Formation of two strands of DNA. Genetic code

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.

Some medicinal substances whose metabolic products have therapeutically important activity
medicinal substance	Active metabolite
Allopurinol	Alloxanthin
Amitriptyline	Nortriptyline
Acetylsalicylic acid*	Salicylic acid
Acetohexamide	Hydroxyhexamide
Glutethimide	4-hydroxyglutethimide
Diazelam	Desmethyldiazepam
Digitoxin	Digoxin
Imipramine	Desipramine
Cortisone	Hydrocortisone
Lidocaine	Desethyllidocaine
Methyldopa	Methylnorepinephrine
Prednisone*	Prednisolone
propranolol	4-hydroxyprolranolol
Spironolactone	canrenon
Trimeperidine	Normeperidine
Phenacetin*	Acetaminophen
Phenylbutazone	Oxyphenbutazone
Flurazepam	Desethylflurazepam
Chloral Hydrate*	Trichloroethanol
Chlordiazepoxide	Desmethylchlordiazepoxide
* prodrugs, the therapeutic effect is mainly the products of their metabolism.

Non-synthetic metabolic reactions 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, 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.

Types of drug metabolism reactions
Reaction type	medicinal substance
I. NON-SYNTHETIC REACTIONS (catalyzed by endoplasmic reticulum or non-microsomal enzymes)
Oxidation
Aliphatic hydroxylation, or oxidation of the side chain of a molecule	Thiolenthal, methohexital, pentazocine
Aromatic hydroxylation, or hydroxylation of an aromatic ring	Amphetamine, lidocaine, salicylic acid, phenacetin, phenylbutazone, chlorpromazine
O-dealkylation	phenacetin, codeine
N-dealkylation	Morphine, codeine, atropine, imipramine, isoprenaline, ketamine, fentanyl
S-dealkylation	Barbituric acid derivatives
N-oxidation	Aminazine, imipramine, morphine
S-oxidation	Aminazine
Deamination	Phenamine, hisgamine
Desulfurization	thiobarbiturates, thioridazine
Dehalogenation	Halothane, methoxyflurane, enflurane
Recovery
Restoration of the azo group	Sulfanilamide
Recovery of the nitro group	Nitrazepam, chloramphenicol
Recovery of carboxylic acids	Prednisolone
Reduction catalyzed by alcohol dehydrogenase	Ethanol, chloral hydrate
Ether hydrolysis	Acetylsalicylic acid, norzpinephrine, cocaine, procainamide
Amide hydrolysis	Lidocaine, pilocarpine, isoniazid novocainamide fentanyl
II. SYNTHETIC REACTIONS
Conjugation with glucuronic acid	Salicylic acid, morphine, paracetamol, nalorphine, sulfonamides
conjugation with sulfates	Isoprenaline, morphine, paracetamol, salicylamide
Conjugation with amino acids:
glycine	salicylic acid, nicotinic acid
glugathione	Isonicotinic acid
glutamine	Paracetamol
Acetylation	Novocainamide, sulfonamides
Methylation	Norepinephrine, histamine, thiouracil, nicotinic acid

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.

Food additives, small doses of alcohol, coffee, chlorinated insecticides (dichlorodiphenyltrichloroethane (DDT), hexachloran) are also considered active inducers of liver enzyme systems. 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 hepatic enzymes, and the second is metabolized in the liver, the dose of the latter must be increased, and when the inductor 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 a decrease in 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 using a combination of drugs, one of which inhibits liver enzymes, the metabolic rate of another drug is slowed down, its concentration in blood and the risk of side effects. 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 effect 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 significance. 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 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 of the 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). 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 may large quantities accumulate inside the cells, forming cellular depots (akrikhin). 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 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 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 levomycetin undergoes 90% conjugation with clucuronic acid, 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. More than 200 such inducers are currently described, including 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. 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, by 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.

In slow acetylators, a certain dose of the drug gives a higher concentration in the blood, and therefore they 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 very a large number 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.

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 of hepatocyte damage is the 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 diseases have different pharmacological mechanisms of 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 preparations: plant origin, synthetic medicines, animal origin, homeopathic and biologically active food supplements. 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, and 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, silydianin, 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 make it protective action 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. With 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 planta is a complex preparation 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, and 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 medicinal 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 biliary tract motility. It normalizes both too weak and increased bile secretion, relieves spasm of the sphincter of ODDI, normalizes the motor function of the biliary tract 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 the 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. are violated important processes for the body - the absorption of triglycerides necessary for the formation of chylomicrons and micelles, bile formation, protein production are reduced, metabolism and the ability of hepatocytes to perform a barrier function are disturbed. 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. In acute and severe forms of liver damage (hepatic ancestor and coma, necrosis of liver cells and toxic lesions, during operations in the hepatobiliary zone, etc.), a solution for intravenous slow administration in 5 ml dark glass ampoules containing 250 mg is used. 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. In the phosphatidylcholine molecule, glycerol, higher fatty acids, phosphoric acid and choline, all 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 of 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, allergic reactions may occur: 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 it is 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 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 integral part 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 cycle tricarboxylic acids(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 drug contains milk thistle, celandine, club-shaped 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 It is used in the complex treatment of acute and chronic liver diseases, 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 eating excessively fatty foods. Available in capsules of 30 pieces.

Essential oil- high-quality fish oil 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 components of plant materials that have antioxidant, choleretic, detoxifying effects. 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; helps to reduce inflammation and accelerate 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, Tyquanol is useful for all 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 is always a 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– it:

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 are drugs classified according to their chemical structure.

Enzymes (enzymes) are specific proteins that participate in biochemical reactions, can speed up or slow down their course. The liver produces a large amount of these compounds due to its important role in the metabolism of fats, proteins and carbohydrates. Their activity is determined by the results of a biochemical blood test. Such studies are important for assessing the condition of the liver and for diagnosing many diseases.

What it is?

Liver enzymes are a group of biologically active proteins that can be produced exclusively by the cells of this organ. They can be found on the inner or outer membrane, inside cells, or in the blood. Depending on the role of enzymes, they are divided into several categories:

• hydrolases - accelerate the breakdown complex connections on molecules;
• synthetases - take part in the reactions of synthesis of complex biological compounds from simple substances;
• transferases - are involved in the transport of molecules through membranes;
• oxidoreductases - are the main condition for the normal course of redox reactions at the cellular level;
• isomerases - necessary for the processes of changing the configuration of simple molecules;
• lyases - form additional chemical bonds between molecules.

IMPORTANT! The activity of enzymes is influenced, among other things, by the presence of other compounds (co-factors). These include proteins, vitamins and vitamin-like substances.

Groups of liver enzymes

Their function in the processes of cellular metabolism depends on the localization of liver enzymes. Thus, mitochondria are involved in energy exchange, the granular endoplasmic reticulum synthesizes proteins, the smooth endoplasmic reticulum synthesizes fats and carbohydrates, and hydrolase proteins are located on lysosomes. All the enzymes that the liver produces can be found in the blood.

Depending on what functions enzymes perform and where they are located in the body, they are divided into 3 large groups:

• secretory - after secretion by liver cells, they enter the bloodstream and are here at the maximum concentration (blood clotting factors, cholinesterase);
• indicator - normally contained inside cells and released into the blood only when they are damaged, therefore, they can serve as indicators of the degree of liver damage in its diseases (ALT, AST, and others);
• excretory - excreted from the liver with bile, and an increase in their level in the blood indicates a violation of these processes.

For the diagnosis of the condition of the liver, each of the enzymes is important. Their activity is determined in case of suspicion of underlying liver pathologies and to assess the degree of damage to the liver tissue. Diagnosis of digestive, gastrointestinal, pancreatic, and biliary tract enzymes may also be required to obtain a more complete picture.

For the determination of liver enzymes, venous blood collected in the morning on an empty stomach is required.

Enzymes that are determined for the diagnosis of liver diseases

The biochemistry of blood is milestone diagnosis of liver diseases. All pathological processes in this organ can occur with the phenomena of cholestasis or cytolysis. The first process is a violation of the outflow of bile, which is secreted by hepatocytes. With other disorders, the destruction of healthy cellular elements occurs with the release of their contents into the blood. By the presence and quantity of liver enzymes in the blood, one can determine the stage of the disease and the nature of pathological changes in the organs of the hepatobiliary tract.

Indicators of cholestasis

Cholestasis syndrome (difficulty in bile secretion) accompanies inflammatory liver diseases, impaired bile secretion and pathology of the biliary tract. These phenomena cause the following changes in biochemical analysis:

• excretory enzymes are increased;
• bile components are also increased, including bilirubin, bile acids, cholesterol, and phospholipids.

The outflow of bile can be disturbed by mechanical pressure on the bile ducts (inflamed tissue, neoplasms, stones), narrowing of their lumen and other phenomena. The complex of characteristic changes in blood parameters becomes the basis for a more detailed study of the state of the gallbladder and biliary tract.

Cytolysis indicators

Cytolysis (destruction of hepatocytes) can occur with infectious and non-contagious hepatitis or with poisoning. In this case, the contents of the cells are released, and indicator enzymes appear in the blood. These include ALT (alanine aminotransferase), AST (aspartate aminotransferase), LDH (lactate dehydrogenase), and aldolase. The higher the levels of these compounds in the blood, the greater the degree of damage to the parenchyma of the organ.

Determination of alkaline phosphatase

Alkaline phosphatase, which is found in the blood, may not only be of hepatic origin. A small amount of this enzyme is produced by the bone marrow. One can speak of liver diseases if there is a simultaneous increase in the level of alkaline phosphatase and gamma-GGT. Additionally, an increase in bilirubin levels may be detected, which indicates pathologies of the gallbladder.

Gamma-glutamyl transpeptidase in the blood

GGT usually rises with alkaline phosphatase. These indicators indicate the development of cholestasis and possible diseases of the biliary system. If this enzyme is elevated in isolation, there is a risk of minor damage to the liver tissue in the initial stages of alcoholism or other poisoning. With more serious pathologies, a simultaneous increase in liver enzymes is observed.

The final diagnosis can only be made on the basis of a comprehensive examination, which includes ultrasound

Liver transaminases (ALT, AST)

ALT (alanine aminotransferase) is the most specific liver enzyme. It is found in the cytoplasm of other organs (kidneys, heart), but it is in the hepatic parenchyma that it is present in the highest concentration. Its increase in the blood may indicate various diseases:

• hepatitis, intoxication with liver damage, cirrhosis;
• myocardial infarction;
• chronic diseases of the cardiovascular system, which are manifested by necrosis of functional tissue areas;
• muscle injury, damage or bruising;
• severe pancreatitis - inflammation of the pancreas.

AST (aspartate dehydrogenase) is found not only in the liver. It can also be found in the mitochondria of the heart, kidneys, and skeletal muscle. An increase in this enzyme in the blood indicates the destruction of cellular elements and the development of one of the pathologies:

• myocardial infarction (one of the most common causes);
• liver diseases in acute or chronic form;
• heart failure;
• injuries, inflammation of the pancreas.

IMPORTANT! In the study of blood and the determination of transferases, the ratio between them (the Ritis coefficient) matters. If it exceeds 2 AST / ALS, we can talk about serious pathologies with extensive destruction of the liver parenchyma.

lactate dehydrogenase

LDH refers to cytolytic enzymes. It is not specific, that is, it is found not only in the liver. However, its definition is important in the diagnosis of icteric syndrome. In patients with Gilbert's disease (a genetic disease that is accompanied by a violation of the binding of bilirubin), it is within the normal range. With other types of jaundice, its concentration increases.

How is the activity of substances determined?

A biochemical blood test for liver enzymes is one of the main diagnostic measures. This will require venous blood collected on an empty stomach in the morning. During the day before the study, it is necessary to exclude all factors that can affect the functioning of the liver, including the intake of alcoholic beverages, fatty and spicy foods. In the blood, a standard set of enzymes is determined:

• ALT, AST;
• total bilirubin and its fractions (free and bound).

Some groups of medicines can also affect the activity of liver enzymes. They can also change normally during pregnancy. Before the analysis, it is necessary to notify the doctor about taking any medications and about chronic diseases any organs in history.

Norms for patients of different ages

For the treatment of liver diseases, a complete diagnosis is mandatory, which includes, among other things, a biochemical blood test. The activity of enzymes is examined in a complex, since different indicators may indicate different disorders. The table shows the normal values ​​​​and their fluctuations.

Compound	Norm indicators
total protein	65-85 g/l
Cholesterol	3.5-5.5 mmol/l
total bilirubin	8.5-20.5 µmol/l
direct bilirubin	2.2-5.1 µmol/l
indirect bilirubin	Not more than 17.1 µmol/l
ALT	For men - no more than 45 units / l; For women - no more than 34 units / l
AST	For men - no more than 37 units / l; For women - no more than 30 units / l
Ritis coefficient	0,9-1,7
Alkaline phosphatase	Not more than 260 units/l
GGT	For men - from 10 to 70 units / l; For women - from 6 to 42 units / l

The enzyme ALS has the most important diagnostic value in suspected hepatitis, fatty degeneration, or cirrhosis of the liver. Its values ​​normally change over time. This compound is measured in units per liter. Normal performance at different ages will be:

• in newborns - up to 49;
• in children under 6 months - 56 or more;
• up to a year - no more than 54;
• from 1 to 3 years - up to 33;
• from 3 to 6 years - 29;
• in older children and adolescents - up to 39.

Drugs accumulate in the liver parenchyma and can cause an increase in the activity of its enzymes.

IMPORTANT! A biochemical blood test is an important, but not the only study that determines the state of the liver. Ultrasounds and additional examinations are also carried out if necessary.

Features of the definition during pregnancy

In the normal course of pregnancy, almost all enzyme indicators remain within the normal range. On the later dates a slight increase in the level of alkaline phosphatase in the blood is possible - the phenomenon is associated with the formation of this compound by the placenta. Elevated liver enzymes can be observed with gestosis (toxicosis) or indicate an exacerbation of chronic diseases.

Changes in enzyme activity in cirrhosis

Cirrhosis is the most dangerous condition in which healthy liver parenchyma is replaced by connective tissue scars. This pathology is not treated, since the restoration of the organ is possible only due to normal hepatocytes. In the blood, there is an increase in all specific and nonspecific enzymes, an increase in the concentration of bound and unbound bilirubin. The protein level, on the contrary, decreases.

A special group - microsomal enzymes

Microsomal liver enzymes are a special group of proteins that are produced by the endoplasmic reticulum. They take part in the neutralization reactions of xenobiotics (substances that are foreign to the body and can cause symptoms of intoxication). These processes take place in two stages. As a result of the first of these, water-soluble xenobiotics (with a low molecular weight) are excreted in the urine. Insoluble substances undergo a series of chemical transformations with the participation of microsomal liver enzymes, and then are eliminated in the bile into the small intestine.

The main element that is produced by the endoplasmic reticulum of liver cells is cytochrome P450. For the treatment of certain diseases, drugs-inhibitors or inducers of microsomal enzymes are used. They affect the activity of these proteins:

• inhibitors - accelerate the action of enzymes, due to which the active substances of the drugs are more quickly excreted from the body (rifampicin, carbamazepine);
• inducers - reduce the activity of enzymes (fluconazole, erythromycin and others).

IMPORTANT! The processes of induction or inhibition of microsomal enzymes are taken into account when choosing a treatment regimen for any disease. Simultaneous administration of drugs of these two groups is contraindicated.

Liver enzymes are an important diagnostic indicator for determining liver diseases. However, for a comprehensive study, it is also necessary to conduct additional tests, including ultrasound. The final diagnosis is made on the basis of clinical and biochemical analyzes of blood, urine and feces, ultrasound of the abdominal organs, if necessary - X-ray, CT, MRI or other data.

When distributed in the body, some drugs can partially linger and accumulate in various tissues. This happens mainly due to the reversible binding of drugs to proteins, phospholipids and nucleoproteins of cells. This process is called depositing. The concentration of the substance at the place of its deposition (in the depot) can be quite high. From the depot, the substance is gradually released into the blood and distributed to other organs and tissues, including reaching the site of its action. Many LVs bind to plasma proteins. Weakly acidic compounds (non-steroidal anti-inflammatory drugs, sulfonamides) bind mainly to albumins (the largest fraction of plasma proteins), and weak bases to α1-acid glycoprotein and some other plasma proteins. Protein-bound drug does not show pharmacological activity. But since this binding is reversible, part of the substance is constantly released from the complex with the protein (this happens when the concentration of the free substance in the blood plasma decreases) and has a pharmacological effect. Biotransformation (metabolism)- change in the chemical structure of medicinal substances and their physico-chemical properties under the action of body enzymes. The main focus of this process is the conversion of lipophilic substances, which are easily reabsorbed in the renal tubules, into hydrophilic polar compounds, which 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:

non-synthetic reactions (metabolic transformation);

Synthetic reactions (conjugation).

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 include 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 P-450 reductase and cytochrome P-450, a hemoprotein that 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). Restoration of medicinal substances can occur with the participation of microsomal (chloramphenicol) and non-microsomal enzymes (chloral hydrate, naloxone). Hydrolysis of medicinal substances is carried out mainly by non-microsomal enzymes (esterases, amidases, phosphatases) in blood plasma and tissues. In this case, due to the addition of water, ester, amide and phosphate bonds break in the molecules of medicinal substances. Esters undergo hydrolysis - acetylcholine, suxamethonium (hydrolyzed with the participation of cholinesterases), amides (procainamide), acetylsalicylic acid. Metabolites that are formed as a result of non-synthetic reactions may, in some cases, have a higher activity than the parent compounds. An example of increasing the activity of drugs in the process of metabolism is the use of drug precursors (prodrugs). Prodrugs are pharmacologically inactive, but they are converted into active substances in the body. In the process of biosynthetic reactions (conjugation), residues of endogenous compounds (glucuronic acid, glutathione, glycine, sulfates, etc.) or highly polar chemical groups (acetyl, methyl groups) are attached to the functional groups of molecules of medicinal substances or their metabolites. These reactions proceed with the participation of enzymes (mainly transferases) of the liver, as well as enzymes of other tissues (lungs, kidneys). Enzymes are localized in microsomes or in the cytosolic fraction. 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, with simultaneous administration of 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.

Routes of drug excretion, their significance for pharmacotherapeutic and side effects of drugs. The secretion of drugs by the salivary glands into the oral cavity.

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.

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 induction of liver microsomal enzymes is phenobarbital. Other barbiturates work in 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 (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 may also enhance the conjugation of other substances with bilirubin.

III. Decreased cellular uptake.

The guanidine derivatives used to treat arterial hypertension (guanethidine and guanadrel) are transferred to adrenergic neurons via 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.

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.

Reactions microsomal oxidation 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 short chains that end in cytochrome P 450 .

Microsomal oxidation reactions include to 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).

Cytochrome P450

The main protein of microsomal oxidation is hemoprotein - cytochrome P 450. In nature, there are up to 150 isoforms of this protein, oxidizing about 3000 different substrates. The ratio of different cytochrome P450 isoforms 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.).

Cytochrome P450 interacts with molecular oxygen and includes one oxygen atom in the substrate molecule, contributing to the appearance (intensification) of its hydrophilicity, and the other - in the water molecule. Its main reactions 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:

• NADH-cytochrome b 5 oxidoreductase, contains FAD,
• NADPH‑cytochrome P 450 ‑oxidoreductase, contains FMN and FAD.

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 P450

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 actions that have the ability to stimulate the synthesis of cytochrome P 450, NADPH-cytochrome P 450 oxidoreductase and glucuronyl transferase. Barbituric acid derivatives are a classic representative - barbiturates, also included in this group diazepam, carbamazepine, rifampicin and etc.

2. narrow spectrum and actions, i.e. stimulate one of the forms of cytochrome P 450 - aromatic polycyclic hydrocarbons (methylcholanthrene, spironolactone), ethanol.

For instance, ethanol stimulates the synthesis of the P 450 2E1 isoform (alcohol oxidase), which is involved in the metabolism of ethanol, nitrosamines, paracetamol, etc.
Glucocorticoids induce the isoform P 450 3A.

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

1. reversible

• directactions- carbon monoxide ( SO), antioxidants,
• indirectactions, i.e. influence through the intermediate products of their metabolism, which form complexes with cytochrome P 450 - erythromycin.

2. irreversible inhibitors - allopurinol, chlorpromazine, progesterone, oral contraceptives, teturam, fluorouracil,

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).

Antipyrine test

Subject takes in the morning on an empty stomach amidopyrine at the rate of 6 mg/kg of weight. 4 portions of urine are collected in the interval, respectively, from 1 to 6 hours, 6-12, 12-24 and 45-48 hours. The volume of urine is measured. Not later than 24 hours later, the urine is centrifuged or filtered. Next, the concentration of 4-aminoantipyrine and its metabolite N-acetyl-4-aminoantipyrine in the urine is examined.