The main task of pharmacodynamics is to find out where and how drugs act, causing certain effects. Thanks to the improvement of methodological techniques, these issues are solved not only at the systemic and organ, but also at the cellular, subcellular, molecular and submolecular levels. So, for neurotropic drugs, those structures of the nervous system are established, the synaptic formations of which have the highest sensitivity to these compounds. For substances that affect metabolism, the localization of enzymes in different tissues, cells and subcellular formations is determined, the activity of which changes especially significantly. In all cases, we are talking about those biological substrates - "targets" with which the drug interacts.

"Targets" for drugs

Receptors, ion channels, enzymes, transport systems, and genes serve as “targets” for drugs.

Receptors are called active groups of substrate macromolecules with which a substance interacts. Receptors that ensure the manifestation of the action of substances are called specific.

The following 4 types of receptors are distinguished (Fig.

I. Receptors that directly control the function of ion channels. This type of receptors directly coupled with ion channels include n-cholinergic receptors, GABAA receptors, glutamate receptors.

II. Receptors coupled to the effector through the "G-proteins - secondary transmitters" or "G-proteins - ion channels" system. Such receptors are available for many hormones and mediators (m-cholinergic receptors, adrenergic receptors).

III. Receptors that directly control the function of an effector enzyme. They are directly related to tyrosine kinase and regulate protein phosphorylation. Insulin receptors, a number of growth factors, are arranged according to this principle.

IV. Receptors that control DNA transcription. Unlike membrane receptors of types I-III, these are intracellular receptors (soluble cytosolic or nuclear proteins). Steroid and thyroid hormones interact with such receptors.

Considering the effect of substances on postsynaptic receptors, it should be noted the possibility of allosteric binding of substances of both endogenous (for example, glycine) and exogenous (for example, benzodiazepine anxiolytics) origin. Allosteric interaction with the receptor does not elicit a "signal". However, there is a modulation of the main mediator effect, which can be both intensified and weakened. The creation of substances of this type opens up new possibilities for regulating the functions of the central nervous system. A feature of neuromodulators of allosteric action is that they do not have a direct effect on the main mediator transmission, but only modify it in the desired direction.

The discovery of presynaptic receptors played an important role in understanding the mechanisms of regulation of synaptic transmission. The pathways of homotropic autoregulation (the action of a releasing mediator on presynaptic receptors of the same nerve ending) and heterotropic regulation (presynaptic regulation due to another mediator) of mediator release were studied, which made it possible to re-evaluate the features of the action of many substances. This information also served as the basis for a targeted search for a number of drugs (for example, prazosin).

The affinity of a substance for a receptor, leading to the formation of a complex “substance-receptor” with it, is denoted by the term “affinity”. The ability of a substance, when interacting with a receptor, to stimulate it and cause one or another effect is called intrinsic activity.

Figure 1. Types of molecular targets for drug action.

A molecular target is a molecule or molecular assembly that has a specific binding site for a biologically active compound. The molecular target can be membrane proteins that recognize hormones or neurotransmitters (receptors), as well as ion channels, nucleic acids, carrier molecules or enzymes. As can be seen from Figure 2, not all drug compounds act on receptors. Most drugs must bind to a molecular target to be effective, but there are exceptions. Already in the first studies of the effects of drugs on animal tissues at the end of the 19th century. it became clear that the majority of PAVs have a specific effect in certain tissues, i.e. a compound that has an effect on one type of tissue may not affect another; the same substance can have completely different effects on different tissues. For example, the alkaloid pilocarpine, like the neurotransmitter acetylcholine, causes contraction of intestinal smooth muscles and slows down the heart rate. In view of these phenomena, Samuel Langley (1852-1925) in 1878, based on a study of the effects of the alkaloids pilocarpine and atropine on salivation, suggested that "there are some receptor substances ... with which both can form compounds." Later, in 1905, while studying the effects of nicotine and curare on skeletal muscle, he discovered that nicotine induces contractions when it acts on certain small areas of the muscle. Langley concluded that the "receptor substance" for nicotine is located at these sites and that curare acts by blocking the interaction of nicotine with the receptor.

Figure 2. Efficacy against endogenous agonist.

Thus, it is obvious that the action of some compounds may be due not so much to the development of a biological response to binding to a molecular target, but rather to an obstacle to the binding of an endogenous ligand. Indeed, if we consider the interaction of the ligand and the receptor, it can be noted that currently existing drug compounds can play the role of both an agonist and an antagonist. Figure 3 shows a more detailed classification of ligands in relation to the effects caused by them. Agonists differ in the strength and direction of the physiological response elicited by them. This classification is not related to the affinity of the ligands and is based only on the magnitude of the receptor response. Thus, the following classes of agonists can be distinguished:

o Superagonist - a compound capable of eliciting a stronger physiological response than an endogenous agonist.

o Full agonist - a compound that elicits the same response as an endogenous agonist (eg, isoprenaline, β-adrenergic receptor agonist).

o If there is less response, the compound is called a partial agonist (for example, aripiprazole is a partial agonist of dopamine and serotonin receptors).

o If the receptor has a basal (constitutive) activity, some substances - inverse agonists - can reduce it. In particular, inverse agonists of GABA A receptors have anxiogenic or spasmogenic effects, but can enhance cognitive abilities.

Considering the binding mechanism of the ligand and the receptor molecule, it can be seen that the specificity and strength of binding is due to the structural features of both components. In particular, an important role is played by the active center of proteins - a certain part of a protein molecule, as a rule, located in its deepening ("pocket"), formed by amino acid radicals collected at a certain spatial site during the formation of a tertiary structure and capable of complementary binding to a ligand. In the linear sequence of the polypeptide chain, the radicals that form the active center can be located at a considerable distance from each other.

The high specificity of protein binding to the ligand is provided by the complementarity of the structure of the active center of the protein to the structure of the ligand. Complementarity is understood as the spatial and chemical correspondence of interacting molecules. The ligand must be able to enter and spatially coincide with the conformation of the active site. This coincidence may be incomplete, but due to the conformational lability of the protein, the active center is capable of slight changes and is "adjusted" to the ligand. In addition, bonds must arise between the functional groups of the ligand and the amino acid radicals that form the active site, which hold the ligand in the active site. The bonds between the ligand and the active center of the protein can be both non-covalent (ionic, hydrogen, hydrophobic) and covalent. The active site of a protein is a site relatively isolated from the surrounding protein environment, formed by amino acid residues. In this area, each residue, due to its individual size and functional groups, forms the "relief" of the active center.

The combination of such amino acids into a single functional complex changes the reactivity of their radicals, just as the sound of a musical instrument in an ensemble changes. Therefore, the amino acid residues that make up the active site are often called the "ensemble" of amino acids.

The unique properties of the active center depend not only on the chemical properties of the amino acids that form it, but also on their exact mutual orientation in space. Therefore, even minor violations of the general conformation of the protein as a result of point changes in its primary structure or environmental conditions can lead to a change in the chemical and functional properties of radicals that form the active center, disrupt the binding of the protein to the ligand and its function. During denaturation, the active center of proteins is destroyed, and their biological activity is lost.

The active center is often formed in such a way that the access of water to the functional groups of its radicals is limited; conditions are created for the ligand to bind to amino acid radicals.

In some cases, the ligand is attached to only one of the atoms with a certain reactivity, for example, the attachment of O 2 to the iron of myoglobin or hemoglobin. However, the properties of this atom to selectively interact with O 2 are determined by the properties of the radicals surrounding the iron atom in the theme. Heme is also found in other proteins such as cytochromes. However, the function of the iron atom in cytochromes is different, it serves as an intermediary for the transfer of electrons from one substance to another, while iron becomes either di- or trivalent.

The ligand-protein binding site is often located between domains. For example, the proteolytic enzyme trypsin, which is involved in the hydrolysis of peptide bonds of food proteins in the intestine, has 2 domains separated by a groove. The inner surface of the groove is formed by the amino acid radicals of these domains, which are located far from each other in the polypeptide chain (Ser 177, His 40, Asp 85).

Different domains in a protein can move relative to each other when interacting with a ligand, which facilitates the further functioning of the protein. As an example, consider the work of hexokinase, an enzyme that catalyzes the transfer of a phosphorus residue from ATP to a glucose molecule (during its phosphorylation). The active site of hexokinase is located in the cleft between the two domains. When hexokinase binds to glucose, the surrounding domains approach each other, and the substrate is trapped, which facilitates its further phosphorylation.

The main property of proteins that underlies their functions is the selectivity of binding specific ligands to certain parts of the protein molecule.

Ligand classification

· Ligands can be inorganic (often metal ions) and organic substances, low molecular weight and high molecular weight substances;

· There are ligands that change their chemical structure when attached to the active center of the protein (changes in the substrate in the active center of the enzyme);

· There are ligands that bind to the protein only at the moment of functioning (for example, O 2 transported by hemoglobin), and ligands that are permanently bound to the protein, which play an auxiliary role in the functioning of proteins (for example, iron, which is part of hemoglobin).

In cases where the amino acid residues that form the active center cannot ensure the functioning of a given protein, non-protein molecules can attach to certain parts of the active center. So, in the active center of many enzymes there is a metal ion (cofactor) or an organic non-protein molecule (coenzyme). The non-protein part, which is tightly bound to the active center of the protein and is necessary for its functioning, is called the "prostatic group". Myoglobin, hemoglobin and cytochromes have a prosthetic group in the active center - heme containing iron.

The joining of protomers in an oligomeric protein is an example of the interaction of high molecular weight ligands. Each protomer, connected to other protomers, serves as a ligand for them, just as they serve for it.

Sometimes the attachment of a ligand changes the conformation of the protein, resulting in the formation of a binding site with other ligands. For example, the protein calmodulin, after binding to four Ca 2+ ions in specific sites, acquires the ability to interact with some enzymes, changing their activity.

An important concept in the theory of interaction between a ligand and an active center of a biological target is “complementarity”. The active center of the enzyme must correspond in a certain way to the ligand, which is reflected in some requirements for the substrate.

Figure 3. Scheme of interaction between ligand and molecular target.

For example, it is expected that for a successful interaction, it is necessary to match the sizes of the active center and the ligand (see position 2 in Figure 3), which makes it possible to increase the specificity of the interaction and protect the active center from obviously unsuitable substrates. At the same time, when the “active center-ligand” complex appears, the following types of interactions are possible:

· Van der Waals bonds (position 1, figure 3), caused by fluctuations of electron clouds around oppositely polarized neighboring atoms;

· Electrostatic interactions (position 3, figure 3), arising between oppositely charged groups;

· Hydrophobic interactions (position 4, figure 3) due to the mutual attraction of non-polar surfaces;

· Hydrogen bonds (position 5, figure 3), arising between a mobile hydrogen atom and electronegative atoms of fluorine, nitrogen or oxygen.

Despite the relatively low strength of the described interactions (in comparison with covalent bonds), one should not underestimate their importance, which is reflected in the increase in the binding affinity.

Summarizing the above, it can be noted that the process of binding of a ligand and a molecular target is a highly specific process, controlled by both the size of the ligand and its structure, which makes it possible to ensure the selectivity of the interaction. Nevertheless, an interaction between a protein and a substrate that is not characteristic of it is possible (so-called competitive inhibition), which is expressed in binding to an active site with a similar, but not target, ligand. It should be noted that competitive inhibition is possible both in vivo (inhibition by malonate of the enzyme succinate dehydrogenase, inhibition of fumarate hydratase by pyromellitic acid), and artificially, while taking medications (inhibition of monoamine oxidase by iproniazide, nialamide, inhibition by dacid structure inhibition of angiotensin-converting enzyme by captopril, enalapril).

Thus, it is possible to purposefully change the activity of many molecular systems using synthetic compounds with a structure similar to natural substrates.

However, a superficial understanding of the mechanisms of interaction between ligands and molecular targets can be extremely dangerous and often lead to tragic consequences. The most famous case can be considered the so-called. "Thalidomide tragedy", which led to the birth of thousands of children with congenital malformations due to the intake of an insufficiently studied drug compound thalidomide by pregnant women.

Lecture 3. Basic questions of pharmacodynamics

Local and resorptive action of drugs

The action of a substance, which manifests itself at the site of its application, is called local. For example, enveloping agents coat the mucous membrane, preventing irritation of the afferent nerve endings. However, a truly local effect is very rarely observed, since substances can either be partially absorbed or have a reflex effect.

The action of a substance that develops after its absorption and entry into the general bloodstream, and then into the tissues, is called resorptive. The resorptive effect depends on the route of administration of the drug and its ability to penetrate biological barriers.

With local and resorptive action, drugs have either a direct or reflex effect. The direct effect is realized at the site of direct contact of the substance with the tissue. With a reflex effect, substances affect extero- or interoreceptors, therefore the effect is manifested by a change in the state of either the corresponding nerve centers or executive organs. So, the use of mustard plasters for pathology of the respiratory system reflexively improves their trophism (through the exteroreceptors of the skin).

The main task pharmacodynamics- to find out where and how drugs act, causing certain effects, that is, to establish the targets with which drugs interact.

Receptors, ion channels, enzymes, transport systems, and genes act as targets for drugs. Receptors are called active groups of substrate macromolecules with which a substance interacts. The receptors that provide the manifestation of the action of a substance are called specific.

There are 4 types of receptors:

§ receptors that directly control the function of ion channels (H-cholinergic receptors, GABAA receptors);

§ receptors coupled to the effector through the system "G-proteins-secondary transmitters" or "G-proteins-ion channels". Such receptors are available for many hormones and mediators (M-cholinergic receptors, adrenergic receptors);

§ receptors that directly control the function of the effector enzyme. They are directly related to tyrosine kinase and regulate the phosphorylation of proteins (insulin receptors);

§ receptors for DNA transcription. These are intracellular receptors. Steroid and thyroid hormones interact with them.

The affinity of a substance for a receptor, leading to the formation of a complex "substance-receptor" with it, is denoted by the term "affinity". The ability of a substance, when interacting with a specific receptor, to stimulate it and cause one or another effect is called intrinsic activity.

Target is a molecule with a binding site for a drug. This molecule may contain membrane proteins that recognize hormones or neurotransmitters (receptors), as well as ion channels, nucleic acids, carrier molecules or enzymes. But not all drugs act on receptors.

Most medicines must bind to a molecular target in order to have an effect, but there are exceptions. Already in the first studies of the effects of drugs on animal tissues at the end of the 19th century. it became clear that most drugs have a specific effect in certain tissues, i.e .:

A drug that works on one type of tissue may not work on another;
a medicine can have very different effects on different tissues.

For example, alkaloid pilocarpine Like the neurotransmitter acetylcholine, it causes contraction of intestinal smooth muscles and slows down the heart rate. In view of these phenomena, Samuel Langley (1852-1925) in 1878, based on a study of the effects of the alkaloids pilocarpine and atropine on salivation, suggested that "there are some receptor substances ... with which both can form compounds."

Later in 1905 g., studying the effects of nicotine and curare on skeletal muscle, he found that nicotine causes contractions when it acts on certain small areas of muscle. Langley concluded that the "receptor substance" for nicotine is located at these sites and that curare acts by blocking the interaction of nicotine with the receptor.

It is believed that Paul Ehrlich(1854-1915) independently developed the theory of receptors, observing how many organic dyes selectively stain specific components of the cell. In 1885, he suggested that cells have "side chains", or "receptors," to which drugs or toxins can bind to act. Ehrlich is still known for his idea of ​​a "magic bullet" - a chemical compound formed to detect selective toxicity, for example, an infectious agent.

Besides, Ehrlich synthesized organic derivatives of arsenic, which were previously used in treatment. Developing the theory of receptors, Ehrlich was the first to show that the rapid reversibility of the action of alkaloids indicates fragile (non-covalent) chemical bonds between the drug and the receptors.

Recent advances in molecular biology disclose the nature of the drug-receptor bond at the molecular level. Today, a receptor is understood as a specific molecular structure that acts as a molecular target for a group of corresponding drugs (previously, the binding center was not defined separately from the molecular target, and the whole complex as a whole was considered as a receptor).

For drugs acting on enzymes, an enzyme is a molecular target. The receptor is the part of the enzyme that binds to the drug. For most drugs, molecular targets are proteins, carbohydrates, lipids, and other macromolecules that the drugs target. From this position, molecular targets are more accurately identified than other receptors.

Receptors today identified and characterized using molecular biology methods. Some types of drugs can be easily explained without involving human molecular targets. These types of drugs include antacids (buffers) that reduce stomach acid, form-forming laxatives, and complexing agents. There are substances whose mechanism of action is characterized by the absence of clear chemical specificity. A prime example is gaseous and volatile general anesthetics, including the inert gas xenon.

For these drugs it is practically impossible to determine a binding site or a single molecular target. However, their pharmacological effects are likely to be due to their action on a membrane component (eg, voltage- or ligand-dependent ion channels). This component is a molecular target for anesthetics.

Pharmacodynamics is a section of clinical pharmacology that studies the mechanisms of action, the nature, strength and duration of the pharmacological effects of drugs used in clinical practice.

Ways of drug exposure to the human body

Most drugs, by binding to receptors or other target molecules, form a "drug-receptor" complex, while certain physiological or biochemical processes (or their quantitative change) are triggered in the human body. In this case, they talk about the direct action of drugs. The structure of a direct-acting drug, as a rule, is similar to the structure of an endogenous mediator (however, when a drug and a mediator interact with a receptor, various effects are often recorded).

Drug groups

For convenience, let us take the value of the effect of the endogenous mediator that binds to the receptor, equal to one. There is a drug classification based on this assumption.

Agonists are drugs that bind to the same receptors as endogenous mediators. Agonists produce an effect equal to one (or greater than one).

Antagonists - drugs that bind to the same receptors as endogenous mediators; do not have any effect (in this case, they speak of "zero effect").

Partial agonists or antagonist agonists are drugs that bind to the same receptors as endogenous mediators. The effect recorded when a partial agonist interacts with a receptor is always greater than zero, but less than one.

All natural mediators are agonists of their receptors.

Often, an indirect effect is noted, which consists in changing the activity of target molecules under the influence of drugs (thus affecting various metabolic processes).

Drug target molecules

A drug, by binding to a target molecule belonging to a cell (or located extracellularly), modifies its functional status, leading to an increase, decrease or stabilization of phylogenetically determined reactions of the organism.

Receptors.

- Membrane (type I, II and III receptors).

- Intracellular (type IV receptors).

Non-receptor target molecules of the cytoplasmic membrane.

- Cytoplasmic ion channels.

- Nonspecific proteins and lipids of the cytoplasmic membrane.

Immunoglobulin target molecules.

Enzymes.

Inorganic compounds (e.g. hydrochloric acid and metals).

Target molecules have complementarity to endogenous mediators and corresponding drugs, which consists in a certain spatial arrangement of ionic, hydrophobic, nucleophilic or electrophilic functional groups. Many drugs (1st generation antihistamines, tricyclic antidepressants and some others) can bind to morphologically similar, but functionally different target molecules.

Types of drug bonds with target molecules

The weakest bonds between the drug and the target molecule are van der Waals bonds due to dipole interactions; most often, the specificity of the interaction between the drug and the target molecule is determined. The hydrophobic bonds characteristic of steroid drugs are stronger. The hydrophobic properties of glucocorticosteroid hormones and the lipid bilayer of the plasma membrane allow such drugs to easily penetrate through the cytoplasmic and intracellular membranes into the cell and nucleus to their receptors. Even stronger hydrogen bonds are formed between the hydrogen and oxygen atoms of neighboring molecules. Hydrogen and van der Waals bonds arise in the presence of complementarity between drugs and target molecules (for example, between an agonist or antagonist and a receptor). Their strength is sufficient for the formation of the drug-receptor complex.

The strongest bonds are ionic and covalent. Ionic bonds are formed, as a rule, between metal ions and residues of strong acids (antacids) during polarization. When a drug is combined with a receptor, irreversible covalent bonds arise. Antagonis-

you of irreversible action bind to receptors covalently. The formation of coordination covalent bonds is of great importance. Stable chelate complexes (for example, the combination of a drug and its antidote, unitiol * with digoxin) is a simple model of a coordination covalent bond. When a covalent bond is formed, the target molecule is usually turned off. This explains the formation of a persistent pharmacological effect (the antiplatelet effect of acetylsalicylic acid is the result of its irreversible interaction with platelet cyclooxygenase), as well as the development of some side effects (the ulcerogenic effect of acetylsalicylic acid is a consequence of the formation of an inextricable connection between this drug and cyclooxygenase of the cells of the gastric mucosa).

Non-receptor plasma membrane target molecules

Drugs used for inhalation anesthesia are an example of drugs that bind to non-receptor target molecules of the plasma membrane. Means for inhalation anesthesia (halothane, enflurane *) nonspecifically bind to proteins (ion channels) and lipids of the plasma membrane of central neurons. There is an opinion that as a result of such binding, drugs disrupt the conductivity of ion channels (including sodium channels), leading to an increase in the threshold of the action potential and a decrease in the frequency of its occurrence. Means for inhalation anesthesia, connecting with the elements of the membranes of central neurons, cause a reversible change in their ordered structure. This fact is confirmed by experimental studies: anesthetized animals quickly come out of the state of general anesthesia when they are placed in a hyperbaric chamber, where membrane disorders are restored.

Non-receptor plasma structures (voltage-gated sodium channels) also serve as target molecules for local anesthetics. The drugs, by binding to the voltage-dependent sodium channels of axons and central neurons, block the channels, and, thus, disrupt their conductivity for sodium ions. As a result, there is a violation of cell depolarization. Therapeutic doses of local anesthetics block the conduction of peripheral nerves, and their toxic amounts also inhibit the central neurons.

Some drugs lack their own target molecules. However, these drugs act as substrates for many metabolic reactions. There is a concept of "substrate action" of drugs:

they are used to compensate for the lack of various substrates necessary for the body (for example, amino acids, vitamins, vitamin-mineral complexes and glucose).

Receptors

Receptors are protein macromolecules or polypeptides, often combined with polysaccharide branches and residues of fatty acids (glycoproteins, lipoproteins). Each drug can be compared with a key that matches its lock - a specific receptor for a given substance. However, only a portion of the receptor molecule, called the binding site, represents the keyhole. The drug, combining with the receptor, potentiates the formation of conformational changes in it, leading to functional changes in other parts of the receptor molecule.

A typical receptor pattern includes four stages.

Binding of drugs to a receptor located on the cell surface (or intracellularly).

Formation of the LS-receptor complex and, consequently, a change in the conformation of the receptor.

Signal transmission from the LS-receptor complex to the cell through various effector systems that amplify and interpret this signal many times over.

Cellular response (fast and delayed).

There are four pharmacologically significant types of receptors.

Receptors are ion channels.

G-protein coupled receptors.

Receptors with tyrosine kinase activity.

Intracellular receptors. Membrane receptors

Receptors of types I, II and III are built into the plasma membrane - transmembrane proteins in relation to the cell membrane. Type IV receptors are located intracellularly - in the nucleus and other subcellular structures. In addition, immunoglobulin receptors are secreted, which are glycoprotein macromolecules.

Type I receptors have the shape and structure of ion channels, have binding sites for a specific drug or mediator that induces the opening of the ion channel formed by the receptor. One of the representatives of type I receptors, the N-cholinergic receptor, is a glycoprotein consisting of five transmembrane polypeptide subunits. There are four types of subunits - α, β, γ and δ type. The glycoprotein contains one subunit of β, γ and δ types and

two α subunits. Transmembrane polypeptide subunits have the form of cylinders penetrating the membrane and surrounding a narrow channel. Each type of subunit encodes its own gene (however, the genes have significant homology). Acetylcholine binding sites are located at the “extracellular ends” of the α-subunits. When the drug binds to these sites, conformational changes are observed, leading to the expansion of the channel and the facilitation of the conductivity of sodium ions, and, consequently, to the depolarization of the cell.

Type I receptors, in addition to the N-cholinergic receptor, also include the GABA A -receptor, glycine and glutamate receptors.

G-protein coupled receptors (type II) are the largest group of receptors found in the human body; perform important functions. Most neurotransmitters, hormones and drugs bind to type II receptors. The most widespread cellular receptors of this type include vasopressin and angiotensin, α-adrenergic receptors, β-adrenergic receptors and m-cholinergic receptors, opiate and dopamine, adenosine, histamine and many other receptors. All of the above receptors are the targets of drugs that make up extensive pharmacological groups.

Each receptor of the second type is a polypeptide chain with an N-terminus (located in the extracellular environment) and a C-terminus (located in the cytoplasm). In this case, the polypeptide chain of the receptor permeates the plasma membrane of the cell seven times (it has seven transmembrane segments). Thus, the structure of the type II receptor can be compared with a thread that alternately sutures tissue on both sides seven times. The specificity of various receptors of the second type depends not only on the amino acid sequence, but also on the length and ratio of "loops" protruding outward and into the cell.

Receptors of the second type form complexes with membrane G-proteins. G-proteins are composed of three subunits: α, β and γ. After binding of the receptor to the drug, the drug-receptor complex is formed. Then conformational changes occur in the receptor. G-protein, binding by one or two subunits with their "targets", activates or inhibits them. Adenylate cyclase, phospholipase C, ion channels, cyclic guanosine monophosphate (cGMP) -phosphodiesterase - G-protein targets. Typically, activated enzymes transmit and amplify a “signal” through secondary messenger systems.

Receptors with tyrosine kinase activity

Receptors with tyrosine kinase activity (type III) - receptors for peptide hormones that regulate growth, differentiation and

development. Peptide hormones include, for example, insulin, epidermal growth factor, platelet growth factor. Typically, binding of a receptor to a hormone activates tyrosine protein kinase, which is the cytoplasmic portion (domain) of the receptor. The target of protein kinase is a receptor with the ability to autophosphorylation. Each polypeptide receptor has one transmembrane segment (domain).

However, as studies have shown, not tyrosine protein kinase, but guanylate cyclase, which catalyzes the formation of a secondary messenger cGMP, performs the functions of the cytoplasmic domain of the atrial natriuretic peptide receptor.

Intracellular receptors

Intracellular receptors (type IV) include receptors for glucocorticosteroid and thyroid hormones, as well as receptors for retinoids and vitamin D. The group of intracellular receptors includes receptors not associated with the plasma membrane, localized inside the cell nucleus (this is the main difference).

Intracellular receptors are soluble DNA-binding proteins that regulate the transcription of specific genes. Each type IV receptor consists of three domains - hormone-binding, central, and N-terminal (domain of the N-terminus of the receptor molecule). These receptors qualitatively and quantitatively regulate the level of transcription of a certain "set" of genes specific to each receptor, and also cause a modification of the biochemical and functional status of the cell and its metabolic processes.

Receptor effector systems

There are various ways of transmitting signals formed during the functioning of receptors to the cell. The signaling pathway depends on the type of receptor (Table 2-1).

The main secondary messengers are cyclic adenosine monophosphate (cAMP), calcium ions, inositol triphosphate, and diacylglycerol.

Immunoglobulins (immunoglobulin receptors)

With the help of immunoglobulin receptors, cells have the ability to "recognize" each other or antigens. As a result of the interaction of receptors, adhesion of a cell to a cell or a cell to an antigen occurs. This type of receptor also includes antibodies that circulate freely in extracellular fluids and are not associated with cellular structures. Antibodies, "labeling" antigens for subsequent phagocytosis, are responsible for the development of humoral immunity.

Table 2-1. Receptor effector systems

Receptor type Receptor example Signal transmission methods

The type of immunoglobulins includes receptors that perform the function of "signaling" in the formation of various types and phases of the immune response and immune memory.

The main representatives of the immunoglobulin type receptors (superfamily).

Antibodies - immunoglobulins (Ig).

T-cell receptors.

MHC I and MHC II glycoproteins (Major Histocompatibility Complex- the main histocompatibility complex).

Cell adhesion glycoproteins (e.g. CD2, CD4 and CD8).

Some polypeptide chains of the CD3 complex associated with T-cell receptors.

Fc receptors located on different types of leukocytes (lymphocytes, macrophages, neutrophils).

The functional and morphological isolation of immunoglobulin receptors allows them to be distinguished into a separate type.

Enzymes

Many drugs, by binding to enzymes, reversibly or irreversibly inhibit or activate them. Thus, anticholinesterase agents enhance the action of acetylcholine by blocking the enzyme that breaks it down, acetylcholinesterase. Carbonic anhydrase inhibitors are a group of diuretics that indirectly (under the influence of carbonic anhydrase) reduce the reabsorption of sodium ions in the proximal tubules. NSAIDs are cyclooxygenase inhibitors. However, acetylsalicylic acid, unlike other NSAIDs, irreversibly blocks cyclooxygenase by acetylating the serine (amino acid) residues in the enzyme molecule. There are two generations of monoamine oxidase (MAO) inhibitors. MAO inhibitors - drugs belonging to the group of antidepressants. First-generation MAO inhibitors (such as phenelzine and isocarboxazid) irreversibly block the enzyme that oxidizes monoamines such as norepinephrine * and serotonin (deficiencies are found in depression). A new generation of MAO inhibitors (eg moclobemide) inhibits the enzyme reversibly; at the same time, less severity of side effects (in particular, "tyramine" syndrome) is noted.

Inorganic compounds

There are drugs that specifically neutralize or bind active forms of various inorganic compounds. So, antacids neutralize the excess of hydrochloric acid in gastric juice, reduce

shaya its damaging effect on the mucous membrane of the stomach and duodenum.

Chelating substances (chelating agents) combine with certain metals to form chemically inert complex compounds. This effect is used in the treatment of poisoning caused by ingestion (or inhalation) of substances containing various metals (arsenic, lead, iron, copper).

Target molecules located on foreign organisms

The mechanisms of action of antibacterial, antiprotozoal, anthelmintic, antifungal and antiviral drugs are very diverse. Taking antibacterial drugs, as a rule, leads to disruption of various stages of the synthesis of the bacterial cell wall (for example, to the synthesis of defective proteins or RNA in a bacterial cell) or to a change in other mechanisms for maintaining the vital activity of the microorganism. Suppression or eradication of the infectious agent is the main goal of treatment.

The mechanism of the bactericidal action of β-lactam antibiotics, glycopeptides and isoniazid is the blockade of various stages of the synthesis of the cell wall of microorganisms. All β-lactam antibiotics (penicillins, cephalosporins, carbapenems, and monobactams) have a similar mode of action. Penicillins produce a bactericidal effect by binding to the penicillin-binding proteins of bacteria (they function as enzymes at the final stage of the synthesis of the main component of the bacterial cell wall - peptidoglycan). The commonality of the mechanism of action of β-lactam antibiotics is to create obstacles for the formation of bonds between polymer chains of peptidoglycans using pentaglycine bridges (part of the structure of antibacterial drugs resembles the D-alanyl-D-alanine-peptide chain of the bacterial cell wall). Glycopeptides (vancomycin and teicoplanin *) interfere with cell wall synthesis in a different way. So, vancomycin has a bactericidal effect, combining with the free carboxyl group of the pentapeptide; thus, a spatial obstacle arises

elongation (lengthening) of the peptidoglycan tail. Isoniazid (anti-tuberculosis drug) inhibits the synthesis of mycolic acids, a structural component of the mycobacterial cell wall.

The mechanism of the bactericidal action of polymyxins is to disrupt the integrity of the cytoplasmic membrane of bacteria.

Aminoglycosides, tetracyclines, macrolides and chloramphenicol * inhibit bacterial cell protein synthesis. Bacterial ribosomes (50S subunits and 30S subunits) and human ribosomes (6OS subunits and 40S subunits) have different structures. This explains the selective effect of the named groups of medicinal substances on microorganisms. Aminoglycosides and tetracyclines bind to the 30S subunit of the ribosome and inhibit the binding of aminoacyl tRNA to the A site of this tRNA. In addition, aminoglycosides interfere with mRNA reading by blocking protein synthesis. Levomycetin * alters the process of transpeptidation (transfer of the growing amino acid chain on the ribosome from the P-site to the A-site to the newly brought tRNA amino acids). Macrolides bind to the 50S-subunit of the ribosome and inhibit the translocation process (transfer of the amino acid chain from the A-site to the P-site).

Quinolones and fluoroquinolones inhibit DNA gyrases (topoisomerase II and topoisomerase IV) - enzymes that help to twist bacterial DNA into a spiral, which is necessary for its normal functioning.

Sulfonamides inhibit dihydropteroate synthetase, thereby blocking the synthesis of precursors of purines and pyrimidines (dihydropteric and dihydrofolic acids) required for the construction of DNA and RNA. Trimethoprim inhibits dihydrofolate reductase (the affinity for the bacterial enzyme is very high), disrupting the formation of tetrahydrofolic acid (a precursor of purines and pyrimidines) from dihydrofolic. So, sulfonamides and trimethoprim act in synergy, blocking different stages of the same process - the synthesis of purines and pyrimidines.

5-Nitroimidazoles (metronidazole, tinidazole) have a selective bactericidal effect against bacteria whose enzyme systems are capable of reducing the nitro group. The active reduced forms of these drugs, disrupting DNA replication and protein synthesis, inhibit tissue respiration.

Rifampicin (an anti-tuberculosis drug) specifically inhibits RNA synthesis.

Antifungal and antiviral agents have some similarities in their mechanisms of action. Derivatives of imidazole and triazole inhibit the synthesis of ergosterol, the main structural component

nent of the fungal cell wall, and polyene antibacterial drugs (amphotericin, nystatin) bind to it. Flucytosine (antifungal drug) blocks the synthesis of fungal DNA. Many antiviral drugs (for example, acyclovir, idoxuridine, zidovudine - nucleoside analogs) also inhibit the synthesis of viral DNA and

N-cholinergic receptors of neuromuscular synapses of helminths are target molecules of such anthelmintic drugs as pyrantel and levamisole. Stimulation of these receptors causes total spastic paralysis.

The nature, strength and duration of drug action

The duration, strength and method of interaction between the drug and the target molecule characterizes the pharmacological response (as a rule, it is caused by the direct action of the drug, less often - by a change in the coupled system, and only in isolated cases a reflex pharmacological response is recorded).

The main effect of drugs is considered to be the effect of the substance used in the treatment of this patient. Other pharmacological effects of the drug in question are called minor (or minor). Functional disorders caused by taking the drug are considered as adverse reactions (see chapter 4 "Side effects of drugs"). One and the same effect in one case may be the main one, and in the other it may be secondary.

Allocate generalized or local (local) actions of drugs. Local effects are observed when using ointments, powders or drugs taken orally, not absorbed in the gastrointestinal tract, or, conversely, well absorbed, but concentrated in one organ. In most cases, when drugs penetrate into biological body fluids, its pharmacological effect can be formed anywhere in the body.

The ability of many drugs to influence, during monotherapy, various levels of regulation and processes of cellular metabolism simultaneously in several functional systems or organs proves the polymorphism of their pharmacological effect. On the other hand, such a wide variety of targets at all levels of regulation explains the same pharmacological effect of drugs with different chemical structures.

Chaotic movement of molecules allows drugs to be close to a certain area (with high affinity for receptors); in this case, the desired effect is achieved even with the appointment of low concentrations of drugs. With an increase in the concentration of drug molecules,

they react with the active centers of other receptors (for which they have less affinity); as a result, the number of pharmacological effects increases, and their selectivity also disappears. For example, β 1 -adrenergic blockers in small doses inhibit only β 1 -adrenergic receptors. However, with an increase in the dose of β 1 -adrenergic blockers, their selectivity disappears, while a blockade of all β-adrenergic receptors is noted. A similar picture is observed with the appointment of β-adrenergic agonists. Thus, with an increase in the dose of drugs, along with a slight increase in the clinical effect, an increase in the number of side effects is always recorded, and significantly.

The state of the target molecule (both in the main and in the conjugated system) must be taken into account when predicting and assessing the effectiveness of the drug action. Often, the prevalence of side effects over the main action is due to a violation of the physiological balance due to the nature of the disease or the individual characteristics of the patient.

Moreover, drugs themselves can change the sensitivity of target molecules by varying the rate of their synthesis or degradation or by inducing the formation of various target modifications under the influence of intracellular factors - all this leads to a change in the pharmacological response.

According to the pharmacological effects, drugs can be divided into two groups - substances with specific and nonspecific effects. Drugs of nonspecific action include drugs that cause the development of a wide range of pharmacological effects by influencing various systems of biological support. This group of drugs includes, first of all, substrate substances: vitamin complexes, glucose and amino acids, macronutrients and trace elements, as well as plant adaptogens (for example, ginseng and eleutherococcus). Due to the lack of clear boundaries that determine the main pharmacological effect of these drugs, they are prescribed to a large number of patients with various diseases.

If a drug acts (as an agonist or antagonist) on the receptor apparatus of certain systems, its effect is considered as specific. This group of drugs includes antagonists and agonists of various subtypes of adrenergic receptors, cholinergic receptors, etc. The organ arrangement of receptors does not affect the effect produced by drugs with a specific action. Therefore, despite the specificity of the action of these drugs, different pharmacological responses are recorded. Thus, acetylcholine causes contraction of the smooth muscles of the bronchi, the digestive tract, and increases the secretion of the salivary glands. Atropine has the opposite effect. Voter-

ness or selectivity of the action of drugs is noted only when the activity of the system changes only in a certain part of it or in one organ. For example, propranolol blocks all β-adrenergic receptors of the sympathoadrenal system. Atenolol - a selective β 1 -adrenergic blocker - blocks only β 1 -adrenergic receptors of the heart and does not affect β 2 -adrenergic receptors of the bronchi (when using small doses). Salbutamol selectively stimulates β 2 -adrenergic receptors of the bronchi, having a slight effect on β 1 -adrenergic receptors of the heart.

Selectivity (selectivity) of drug action - the ability of a substance to accumulate in tissue (depending on the physicochemical properties of drugs) and produce the desired effect. Selectivity is also due to the affinity for the considered morphological link (taking into account the structure of the cell membrane, the characteristics of cell metabolism, etc.). Large doses of selectively acting drugs most often affect the entire system, but cause a pharmacological response corresponding to the specific action of the drug.

If the bulk of the receptors interacts with drugs, then a rapid onset of the pharmacological effect and its greater severity are noted. The process occurs only with a high affinity of the drug (its molecule can have a structure similar to that of a natural agonist). The activity of the drug and the duration of its action in most cases is proportional to the rate of formation and dissociation of the complex with the receptor. With repeated administration of drugs, a decrease in the effect (tachyphylaxis) is sometimes recorded, because not all receptors were released from the previous dose of the drug. A decrease in the severity of the effect also occurs in the case of depletion of receptors.

Reactions recorded during drug administration

The expected pharmacological response.

Hyperreactivity - increased sensitivity of the body to the drug used. For example, when the body is sensitized with penicillins, their repeated administration can lead to an immediate hypersensitivity reaction or even to the development of anaphylactic shock.

Tolerance - a decrease in sensitivity to the drug used. For example, with uncontrolled and prolonged use of β 2 -adrenomimetics, tolerance to them increases, and the pharmacological effect decreases.

Idiosyncrasy - individual hypersensitivity (intolerance) to this drug. For example, the cause of idiosyncrasy may be a genetically determined lack of

the presence of enzymes that metabolize this substance (see Chapter 7 "Clinical Pharmacogenetics").

Tachyphylaxis is a rapidly developing tolerance. To some drugs, for example, to nitrates (with their continuous and prolonged use), tolerance develops especially quickly; in this case, the drug is replaced or its dose is increased.

When evaluating the time of drug action, it is necessary to highlight the latency period, maximum action, retention time of the effect and the aftereffect time.

The time of the latent period of drugs, especially in urgent situations, determines their choice. So, in some cases, the latency period is seconds (sublingual form of nitroglycerin), in others - days and weeks (aminoquinoline). The duration of the latent period may be due to the constant accumulation of drugs (aminoquinoline) at the site of its exposure. Often, the duration of the latent period depends on the mediated mechanism of action (the hypotensive effect of β-blockers).

The retention time of the effect is an objective factor that determines the frequency of administration and the duration of drug use.

Dividing drugs according to their pharmacological effects, it is necessary to take into account that different mechanisms of action underlie one and the same symptom. An example is the antihypertensive effect of drugs such as diuretics, β-blockers, slow calcium channel blockers (different mechanisms of action produce the same clinical effect). This fact is taken into account when choosing drugs or their combination when conducting individual pharmacotherapy.

There are factors that affect the speed of the onset of the effect, its strength and duration when using medicinal substances.

The rate, route of administration and dose of the drug that interacts with the receptor. For example, an intravenous jet injection of 40 mg of furosemide produces a faster and more pronounced diuretic effect than 20 mg of the drug injected intravenously or 40 mg of a diuretic taken by mouth.

Severe course of the disease and associated organic damage to organs and systems. Age-related aspects also have a great influence on the functional state of the main systems.

Interaction of the drugs used (see chapter 5 "Drug interactions").

It is important to know that the use of some drugs is justified only under the condition of an initial pathological change in the system or target acceptors. So, antipyretic drugs (antipyretics) reduce the temperature only with fever.