessment of reactions of the 1st phase

Microsomal oxidation can be assessed in the following ways:

• determination of the activity of microsomal enzymes after a biopsy,
• on the pharmacokinetics of drugs,
• using metabolic markers (antipyrine test).

Microsomal enzymes are

Hepatologist → About the liver → Changes in liver enzymes in various pathologies, their diagnostic value

A group of protein substances that increase the activity of various metabolic processes is called enzymes.

The successful course of biological reactions requires special conditions - elevated temperature, a certain pressure, or the presence of certain metals.

Enzymes help speed up chemical reactions without these conditions being met.

What are liver enzymes

Based on their function, enzymes are located inside the cell, on the cell membrane, are part of various cellular structures and participate in reactions within it. According to the function performed, the following groups are distinguished:

hydrolases - break down the molecules of substances; synthetases - participate in molecular synthesis; transferases - transport sections of molecules; oxidoreductases - affect redox reactions in the cell; isomerases - change the configuration of molecules; lyases - form additional molecular bonds.

The work of many enzymes requires the presence of additional co-factors. Their role is performed by all vitamins, microelements.

What are liver enzymes

Each cell organelle has its own set of substances that determine its function in the life of the cell. Enzymes of energy metabolism are located on mitochondria, granular endoplasmic reticulum is tied to protein synthesis, smooth reticulum is involved in lipid and carbohydrate metabolism, lysosomes contain hydrolysis enzymes.

Enzymes that can be found in blood plasma are conventionally divided into three groups:

Secretory. They are synthesized in the liver and released into the blood. An example is blood coagulation enzymes, cholinesterase. Indicator, or cellular (LDH, glutamate dehydrogenase, acid phosphatase, ALT, AST). Normally, only their traces are found in the serum, tk. their location is intracellular. Tissue damage causes the release of these enzymes into the blood, by their number one can judge the depth of the lesion. Excretory enzymes are synthesized and excreted along with bile (alkaline phosphatase). Violation of these processes leads to an increase in their indicators in the blood.

What enzymes are used in diagnosis

Pathological processes are accompanied by the appearance of cholestasis and cytolysis syndromes. Each of them is characterized by its own changes in the biochemical parameters of serum enzymes.

Cholestatic syndrome is a violation of bile secretion. It is determined by the change in the activity of the following indicators:

increase in excretory enzymes (alkaline phosphatase, GGTP, 5-nucleotidase, glucuronidase); increase in bilirubin, phospholipids, bile acids, cholesterol.

Cytolytic syndrome indicates the destruction of hepatocytes, an increase in the permeability of cell membranes. The condition develops with viral, toxic damage. A change in indicator enzymes is characteristic - ALT, AST, aldolase, LDH.

Alkaline phosphatase can be of both hepatic and bone origin. A parallel rise in GGTP speaks of cholestasis. Activity increases with liver tumors (jaundice may not appear). If there is no parallel increase in bilirubin, one can assume the development of amyloidosis, liver abscess, leukemia or granuloma.

GGTP rises simultaneously with an increase in alkaline phosphatase and indicates the development of cholestasis. An isolated increase in GGTP can occur with alcohol abuse, when there are no gross changes in the liver tissue yet. If fibrosis, cirrhosis or alcoholic hepatitis has developed, the level of other liver enzymes also increases.

Transaminases are represented by ALT and AST fractions. Aspartate aminotransferase is found in the mitochondria of the liver, heart, kidneys, and skeletal muscles. Damage to their cells is accompanied by the release of a large amount of the enzyme into the blood. Alanine aminotransferase is a cytoplasmic enzyme. Its absolute amount is small, but the content in hepatocytes is the highest, compared with the myocardium and muscles. Therefore, an increase in ALT is more specific for damage to liver cells.

The change in the ratio of AST / ALT matters. If it is 2 or more, then this indicates hepatitis or cirrhosis. Especially high enzymes are observed in hepatitis with active inflammation.

Lactate dehydrogenase is a cytolysis enzyme, but is not specific to the liver. May increase in pregnant women, newborns, after heavy physical exertion. Significantly increases LDH after myocardial infarction, pulmonary embolism, extensive injuries with muscle relaxation, with hemolytic and megaloblastic anemia. The level of LDH is based on the differential diagnosis of Gilbert's disease - cholestasis syndrome is accompanied by a normal LDH indicator. In other jaundices, at the beginning, LDH remains unchanged, and then rises.

Analysis for liver enzymes

Preparation for analysis begins the day before. It is necessary to completely exclude alcohol, in the evening do not eat fatty and fried foods. Do not smoke one hour before the test.

Perform venous blood sampling on an empty stomach in the morning.

The hepatic profile includes the definition of the following indicators:

ALT; AST; alkaline phosphatase; GGTP; bilirubin and its fractions.

Also pay attention to the total protein, separately the level of albumin, fibrinogen, glucose, 5-nucleotidase, ceruloplasmin, alpha-1-antitrypsin.

Diagnostics and norms

Normal biochemical parameters characterizing the work of the liver are shown in the table

/ pharmacology lectures / Lecture №1. Introduction to pharmacology. General pharmacology (beginning)

The listed mechanisms of absorption (absorption) "work", as a rule, in parallel, but the predominant contribution is usually made by one of them (passive diffusion, filtration, active transport, pinocytosis). So, in the oral cavity and in the stomach, passive diffusion is mainly realized, and filtration is to a lesser extent. Other mechanisms are practically not involved.

In the small intestine there are no obstacles to the implementation of all mechanisms of absorption; which one dominates depends on the drug.

Passive diffusion and filtration processes predominate in the large intestine and rectum. They are also the main mechanisms of drug absorption through the skin.

The use of any drug for therapeutic or prophylactic purposes begins with its introduction into the body or application to the surface of the body. The rate of development of the effect, its severity and duration depend on the routes of administration. Existing routes of administration are usually divided into ENTERAL (that is, through the digestive tract: administration through the mouth, under the tongue, into the 12 duodenum, into the rectum or rectally), and PARENTERAL (that is, bypassing the digestive tract: in / venous administration, in / arterial, intramuscular, subcutaneous, inhalations - aerosols, gases, powders); intrathecal or subarachnoid administration; finally, local application of drugs: intrauterine, vaginal, bladder, intraperitoneal, etc.).

The route of administration of the drug largely determines whether it can get to the site of action (into the biophase) (for example, in the focus of inflammation) and have a therapeutic effect.

II. DISTRIBUTION OF DRUGS IN THE BODY. BIOLOGICAL BARRIERS. DEPOSIT

After absorption, medicinal substances enter, as a rule, into the blood, and then they are carried to different organs and tissues. The nature of the distribution of the drug is determined by many factors, depending on which the drug will be distributed in the body evenly or unevenly. It should be said that most drugs are distributed unevenly and only a small part is relatively evenly distributed (inhalation drugs for anesthesia). The most important factors influencing the distribution pattern of a drug are: 1) lipid solubility,

2) the degree of binding to plasma proteins, 3) the intensity of regional blood flow.

The lipid solubility of a drug determines its ability to cross biological barriers. This is, first of all, the wall of capillaries and cell membranes, which are the main structures of various histohematic barriers, in particular, such as the blood-brain and placental barriers. Non-ionized fat-soluble drugs easily penetrate cell membranes and are distributed in all body fluids. The distribution of drugs that do not penetrate well through cell membranes (ionized drugs) is not so uniform.

The permeability of the BBB increases with an increase in the osmotic pressure of the blood plasma. Various diseases can change the distribution of drugs in the body. Thus, the development of acidosis can contribute to the penetration of drugs into tissues - weak acids, which are less dissociated under such conditions.

Sometimes the distribution of a medicinal substance depends on the affinity of the drug for certain tissues, which leads to their accumulation in individual organs and tissues. An example is the formation of a tissue depot in the case of the use of drugs containing iodine (J) in the tissues of the thyroid gland. When using tetracyclines, the latter can selectively accumulate in bone tissue, in particular, teeth. Teeth in this case, especially in children, may acquire a yellow color.

Such selectivity of action is due to the affinity of tetracyclines for biological substrates of bone tissue, namely the formation of tetracycline-calcium complexes by the type of chelates (hela - cancer claw). These facts are important to remember, especially for pediatricians and obstetrician-gynecologists.

Some drugs can accumulate in large quantities inside the cells, forming cellular depots (Acrichin). This happens due to the binding of the drug substance to intracellular proteins, nucleoproteins, phospholipids.

Some anesthetics, due to their lipophilicity, can form fat depots, which should also be taken into account.

Drugs are deposited, as a rule, due to reversible bonds, which, in principle, determines the duration of their stay in tissue depots. However, if persistent complexes are formed with blood proteins (sulfadimethoxine) or tissues (heavy metal salts), then the presence of these funds in the depot is significantly prolonged.

It should also be borne in mind that after absorption into the systemic circulation, most of the drug substance in the first minutes enters those organs and tissues that are most actively perfused by blood (heart, liver, kidneys). The saturation of the muscles, mucous membranes, skin and adipose tissue with the drug occurs more slowly. To achieve therapeutic concentrations of drugs in these tissues takes time from several minutes to several hours.

The influence of the state of hemodynamics on the distribution of drugs is most clearly seen in pathological conditions. The fact is that hemodynamic disturbances can significantly change the distribution kinetics. Thus, in hemorrhagic shock or congestive heart failure, perfusion of most organs decreases. Violation of the rate of glomerular filtration and hepatic blood flow lead to a decrease in renal and hepatic clearance, respectively, which will immediately affect the increase in the concentration of the drug in the blood plasma. Accordingly, the intensity and duration of the drug will be increased. As an example, one can point to an increase in the duration of action of thiopental in shock.

Many medicinal substances have a strong physicochemical affinity for various plasma proteins. The most important in this regard are albumins and, to a lesser extent, acidic alpha-glycoproteins. Such a drug agent ultimately leads to the fact that, after absorption, it can circulate in the blood not only in free form, but also in protein-bound form. This is the so-called EXTRACELLULAR (extracellular) depot of a medicinal substance, its kind of reservoir in the blood. The plasma protein-bound fraction of the drug is a temporary depot and prevents sharp fluctuations in the concentration of the unbound substance in the blood and body fluids. The binding of drugs to plasma proteins limits their concentration in tissues and at the site of action, since only free (unbound) drug can pass through the membranes. A substance that is in a complex with a protein is devoid of specific activity. Protein binding reduces the diffusion of the drug into the cell and therefore slows down the process of metabolism. Protein binding reduces the amount of drug that can be filtered in the renal glomeruli, resulting in slowing down the process of its excretion (excretion).

It is practically noticeable if the drug substance binds to proteins very actively, that is, more than 90%. The strength of the interaction of blood proteins and drugs is expressed by affinity or affinity. An important conclusion follows from this definition (provision):

If A is a drug,

and O is a protein, then A + B \u003d AO

As can be seen from this equation, the free and bound parts of the medicinal substance are in a state of dynamic equilibrium. Since the drug is active only in the free state, it is inactive in connection with the protein. A somewhat simplified comparison can be assumed that in the free state, the drug acts on the pharmacological receptors of tissues like a key to a lock, but in connection with a protein, this key does not work.

The degree of affinity, that is, the strength of drug binding to protein, depends on:

1) the rate of entry of the drug into the tissue. Since drug activity is determined by the diffusible moiety, drugs with high affinity, high affinity for proteins, such as long-acting sulfonamides (affinity > 90%), act slowly and are found in the interstitial (intercellular) fluid and in tissue cells. in low concentrations.

Another example is the cardiac glycoside (digitoxin), which is 97% protein bound. After taking this drug inside, it begins to act only after an hour.

2) The duration of their action depends on the degree of affinity of drugs with plasma proteins. Digitoxin after a single dose has a pharmacological effect for 2-3 days, and its residual effect is realized even after a few weeks (14-21 days). If in chronic heart failure, the binding of drugs to plasma proteins decreases, then in chronic pulmonary insufficiency or in the postoperative period it increases (by about 10%). In patients with reduced kidney function, the percentage of protein binding of acidic drugs with acidic properties is reduced.

3) The degree of drug affinity with blood proteins affects the difference in the effects of drugs in people with different pathologies. For example, when a patient with a burn disease develops deep hypoproteinemia, the fraction of free drug substance increases, which in such a situation requires a reduction in therapeutic doses of the drug. A similar situation can develop during starvation, when, if the dose of the drug is not reduced, a toxic effect will develop on its usual dose (similarly with radiation sickness).

4) The simultaneous use of drugs that bind to the same radicals of protein molecules can cause the effect of their competition for binding to proteins. If, then, these drugs have different binding powers, that is, different affinities, there may be a sudden increase in the concentration of one of them, sometimes to dangerous levels. So, if a patient receives an indirect anticoagulant (a drug such as phenylin, neodocoumarin), the coagulation potential of which is corrected, then with the additional introduction (inflammation of the joints) of salicylates or butadione in the blood plasma, the level of the free drug (anticoagulant) can significantly increase due to its displacement by salicylate (butadion ) from a complex with proteins. As a result, there is a risk of bleeding. Schematically, this can be shown as follows:

A + O \u003d AO + B \u003d BO + A, where B is butadione.

These pharmacokinetic data have become known only in recent years.

What is the further fate of drugs in the body? After soaking and dispensing, drugs may:

1) be metabolized under the influence of adequate enzymes;

2) change spontaneously, turning into other substances without the action of enzymes;

3) or can be excreted from the body (or excreted) unchanged.

Some medicinal substances spontaneously change (embichin), turning into other substances with corresponding changes in the acidity of the environment in the body. Thus, in a living organism, medicinal substances undergo certain changes or BIOTRANSFORMATION. Biotransformation (or transformation, or metabolism) is understood as a complex of physicochemical and biochemical transformations of medicinal substances that contribute to their conversion into simpler, ionized, more polar and, therefore, water-soluble components (metabolites), which are more easily excreted from the body. In other words, no matter what structure a xenobiotic has, an adequate enzyme encountered with it transfers it to a state convenient for excretion from the body (as a rule, a xenobiotic becomes less lipophilic) or to a state for use as an energy and plastic material (cocarboxylase, sodium nucleinate) . Although some medicinal substances, when biotransformed, form metabolites that are more active than substances introduced into the body, the vast majority of drugs are inactivated, decomposed, transformed into simpler, pharmacologically less active and less toxic metabolites. Biotransformation of administered drugs occurs predominantly in the liver, but may occur in the kidneys, intestinal wall, lungs, muscles, and other organs. The processes of biotransformation are complex and usually involve a series of successive steps, each of which is mediated by a specific blood enzyme.

There are two (2) types of drug metabolism reactions in the body: NON-SYNTHETIC and SYNTHETIC.

1. Non-synthetic reactions include OXIDATION, REDUCTION and HYDROLYSIS. All non-synthetic reactions of metabolism, also called metabolic transformation of drugs, can also be divided into 2 groups depending on the localization of the 2 main biotransforming systems:

a) the main group of reactions by which most drugs are biotransformed are reactions catalyzed by enzymes of the endoplasmic reticulum of hepatocytes or MICROSOMAL reactions;

b) reactions catalyzed by enzymes of other localization, NON-MICROSOMAL reactions.

That is, if the microsomal biotransforming system is represented by enzymes of the endoplasmic reticulum of liver hepatocytes, then the non-microsomal system is represented by enzymes of a different localization.

Microsomal reactions of oxidation or reduction of drugs, or rather their individual active groups in the structure of the drug molecule, occur with the participation of monooxygenase systems, the main components of which are cytochrome P-450 and phosphorus-reduced nicotine-amidadenine dinucleotide (NADPH).

These cytochromes are the primary components of the oxidative enzyme monooxygenase system. In most cases, the pharmacological activity of such metabolites becomes less than the activity of the parent substance.

Further oxidation of medicinal substances occurs under the influence of other oxidative enzymes, such as OXIDASES and REDUCTASES, with the obligatory participation of NADP and molecular oxygen.

Microsomal enzymes mainly catalyze the oxidation processes of many drugs, then the REDUCTION and HYDROLYSIS reactions of these drugs are associated not only with microsomal, but also with non-microsomal enzymes. Although non-microsomal enzymes are involved in the biotransformation of a small number of drugs, they still play an important role in their metabolism. Non-microsomal biotransformation of drugs also occurs in the liver, but can occur in blood plasma and other tissues (stomach, intestines, lungs). An example is the biotransformation of acetylcholine in blood plasma, carried out by the enzyme ESTERASE, in our case, ACETYLCHOLINESTERASE. According to such reactions, a number of commonly used drugs are biotransformed, for example, aspirin and sulfonamides.

Synthetic reactions are based on the formation of paired esters of drugs with glucuronic, sulfuric, acetic acids, as well as with glycine and glutathione, which helps to create

juice-polar compounds, highly soluble in water, slightly soluble in lipids, poorly penetrating into tissues and, in most cases, pharmacologically inactive. Naturally, these metabolites are well excreted from the body. Thus, synthetic reactions lead to the formation and synthesis of a new metabolite and are carried out using conjugation, acetylation, methylation, etc.

As an example, the biotransformation of drugs by synthetic reactions can be given the following illustration. In the liver of adults, the antibiotic chloramphenicol undergoes conjugation with clucuronic acid by 90%, and only 10% of it is excreted in the urine unchanged. The resulting glucuronides are easily biotransformed and excreted. In the same way, estrogen and glucocorticoid drugs, opium alkaloids, salicylates, barbiturates and other drugs are excreted from the body.

From the point of view of evolution, a more ancient way of biotransformation is the attachment to the xenobiotic (conjugation) of highly polar groups: glucuronic acid, sulfate, glycine, phosphate, acetyl, epoxy group, making xenobiotics more soluble in water. An evolutionarily younger path - redox (oxidation, reduction, hydrolysis reactions) is considered as the initial phase of biotransformation. The products of oxidation or reduction (I phase) are usually then subjected to conjugation (II phase). Thus, it can be said that phase I reactions of drug biotransformation are usually non-synthetic, while phase II reactions are synthetic.

As a rule, only after phase II of biotransformation, inactive or low-active compounds are formed; therefore, it is synthetic reactions that can be considered blue reactions of detoxification of xenobiotics, including drugs.

From a practical point of view, it is important that with the help of a number of means it is possible to actively influence the processes of microsomal transformation of drugs. It has been noted that both INDUCTION (increase in activity) and DEPRESSION of microgomal enzymes can develop under the influence of drugs. There are significantly more substances that stimulate biotransformation by inducing the synthesis of enzymatic proteins in the liver than substances that suppress this synthesis. These inducer substances, which are currently described more than 200, include phenobarbital, barbiturates, hexobarbital, caffeine, ethanol, nicotine, butadione, antipsychotics, diphenhydramine, quinine, cordiamine, many chlorine-containing pesticides and insecticides.

Microsomal glucuronyltranson phase is involved in the activation of liver enzymes by these substances. At the same time, the synthesis of RNA and microsomal proteins increases. It is important to remember that inductors increase not only the metabolism of drugs in the liver, but also their excretion with bile.

All these substances accelerate the processes of liver metabolism by 2-4 times only by inducing the synthesis of microsomal enzymes. At the same time, the metabolism is accelerated not only of drugs administered together with them or against their background, but also of themselves. However, there is also a large group of substances (inhibitors) that suppress and even destroy cytochrome P-450, that is, the main microsomal enzyme. These drugs include a group of local anesthetics, antiarrhythmic drugs (anaprilin or inderal, visken, eraldin), as well as cimeticine, levomycetin, butadione, anticholinesterase agents, MAO inhibitors. These substances prolong the effects of drugs administered with them. In addition, many of the inhibitors cause the phenomenon of autoinhibition of metabolism (verapamil, propranolol). It follows from the foregoing that it is necessary to take this possibility into account when combining drugs in a patient. For example, the induction of hepatic microsomal enzymes by phenobarbital underlies the use of this drug to eliminate hyperbilirubinemia in newborns with hemolytic disease.

The decrease in the effectiveness of drugs with repeated use is called tolerance. The use of the same phenobarbatal as a sleeping pill leads to the gradual development of addiction, i.e. to tolerance, which dictates the need to increase the dose of the drug. A special type of addiction is tachyphylaxis.

TACHYPHILAXIA - very quickly addictive, sometimes after the first injection of the substance. So, the introduction of ephedrine intravenously repeatedly with an interval of minutes causes a smaller rise in blood pressure than with the first injection. A similar situation can be traced when ephedrine solutions are instilled into the nose.

Substances-inducers, activating microsomal enzymes, contribute to increased excretion of vitamin D from the body, as a result of which softening of the bones can develop and a pathological fracture occurs. These are all examples of drug interactions.

It must also be remembered that pharmacological agents can be divided into 2 groups according to the rate of inactivation in the liver: the former are oxidized at a low rate, for example, diphenine, carbamazenine; the second - with medium or high speed, for example, imizin, isadrin, lidocaine, anaprilin.

In addition, the metabolism of medicinal substances depends both on the type and kind of animals, the race of the patient, and on age, gender, nutrition (in vegetarians, the rate of drug biotransformation is lower, if there are a lot of proteins in food, metabolism is enhanced), the state of the nervous system, ways of application , from the simultaneous use of other drugs.

Moreover, it is important to remember that each person has his own, genetically determined rate of biotransformation. In this regard, we can refer to the example of alcohol, when there is an individual feature of the work of alcohol dehydrogenase in an individual. These features of the individual work of enzymes depending on the genotype are studied by pharmacogenetics.

An excellent example of genetic dependence is the inactivation of the anti-tuberculosis drug isoniazid (ftivazid) by acetylation. It has been established that the rate of this process is genetically determined. There are individuals who slowly inactivate isoniazid. At the same time, its concentration in the body decreases more gradually than in people with rapid inactivation of the drug. Among the European population of slow acetylators, according to some authors, 50-58.6% are noted, and fast - up to 30-41.4%. At the same time, if the peoples of the Caucasus and the Swedes are mostly fast acetylators, then the Eskimos, on the contrary, are slow acetylators.

The dependence of individual biotransformation is studied by the science of PHARMACOGENETICS.

Slow acetylators have a higher blood concentration for a certain dose of the drug and therefore may have more side effects. Indeed, isoniazid causes complications in the form of peripheral neuropathy in 20% of patients with tuberculosis, slow acetylators, and in fast acetylators only in 3% of cases.

Liver diseases change the biotransformation of drugs in this organ. For substances that are slowly transformed in the liver, an important role is played by the function of liver cells, the activity level of which decreases with hepatitis, cirrhosis, reducing the inactivation of these substances. Such multifactorial features of drug biotransformation make it necessary to study this problem in each specific case.

The last step in the interaction of drugs with a living organism is their excretion or EXECRETION.

Drugs, with the exception of drugs for inhalation anesthesia, as a rule, are not excreted through the structures in which absorption (absorption) occurred. The main routes of excretion are the kidneys, liver, gastrointestinal tract, lungs, skin, salivary glands, sweat glands, and mother's milk. We are particularly interested in the kidneys clinically.

Excretion of drugs by the kidneys is determined by three processes carried out in the nephron:

1) passive glomerular filtration;

2) passive diffusion through the tubules or REABSORPTION;

3) active tubular secretion.

As you can see, all physiological processes in the nephron are characteristic of drugs. Non-ionized drugs that are well absorbed may be filtered in the renal glomeruli, but from the lumen of the renal tubules they may again diffuse into the cells lining the tubules. Thus, only a very small amount of the drug appears in the urine.

Ionized drugs that are poorly absorbed are excreted almost entirely by glomerular filtration and are not reabsorbed.

Passive diffusion is a bidirectional process, and drugs can diffuse through the wall of the tubules in any direction, depending on their concentration and the pH of the medium (for example, quinacrine, salicylates).

The pH value of the urine affects the excretion of some weak acids and bases. Thus, weak acids are rapidly excreted in alkaline urine, such as barbiturates and salicylates, and weak bases are rapidly excreted in an acidic environment (phenamine). Therefore, in acute poisoning with barbiturates, it is necessary to alkalize the urine, which is achieved by intravenous administration of sodium bicarbonate (soda) solutions, the latter improves the excretion of sleeping pills.

If the pH value of the urine does not correspond to the optimal value for the excretion of the drug, the action of these drugs can be prolonged.

With an alkaline urine reaction, the tubular reabsorption of weak acids is minimal, since the bulk of these substances are in an ionized state in an alkaline environment. The situation is similar for weak bases in acidic urine. The excretion of weak bases and acids can be accelerated if high diuresis is maintained by the administration of mannitol and diuretics (diuretics), and also corrected by the pH value of the urine to the optimum in relation to this drug.

With pathology of the kidneys, their ability to excrete medicinal substances is reduced. As a result, even when using normal doses of drugs, their level in the blood rises and the effect of drugs is prolonged. In this regard, when prescribing drugs such as aminoglycoside antibiotics (streptomycin, gentamicin), coumarin anticoagulants, patients with reduced kidney function (renal failure) require a special monitoring regimen.

In conclusion of this section, a few words about the term "ELIMINATING". In the literature, the terms "elimination" and "excretion" are often used interchangeably. But it must be remembered that ELIMINATION is a broader term, corresponding to the sum of all metabolic (biotransformation) and excretory processes, as a result of which the active substance disappears from the body.

The result of insufficiency of excretion or elimination may be the accumulation or cumulation of the drug in the body, in its tissues. Cumulation - (accumulator - storage) is a consequence of insufficient excretion and elimination, and, as a rule, is associated with pathology of the excretory organ (liver, gastrointestinal tract, etc.) or with increased binding to plasma proteins, which reduces the amount of substance that can be filtered in the glomeruli.

There are three (3) main ways to deal with cumulation:

1) reducing the dose of the medicinal substance;

2) a break in prescribing drugs (2-3-4 days-2 weeks);

3) at the first stage, the introduction of a large dose (dose of saturation), and then the transfer of the patient to a low, maintenance dose. Thus, for example, cardiac glycosides (digitoxin) are used.