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What is the difference between agonists and antagonists. B. Internal activity of medicinal substances. The concept of agonists and receptor antagonists. Watch what is "agonist" in other dictionaries

Substances that have affinity may have internal activity.

Internal activity - The ability of the substance when interacting with the receptor to stimulate it and thus cause certain effects.

Depending on the presence of internal activity, medicinal substances are divided into agonists and Antagonists receptors.

Agonists (from Greek Agonistes - rival, agon - struggle) or mimetics - Substances with affinity and internal activity. When interacting with specific receptors, they stimulate them, i.e. cause a change in the conformation of the receptors, as a result of which the chain of biochemical reactions occurs and certain pharmacological effects develop.

Full agonists, interacting with receptors, cause the highest possible effect (possess maximum internal activity).

Partial agonists When interacting with receptors, the effect causes a smaller maximum (do not possess maximum internal activity).

Antagonists(From Greek Antagonisma - rivalry, anit - against, agon - struggle) - Substances with affinity, but devoid of internal activity. Combining receptors, they impede the action on these receptors of endogenous agonists (neuromediators, hormones). Therefore, antagonists are also called blockers receptors. The pharmacological effects of antagonists are due to the elimination or weakening of the endogenous receptor data agonists. In this case, effects arise opposite to the effects of agonists. Thus, acetylcholine causes bradycardia, and the antagonist M-cholinoreceptors Atropine, eliminating the effect of acetylcholine on the heart, increases the frequency of heart abbreviations.

If antagonists occupy the same binding sites as agonists, they can exhibit each other from receptors. A similar type of antagonism is indicated as competitive antagonism and antagonists call competitive antagonists . Competitive antagonism depends on comparative affinity of competing substances to this receptor and their concentration. In sufficiently high concentrations, even a low affinity substance can exhibit a substance with a higher affinity due to the receptor. therefore with competitive antagonism, the effect of the agonist can be fully restored with an increase in its concentration in the medium. Competitive antagonism is often used to eliminate the toxic effects of medicinal substances.

Partial antagonists can also compete with complete agonists for binding sites. Pusing complete agonists from receptors, partial agonists reduce their effects and therefore in clinical practice can be used instead of antagonists. For example, partial agonists of B-adrenoreceptors (pindolol) as well as the antagonists of these receptors (propranolol, atenolol) are used in the treatment of hypertension.

Non-competitive antagonism It develops when the antagonist will undertake the so-called alto-cell binding sites on receptors (parts of macromolecules that are not binding to agonist, but regulating receptor activity). Non-competitive antagonists change the conformation of receptors in such a way that they lose the ability to interact with agonists. In this case, an increase in the concentration of agonist cannot lead to the complete restoration of its effect. Non-competitive antagonism also takes place with an irreversible (covalent) binding of a substance with a receptor.

Some medicinal substances combine the ability to stimulate one subtype of receptors and block the other. Such substances indicate as agonists - antagonists (for example, butorofenol - antagonist μ and agonist to Opioid receptors).

Other "targets" for medicinal substances

To other "targets" referred ion canals, enzymes, transport proteins.

Ion canals. One of the main "targets" for medicinal substances is potential-dependent ion channels, selectively conducting Na +, Ca 2+, K + and other ion through the cell membrane. Unlike receptor-controlled ion channels opened in the interaction of a substance with a receptor, these channels are regulated by the potential of the action (open during depolarization. cell membrane). Medicinal substances can or block potential-dependent ion channels and thus disrupt the arrival of ions through them, or activate, i.e. contribute to the passage of ion currents. Most medicinal substances block ion channels.

Local anesthetics block potential-dependent Na +-channels. Many antiarrhythmic drugs (County, Lidocaine, Plosanamide) are also among the Blockers Na + -Kanalov. Some antiepileptic means (phenytoin, carbamazepine) also block potential-dependent Na + -Kanals, and their anticonvulsant activity is associated with it. Sodium channel blockers disrupt the entry into the Na + cell and thus prevent the depolarization of the cell membrane.

Extremely effective in the treatment of many cardiovascular diseases (hypertension, cardiac arrhythmias, angina) was the Blocations of Ca 2+ - channels (nifedipine, verapamil, etc.). Calcium ions take part in many physiological processes: in the reduction of smooth muscles, generating pulses in a sinus-atrial node and carrying out the excitation of the atrial and ventricular assembly, platelet aggregations, etc. Blockers of slow calcium channels prevent the flow of calcium ions inside the cells through potential-dependent channels and cause Relaxation of smooth vessel muscles, reduce the frequency of heart cuts and AV conduction, violate platelet aggregation. Some calcium channel blockers (nimodipine, zinnarizine) are preferably expanding the brain vessels and have a neuroprotective effect (prevent the excess of excess calcium ions inside neurons).

As medicines are used both activators and potassium channel blockers. Activators of potassium channels (minoxidil) have found applied as antihypertensive agents. They contribute to the output of potassium ions from the cell, which leads to the hyperpolarization of the cell membrane and a decrease in the tone of the smooth muscles of the vessels. As a result, blood pressure decreases. Medicinal substances that block potential-dependent potassium channels (amiodar, Satolol), found use in the treatment of heart arrhythmias. They prevent the output of potassium potassium ions from cardiomyocytes, as a result of which increase the duration of the potential of the action and extend the effective refractory period (ERP). The blockade of ATP-dependent potassium channels in the B-cells of the pancreas leads to an increase in insulin secretion; The blockers of these channels (sulfonylurevine derivatives) are used as antidiabetic agents.

Enzymes. Many medicinal substances are inhibitors of enzymes. MAO inhibitors violate the metabolism (oxidative deamination) of catecholamines (norepinephrine, dopamine, serotonin) and increase their content in the central nervous system. In this principle, the effect of antidepressants - Mao inhibitors (for example, Niamida) is based. The mechanism of the action of non-steroidal anti-inflammatory means is associated with the inhibition of cyclooxygenase, the biosynthesis of ProTaglandinov E 2 and I 2 decreases and the anti-inflammatory effect develops. Acetylcholinesterase (anticholinesterase drugs) inhibitors prevent acetylcholine hydrolysis and increase its content in the synaptic slit. Preparations of this group are used to increase the tone of smooth muscle organs (gastrointestinal tract, bladder and skeletal muscles).

Tarn Systems Medicinal substances can operate on transport systems (transport proteins) carrying molecules of certain substances or ions through cell membranes. For example, tricyclic antidepressants block transport proteins that carry norepinephrine and serotonin through the presynaptic membrane of the nervous end (block the reverse non-corrosive grip of norepinephrine and serotonin). Cardiac glycosides are blocked by Na + -, K + -ATFase cardiomyocyte membranes, carrying out transport Na + from cells in exchange for K +.

Other "targets" are possible, which can act drugs. Thus, antacid agents neutralize the hydrochloric acid of the stomach, they are used at elevated acidity of the gastric juice (hyperacid gastritis, ulcer of stomach).

A promising "target" for medicines are genes. With the help of selectively active medicines, it is possible to directly affect the function of certain genes.

Noodynakovo act on various types of opioid receptors.

Pentazocin -agonist delta and kappa receptor antagonist MJ receptors. Given the morphine by analgesic activity and duration of action. It rarely causes the development of drug dependence (does not cause euphoria, can cause a dysphoroid). Less than morphine inhibits breathing. With the introduction of pentazocin faces with drug dependence on narcotic analgesics, they develop abstinence.

Bujofanol.- Kappa-agonist, MJ antagonist. Morphine is 3-5 times more active. Less often causes medicinal dependence and inhibits breathing less. Can be introduced in / in, in / m, intranasally.

Nalbufin- Capp- and antagonist MJ receptor. The activity corresponds to morphine, the breathing is less inhibited, drug addiction rarely causes drug addiction.

Buprenorphin- partial agonist MJ and Cappa- and antagonist Delta receptor. According to analgesic activity, the morphine is somewhat surpassed and acts longer (6 hours). Less inhibits breathing. Rarely causes drug addiction. Enter parenteral and sublingual. Not applied in children under 12 years old.

nonopioid analgesics of the central action

Paraoaminophenol derivatives (Analina): paracetamol.

Agonist α 2 - adreno- andi 1 -imidazoline receptors klonidin.

Antidepressants amitriptyline and imizin. Inhibit the neuronal seizure of serotonin in the descending paths controlling the rear horns of the spinal cord. Effective in chronic pains, and in combination with antipsychotic means - and with strong pains.

Nitrogen Zakusexhibits an effect in subgipnotic concentrations and can be used to relieve strong pain within a few hours.

Antagonist VAC ketamine.

Antichokes (DIDEDROL)may be involved in the central regulation of the conduct and perception of pain.

Antiepileptic means carbamazepine, sodium Valproatapplied in chronic pains (trigeminal nerve neuralgia).

GAMK-Mimetic baclofen..

Hormones somatostatin and Calcithonin.

Paracetamol(Panadol, Effergangan, Tilenol, Koldrex, Ibuklin):

a) inhibits the formation of prostaglandins in the central nervous system, because inhibits COF-3,

b) activates the brake pulses from the colonid gray matter,

c) has an oppressive effect on the Talalamic Centers of Pain,

d) strengthens the release of endorphins.

It has a moderate painkillers and antipyretic effect. It does not have an anti-inflammatory effect, since practically does not violate the synthesis of PG in peripheral tissues. Typically, the drug is well tolerated. It does not have a damaging effect on the gastric mucous membrane, does not cause dyspepsia, and does not reduce platelet aggregation, does not cause hemorrhagic syndrome.

However, paracetamol has a small latitude of therapeutic action. In acute poisoning, paracetamol is noted toxic lesion of liver and kidney, encephalopathy, brain swelling (develops in 24-48 hours). This is due to the accumulation of toxic acetylbenzene metabolite, which is inactivated by conjugation with glutathyon. In children under 12 years old, the drug is less toxic than in adults, since it is mainly subjected to sulfate, since the system of the R-450 is insufficient. Antids are acetylcysteine \u200b\u200b(stimulates the formation of glutathion in the liver) and methionine (stimulates the conjugation process).

Appliedto eliminate fever and various types of pain.

Pharmacodynamics includes the concepts of pharmacological effects, the localization of the action and the mechanisms of the LV (i.e., ideas about how and how and how the LV acts in the body). Pharmacodynamics also includes the concept of the types of LV.

2.1. Pharmacological effects, localization and mechanisms of medicinal substances

Pharmacological effects - changes in the function of organs and organism systems caused by LV. The pharmacological effects of LV include, for example, an increase in heart rate, decrease in blood pressure, increasing the threshold of pain sensitivity, decrease in body temperature, an increase in sleep duration, elimination of nonsense and hallucinations, etc. Each substance, as a rule, causes a number of certain pharmacological effects characteristic of it. At the same time, some pharmacological effects of LV are useful - thanks to them, LVs are used in medical practice (basic effects),

and others are not used and, moreover, are undesirable (side effects).

For many substances, the places of their preferential action in the body are known - i.e. Localization of action. Some substances mainly act on certain structures of the brain (anti-parkinsonic, antipsychotic drugs), others are mainly acting on the heart (heart glycosides).

Thanks to modern methodological techniques, it is possible to determine the localization of the substances not only on the system and organ, but at the cellular and molecular levels. For example, cardiac glycosides act on the heart (organ level), on cardiomyocytes (cellular level), on Na + -, K + -ATFase cardiomyocyte membranes (molecular level).

The same pharmacological effects may be caused by various ways. So, there are substances that cause a reduction in blood pressure by reducing the synthesis of angiotensin II (ACE inhibitors), or blocking the intake of Ca 2+ in smooth muscle cells (blockers of potential-dependent calcium channels) or reducing the selection of norepinephrine from the endings of sympathetic nerves (sympatholites). Methods, with the help of which LV cause pharmacological effects, are defined as M E C and Z - we are actions.

The pharmacological effects of most LV are caused by their action on certain molecular substrates, the so-called "targets".

The main molecular "targets" for LV includes receptors, ion canals, enzymes, transport systems.

Receptors

A. Properties and types of receptors. Interaction of receptors with enzymes and ion channels

Receptors are functionally active macromolecules or fragments (mainly protein molecules - lipoproteins, glycoproteins, nucleoproteins, etc.). In the interaction of substances (ligands) with receptors, a chain of biochemical reactions occurs, leading to the development of certain

pharmacological effects. Receptors serve as targets for endogenous ligands (neurotransmitters, hormones, other endogenic biologically active substances), but can interact with exogenous biologically active substances, including LV. Receptors interact only with defined substances (having a certain chemical structure and spatial orientation), i.e. possess selectivity, so they are called specific receptors.

Receptors are not stable, constantly existing cell structures. Their amount may increase due to the prevalence of the synthesis of receptor proteins or decrease due to the prevalence of the process of their degradation. In addition, receptors may lose their functional activity. (desensitization),as a result, the interaction of the receptor with the ligand does not arise biochemical reactions leading to the pharmacological effect. All these processes are regulated by the concentration of the ligand and the duration of its impact on the receptors. With long-term exposure of the ligand, the desessitization of receptors and / or a decrease in their number develops (DOWN regulation)and, on the contrary, the lack of ligand (or reduced its concentration) leads to an increase in the number of receptors (UP regulation).

Receptors may be in the cell membrane (membrane receptors) or inside the cells - in a cytoplasm or core (intracale-precise receptors) (Fig. 2-1).

Membrane receptors. In the membrane receptors, extracellular and intracellular domains are isolated. The extracellular domain has binding sites for ligands (substances that interact with receptors). Intracellular domains interact with effector proteins (enzymes or ion channels) or themselves have enzymatic activity.

There are three types of membrane receptors.

1. Receptors directly conjugate with enzymes.Since the intracellular domain of these receptors exhibits enzymatic activity, they are also called enzyme receptors, or catalytic receptors. Most of the receptors of this group have tyrosine kinaseactivity. When binding a receptor with a substance, tyrosine kinase is activated, which phosphorylates intracellular proteins and thus changes their activity. These receptors include receptors for insulin, some growth factors and cytokines. The receptors directly related to the guanillatcyclase (when exposed to the atrial sodium systemic factor, the guanillates is activated, and the content of cyclic guanosine monophosphate increases in cells).

2. Receptors directly conjugate with ion channels,consist of several subunits, which permeate the cell membrane and form an ion channel. When binding a substance with an extracellular receptor domain, ion channels open, the permeability of cell membranes for various ions changes. Such receptors include n-cholinoreceptors, receptors for gamma-amine oil acid (GABA) related to the subtype A, glycine receptors, glutamate receptors.

The n-cholinoreceptor consists of five subunits that permeate the cell membrane. When binding two acetylcholine molecules with two α-subunits of the receptor, a sodium channel and sodium ions are opened in a cell, causing depolarization of the cell membrane (in skeletal muscles it leads to a muscular reduction).

GABA and -receptors are directly conjugated with chlorine channels. In the interaction of receptors with GABC, chlorine channels open and chlorine ions come into the cell, causing

hyperpolarization of the cell membrane (this leads to an increase in the brake processes in the CNS). In the same way, glycine receptors are functioning. 3. Receptors interacting with G-proteins.These receptors interact with enzymes and ion cells of cells through intermediary proteins (G-proteins - Guanozintriphosphate (GTP) - binding proteins). Under the action of the substance to the receptor, the α-subunit G-protein is associated with a guanosintriffhosphate. At the same time, the G-protein-guanosintriffhosphate complex comes into account with enzymes or ion channels. As a rule, one receptor is associated with several G-proteins, and each G-protein can simultaneously interact with several enzyme molecules or several ion channels. As a result of this interaction, the effect (amplification) effect occurs.

Well studied the interaction of G-proteins with adenylate cyclase and phospholipase S.

Adenylate cyclase - a membrane-bound enzyme, hydrolyzing ATP. As a result of hydrolysis of ATP, cyclic adenosine monophosphate (CAMF) is formed, which activates CAMF-dependent protein kinases, phosphorylating cellular proteins. This changes the activity of proteins and the processes regulated by them. The effect on the activity of adenylate cyclase G-proteins are divided into G S-Clamps, stimulating adenylate cyclase, and G I-callers inhibiting this enzyme. An example of receptors interacting with G S -kels are β 1 -adrenoreceptors (indirect the stimulating effect on the heart of sympathetic innervation), and the receptors interacting with G i-Calves - M 2 -Holinoreceptors (mediating the braking effect on the heart of parasympathetic innervation). These receptors are localized in the cardiomyocyte membrane.

With stimulation of β 1 -adrenoreceptors, adenylate cyclase activity increases and the CAMF content in cardiomyocytes increases. As a result, proteinkinase is activated, which phosphorylates calcium channels of cardiomyocyte membranes. Through these channels, calcium ions enter the cell. The Ca 2+ input into the cell increases, which leads to an increase in the automatism of the sinus node and an increase in the frequency of heart abbreviations. The intracellular effects of the opposite direction are developing with the stimulation of M 2 -Holinaroreceptors of cardiomyocytes, as a result there is a decrease in the automatism of the sine node and the heart rate of heart rate.

With phospholipase with interact gq. -belki, causing its activation. Example of receptors associated with Gq. - Belts, are a g of adrenoreceptors of smooth muscle cells of vessels (mediating effect on sympathetic innervation vessels). In the stimulation of these receptors, the activity of phospholipase S. phospholipase with hydrolyzes phosphatidylositol-4,5-diphosphate of cell membranes to form an inositol-1,4,5-triphosphate hydrophilic substance, which interacts with the calcium channels of sarcoplasmic reticulum cells and causes the release of CA 2 + in cytoplasm. When the concentration of Ca 2+ increases in the cytoplasm of smooth muscle cells, the rate of formation of the CA 2+ complex is increased, which activates the kinase of the light chains of myosin. This enzyme phosphorylates the light chains of myosin, as a result of which the interaction of actin with myosine is facilitated, and the smooth muscles of vessels occur.

Preceptors interacting with G-proteins also include dopamine receptors, some subtypes of serotonin (5-HT) receptors, opioid receptors, histamine receptors, receptors for most peptide hormones, etc.

Intracellular receptors are soluble cytosolic or nuclear proteins that mediate the regulating effects of substances on DNA transcription.Ligands of intracellular receptors are lipophilic substances (steroid and thyroid hormones, vitamins A, D).

The interaction of the ligand (for example, glucocorticoids) with cytosolic receptors causes their conformational change, as a result, the complex of the receptor substance moves to the cell core, where it binds to certain areas of the DNA molecule. There is a change (activation or repression) of the transcription of genes encoding the synthesis of various functionally active proteins (enzymes, cytokines, etc.). An increase (or decrease) of the synthesis of enzymes and other proteins leads to a change in biochemical processes in the cell and the emergence of pharmacological effects. Thus, glucocorticoids, activating genes responsible for the synthesis of gluconeogenesis enzymes, stimulate glucose synthesis, which contributes to the development of hyperglycemia. As a result of the reprisals of genes encoding the synthesis of cytokines, intercellular adhesion molecules, cyclooxygenase, glucocorticoids have an immunosuppressive and anti-inflammatory effect. Pharmacological

the effects of substances in their interaction with intracellular receptors are developing slowly (for several hours and even days).

Interaction with nuclear receptors is characteristic of thyroid hormones, vitamins A (Retinoidov) and D. A new subtype of nuclear receptors was discovered - receptors activated by pencil proliferators.These receptors participate in the regulation of lipid metabolism and other metabolic processes and are targets for clofibrate (hypolypidemic drug).

B. Binding of a substance with a receptor. Concept of affinity

In order for the LV to have a receptor, it should contact him. As a result, the complex "Substance-receptor" is formed. The formation of such a complex is carried out using intermolecular ties. There are several types of such connections.

Covalent bonds are the most durable type of intermolecular ties. They are formed between two atoms due to the general pair of electrons. Covalent bonds most often provide irreversible bindingsubstances, however, they are not characteristic of the interaction of LV with receptors.

Ion bonds are less durable, arise between groupings that carry multi-way charges (electrostatic interaction).

Ion-dipole and dipole-dipole bonds are close in character to ionic relations. In electrophetral molecules of LVs, entering the electric field of cell membranes or surrounded by ions, the formation of induced dipoles occurs. Ion and dipole ties are characteristic of the interaction of LV with receptors.

Hydrogen bonds play a very significant role in the interaction of LV with receptors. The hydrogen atom is able to bind oxygen atoms, nitrogen, sulfur, halogen. Hydrogen bonds are weak, it is necessary for their formation so that the molecules are from each other at a distance of no more than 0.3 nm.

Van der Waalsum communication is the weak bonds, are formed between two any atoms if they are at a distance of no more than 0.2 nm. With increasing distance, these bonds weaken.

Hydrophobic bonds are formed in the interaction of non-polar molecules in the aquatic environment.

Affinity is used to characterize the binding of the substance with the receptor.

Affinity (from Lat. affinis- related) - the ability of the substance to bind to the receptor, resulting in the formation of the complex "Substance-receptor". In addition, the term "affinity" is used to characterize the binding strength of the substance with the receptor (i.e. the duration of the existence of the "substance-receptor" complex). Quantitative measure of affinity as the binding strength of the substance with the receptor is dissociation constant(K d).

The dissociation constant is equal to the concentration of the substance at which half of the receptors in this system is associated with the substance. This indicator is expressed in moles / l (m). There is a proportional ratio between the affinity and constant of dissociation: the less to D, the higher the affinity. For example, if To D.substances A is 10 -3 m, and to D substance in equal to 10-10 m, the affinity of the substance is higher than the affinity of the substance A.

B. Internal activity of medicinal substances. The concept of receptor agonists and antagonists

Substances that have affinity may have internal activity.

Internal activity - the ability of the substance when interacting with the receptor to stimulate it and thus cause certain effects.

Depending on the presence of internal activity of LVs divided into agonistsand antagonistsreceptors.

Agonists (from Greek. agonistes.- rival, agon.- Fight) or mimetics- Substances with affinity and internal activity. When interacting with specific receptors, they stimulate them, i.e. Changes the conformation of the receptors, resulting in a chain of biochemical reactions and develop certain pharmacological effects.

Full agonists, interacting with receptors, cause the highest possible effect (possess maximum internal activity).

Partial agonists when interacting with receptors cause an effect less than the maximum (do not possess maximum internal activity).

Antagonists (from Greek. antagonisma.- rivalry, anti.- vs, agon.- Fight) - Substances with affinity, but devoid of internal activity. Combining receptors, they impede the action on these receptors of endogenous agonists (neuromediators, hormones). Therefore, antagonists are also called a b l o k a t o r a m and receptors. The pharmacological effects of antagonists are due to the elimination or weakening of the endogenous receptor data agonists. In this case, effects arise opposite to the effects of agonists. Thus, acetylcholine causes bradycardium, and an antagonist of M-cholinoreceptor atropine, eliminating the action of acetylcholine on the heart, increases the frequency of heart rate.

If antagonists occupy the same binding sites as agonists, they can exhibit each other from receptors. A similar type of antagonism is denoted as competitive antagonism, and antagonists call competitive antagonista and. Competitive antagonism depends on comparative affinity of competing substances to this receptor and their concentration. In sufficiently high concentrations, even a low-affinity substance may displace a substance with a higher affinity due to the receptor. therefore with competitive antagonism, the effect of the agonist can be fully restored with an increase in its concentration in the medium.Competitive antagonism is often used to eliminate the toxic effects of LV.

Partial antagonists can also compete with complete agonists for binding sites. Pusing complete agonists from receptors, partial agonists reduce their effects and therefore in clinical practice can be used instead of antagonists. For example, partial agonists of β-adrenoreceptors (pindolol) as well as antagonists of these receptors (propranolol, atenolol) are used in the treatment of hypertensive disease.

Non-competitive antagonism develops when the antagonist occupies the so-called alto-space binding places in the receptors (parts of the macromolecule, which are not places of binding agonist, but regulating receptor activity). Non-competitive antagonists change the conformation of receptors

in such a way that they lose the ability to interact with agonists. In this case, an increase in the concentration of agonist cannot lead to the complete restoration of its effect. Non-competitive anthamonds also takes place with an irreversible (covalent) binding of a substance with a receptor.

Some LV combine the ability to stimulate one subtype of receptors and block the other. Such substances are denoted as agonistagonists (for example, butorofanol - antagonist μ and agonist κ opioid receptors).

Other "targets" for medicinal substances

Other "targets" include ion channels, enzymes, transport proteins.

Ion canals.One of the main "targets" for LV is potentially dependent ion channels, selectively conductive Na +, Ca 2+, K + and other ions through the cell membrane. In contrast to receptor-controlled ion channels opened in the interaction of the substance with the receptor, these channels are regulated by the potential of action (open during the depolarization of the cell membrane). LVs can or block potential-dependent ion channels and thus disrupt the arrival of ions through them, or activate, i.e. Contribute to the passage of ion currents. Most LV block ion channels.

Local anesthetics block potential-dependent NA +-channels. Many antiarrhythmic drugs (County, Lidocaine, Plosanamide) are also among the Blockers Na + -Kanalov. Some anti-epileptic agents (phenytoin, carbamazepine) also block potential-dependent NA +-channels, and their anticonvulsant activity is associated with it. Sodium channel blockers disrupt the entry into the Na + cell and thus prevent the depolarization of the cell membrane.

the channels prevent the entry of calcium ions inside the cell through potential-dependent channels and cause relaxation of the smooth muscles of the vessels, a decrease in the frequency of heart cuts and AU conduction, disturb the aggregation of platelets. Some calcium channel blockers (nimodipine, zinnarizine) preferably expand the brain vessels and have a neuroprotective effect (prevent the proceeds of excess Ca 2+ inside neurons).

As medicines are used both activators and potassium channel blockers. Activators of potassium channels (minoxidil) have found applied as antihypertensive agents. They contribute to the output of potassium ions from the cell, which leads to the hyperpolarization of the cell membrane and a decrease in the tone of the smooth muscles of the vessels. As a result, blood pressure decreases. LV blocking potential-dependent potassium channels (amiodar, sotalol), found an inflammation in the treatment of heart arrhythmias. They prevent the exit to + from cardiomyocytes, as a result of which increase the duration of the potential of the action and extend the effective refractory period (ERP). The blockade of ATP-dependent potassium channels in the β-cells of the pancreas leads to an increase in insulin secretion; The blockers of these channels (sulfonylurevine derivatives) are used as antidiabetic agents.

Enzymes.Many LV are inhibitors of enzymes. MAO inhibitors violate the metabolism (oxidative deamination) of catecholamines (norepinephrine, dopamine, serotonin) and increase their content in the central nervous system. In this principle, the effect of antidepressants - Mao inhibitors (for example, Niamida) is based. The mechanism of action of non-steroidal anti-inflammatory means is associated with the inhibition of cyclooxygenase, as a result, the biosynthesis of prostaglandins E 2 and I 2 decreases and a provisional action is developing. Acetylcholinesterase (anticholinesterase drugs) inhibitors prevent acetylcholine hydrolysis and increase its content in the synaptic slit. Preparations of this group are used to increase the tone of smooth muscle organs (gastrointestinal tract, bladder) and skeletal muscles.

Transport systems. LV can act on transport systems (transport proteins) carrying molecules of some substances or ions through cell membranes. For example, tricyclic antidepressants block transport proteins that carry norepinephrine and serotonin through the presynaptic membrane

wound of the nervous end (block the reverse neuronal grip of norepinephrine and serotonin). Heart glycosides are blocked K + -ATPase cardiomyocyte membranes, carrying out transport Na + from a cell in exchange for K +.

Other "targets" are possible, which may be valid. Thus, antacid agents neutralize the hydrochloric acid of the stomach, they are used at elevated acidity of the gastric juice (hyperacid gastritis, ulcerative gastric disease).

The promising "target" for LS are genes. With the help of selectively operating drugs, it is possible to directly affect the function of certain genes.

2.2. Types of action of medicinal substances

The following types of action are distinguished: local and resorbative, reflex, direct and indirect, basic and side and some others.

The local action of LV has in contact with the tissues at the place of its application (usually it is the skin or mucous membranes). For example, with surface anesthesia, a local anesthetic acts on the end of sensitive nerves only at the place of application on the mucous membrane. To provide local action, the LV is prescribed in the form of ointments, rings, rinsing, patches. When prescribing some LVs in the form of eye or ear drops, they also count on their local action. However, some amount of LV is usually absorbed from the place of application to blood and has a general (resorbative) action. Under the local application of LV, a reflex action is also possible.

Resortal action (from lat. resorBeo.- absorbing) - the effects caused by the LV after suction to blood or directly introducing into the blood vessel and distribution in the body. With resorbative action, as at the local, the substance can excite sensitive receptors and cause reflex reactions.

Reflex action. Some LVs are able to excite the end of the sensitive nerves of the skin, mucous membranes (exteroraceptors), vessel chemoreceptors (interior bearing) and cause reflex reactions from the organs located in the distance from the location of the direct contact of the substance with sensitive receptors. Example of excitation exterorceceptors

the skin with essential mustard oil is the action of mustard pieces. Lobelin, with intravenous administration, excites vessel chemoreceptors, which leads to reflex stimulation of respiratory and vascular centers.

Direct (primary) Action of LV on the heart, vessels, intestines and other organs develop with direct impact on these organs. For example, cardiac glycosides cause a cardiotonic effect (enhancing myocardial cuts) due to their direct influence on cardiomyocytes. The raising of diuresis in patients with heart failure caused by cardiac glycosides is due to an increase in cardiac output and improved hemodynamics. Such an action in which LV changes the function of some organs, affecting other organs, is denoted as an indirect (secondary) action.

Basic action. The action for which the LV is used in the treatment of this disease is used. For example, phenytoin has anticonvulsant and antiarrhythmic properties. In a patient epilepsy, the main effect of phenytoin is an anticonvulsant, and in a patient with cardiac arrhythmia caused by the overdose of heart glycosides - antiarrhythmic.

All other (except basic) effects of LV, arising from its reception in therapeutic doses, regard as actions. These effects are often unfavorable (negative) (see chapter "Side and toxic effect of medicinal substances"). For example, acetylsalicylic acid can cause ulceration of the stomach mucosa, antibiotics from the aminoglycoside group (Kanamycin, gentamicin, etc.) is a hearing impairment. The negative side effect often serves as the restriction of the use of one or another LV and even exceptions from the list of drugs.

The electoral action of LV is directed mainly to one body or system of the body. Thus, cardiac glycosiums have a selective action on myocardium, oxytocin - on the uterus, sleeping pills - on the central nervous system.

The central action is developing as a result of the direct effect of the LV on the CNS. The central action is characteristic of substances penetrating through the BGB. For sleeping pills, antidepressants, anxiolyts, drugs for anesthesia is a basic action. At the same time, the central action may be by-way (undesirable).

So, many antihistamines due to central action cause drowsiness.

The peripheral action is due to the effect of the LV on the peripheral department of the nervous system or on organs and fabrics. The stripping means (peripherals minelaxants) relax the skeletal muscles, blocking the excitation transmission in neuromuscular synapses, some peripheral vasodilators expand blood vessels, acting directly on smooth muscle cells. For substances with the main central action, peripheral effects are usually side. For example, the chlorpromazine antipsychotic means causes the extension of the vessels and decreased blood pressure (undesirable effect), blocking peripheral α-adrenoreceptors.

The reversible action is a consequence of the reversible binding of the LV with the "targets" (receptors, enzymes). The effect of such a substance can be discontinued by displacing it from the connection with the "target" by another LV.

The irreversible action occurs, as a rule, as a result of a solid (covalent) binding of the LV with the "targets". For example, acetylsalicylic acid irreversibly blocks cyclooxygenase, so the effect of the drug is terminated only after the synthesis of the new enzyme.

Agonist (Fig. A) has affinity to, modifies the receptor protein, which in turn affects the cell function ("internal activity"). The biological effectiveness of agonists, i.e. their influence on the cell function depends on how much receptor activation can affect the signal transmission in the cell.

Consider two agonists A and B (Fig. B). Agonist A can cause the maximum effect even when binding part of receptors. Agonist in with the same affinity, but with limited ability to activate the receptor (limited internal activity) and influence the transmission of the signal can communicate with all receptors, but causes only a limited effect, that is, it shows limited efficiency. Agonist B is a partial agonist. The agonist potential is characterized by the concentration of the EC50, at which half of the maximum effect is achieved.

Antagonists (A) Weaken the effect of agonists: they affect "antagonistically". Full antagonists have affinity for receptors, but their connection does not lead to a change in cell function (no internal activity). With the simultaneous use of agonist and a complete antagonist, the result of their competitive action is determined by affinity and concentration of each of these substances. Thus, with an increase in the concentration of agonist, despite opposition to the antagonist, the full effect can be achieved (Fig. B): i.e., in the presence of an antagonist, the concentration of agonist - the effect is shifted to the right on the abscissa to higher concentration values. Model of the molecular mechanism of action of agonists / antagonists (a)

The agonist causes the transformation into an active conformation. The agonist joins the inactive receptor and contributes to its transition to active conformation. The antagonist joins an inactive receptor, while not changing his conformation.

The agonist stabilizes spontaneously emerging active conformation. The receptor can spontaneously go to active shape. However, the statistical probability of such an event is very small. The agonist is selectively joined by receptors in the active conformation, and supports this state of the receptor. The antagonist has affinity for "inactive" receptors and supports their conformation. If the spontaneous receptor activity is practically absent, the introduction of the antagonist does not lead to a significant effect. If the system has high spontaneous activity, the antagonist has an action opposite to the action of agonist: reverse agonist. The "true" antagonist without internal activity has the same affinity for both active and inactive receptor and does not affect the initial activity of the cell. A partial agonist not only selectively joins the active receptor, but can partially contact the inactive form. Other forms of antagonistic

Alosteric antagonism. The antagonist joins the receptor outside the zone of attachment of the agonist and reduces the affinity of the agonist to this receptor. With altoherectic synergies, the affinity of the agonist is enhanced.

Functional antagonism. Two agonists through different receptors affect the same parameter (for example, the lumen of the bronchi) in opposite directions (adrenaline causes an extension, histamine - narrowing).

Substances that possess affinity may have internal activity.

Internal activity - the ability of the substance when interacting with the receptor to stimulate it and thus cause certain effects.

Depending on the presence of internal activity, medicinal substances are divided into: agonistsand antagonists.

Agonists (from Greek. agonistes.- rival, agon.- Fight) or mimetics -substances with affinity and internal activity. When interacting with specific receptors, they stimulate them, i.e. Changes the conformation of the receptors, resulting in a chain of biochemical reactions and develop certain pharmacological effects.

Full agonists, interacting with receptors, cause the highest possible effect (possess maximum internal activity).

Partial agonists when interacting with receptors cause an effect less than the maximum (do not possess maximum internal activity).

Antagonists (from Greek. antagonisma -rivalry, anti.- vs, agon.-Baby) - Substances with affinity, but devoid of internal activity. They are associated with receptors and impede action on receptors of endogenous agonists (neurotransmitters, hormones). Therefore, they are also called receptor blockers. The pharmacological effects of antagonists are due to the elimination or decrease in the action of endogenous receptor data agonists. At the same time, the effects opposite to the effects of agonists arise. Thus, acetylcholine causes bradycardia, and the antagonist M-cholinoreceptors Atropine, eliminating the effect of acetylcholine on the heart, increases the frequency of heart abbreviations.

If antagonists occupy the same receptors as agonists, they can exhibit each other from receptors. Such antagonism is called competitive, and antagonists are called competitive antagonists. Competitive antagonism depends on the comparative affinity of competing substances and their concentration. In sufficiently high concentrations, even a substance with a lower affinity can displace a substance with a higher affinity due to the receptor. Competitive antagonists are often used to eliminate the toxic effects of medicinal substances.

Partial antagonists can also compete with complete agonists for binding sites. Obtaining complete agonists from receptors, partial agonists reduce the effects of complete agonists and therefore in clinical practice can be used instead of antagonists. For example, partial agonists of β-adrenoreceptor (oxporalolol, pindolol) as well as antagonists of these receptors (propranolol, atenolol) are used in the treatment of hypertensive disease.

If antagonists occupy other sections of macromolecules that are not related to a specific receptor, but interrelated with it, they are called non-competitive antagonists.

Some medicinal substances combine the ability to stimulate one subtype of receptors and block the other. Such substances indicate as

antagonist agonists. So, narcotic analgesic Pentazocin is an antagonist μ -, and an agonist Δ-, and κ-opioid receptors.

Other "targets" for medicinal substances

Medicinal substances can act on other targets, including ion channels, enzymes, transport proteins.

One of the main "targets" for medicinal substances is the potential of physical ion channels, which selectively conduct Na +, Ca 2+, K + and other ions through the cell membrane. Unlike receptor-controlled ion channels, which are opened when the substance interacts with the receptor (see the "Receptors" section), these channels are regulated by the potential of the action (open during the depolarization of the cell membrane). Medicinal substances can or block potential-dependent ion channels and thus disrupt the penetration of ions along these channels through the cell membrane, or activate these channels, i.e. Promote their opening and passing ion currents. Many medicinal substances that are widely used in medical practice are ion channel blockers.

It is known that local anesthetics block potential-dependent Na + -Ka-beds. Na + channels include many anti-arhydrous funds (quinidine, lidocaine, plosenamide). Some antiepileptic means (diphenin, carbamazepine) also block potential-dependent Na + -Kanals and their anticonvulsant activity is associated with it. B Locators of sodium channels disrupt the entry into the Na + ions cell and thus prevent the depolarization of the cell membrane.

Extremely effective in the treatment of many cardiovascular diseases (hypertension, heart arrhythmias, angina) turned out to be blocate-ry s Ca 2+ - channels (nifedipine, verapamil, etc.). Ca 2+ ions take part in many physiological processes: in reducing smooth muscles, in the generation of pulses in a synoatrial node and carrying out excitation by atrioventric-fiber assembly, in platelet aggregations, etc. Blocators Ca 2+ - channels prevent the entry of Ca 2+ ions inside Cells through potential-dependent channels and cause relaxation of smooth vessel muscles, reducing the frequency of heart cuts and atrioventricular conductivity, disturb the aggregation of platelets. Some calcium channel blockers (nimodipine, zinnarizine) preferably expand the brain vessels and have a neuroprotective effect (prevent the proceeds of excess Ca 2+ inside neurons).

Among the medicinal substances are both activators and blockers of in-α-cannels.

Activators K + -Kanalov (minoxidil, diazoxide) have been used as hypotensive drugs. They contribute to the opening of K + -Kanals and the output of ions to + from the cell - it leads to hyperpolarization of the cell membrane and a decrease in the tone of smooth vessel muscles. As a result, blood pressure decreases.

Some substances blocking potential-dependent K +-channels (Amio-Damary, Satolol) are used in the treatment of heart arrhythmias. They prevent the exit to + from cardiomyocytes, as a result of which increase the duration of the potential of the action and extend the effective refractory period.

ATP-dependent K + -Kanals (these channels are opened under the action of ATP) in the beta cells of the pancreas regulate the secretion of insulin. Their block-

yes leads to an increase in insulin secretion. Blockers of these channels (sulfonylurea derivatives) are used as antidiabetic agents.

Many medicinal substances are inhibitors of enzymes. Monoaminoxidase inhibitors (MAO) violate the metabolism (oxidative dispenser) of catecholamines (norepinerenaline, dopamine, serotonin) and increase their content in the CNS. In this principle, the action of antidepressants - Mao inhibitors (Nialamid, Pyrazidol) is based. The mechanism of the action of non-steroidal anti-inflammatory means is associated with the inhibition of cyclooxygenase, as a result, the biosynthesis of prostaglandin E 2 and pro-stalklin, which have a conductive action is reduced. Acetyllo-linesterase inhibitors (anticholinesterase agents) prevent the hydrolysis of acetyl lines and increase its content in the synaptic slit. These drugs are used to increase the tone of smooth muscle organs (gastrointestinal tract, bladder) and skeletal muscles.

Drugs can act on transport systems (transport proteins) that carry molecules of certain substances or ions through the cell membranes. For example, tricyclic antidepressants block transport proteins that carry norepinephrine and serotonin through the previe-suppress membrane of the nervous end (block the reverse neural capture of norepinephrine and serotonin). Cardiac glycosides are blocked by Na +, k + -atf-az membranes of cardiomyocytes, which carries out transport Na + H3 cells in exchange for K +.

Other "targets" are possible to which medicinal substances can act. Thus, the antacid agents act on the chloride hydrochloric acid of the stomach, neutralizing it, and therefore are used at elevated acidity of the gastric juice (hyperacid gastritis, stomach ulcer).

The promising "target" for medicines are genes. With the help of selectively active medicines, it is possible to directly affect the function of certain genes.