Molecular basis of action of agonists and antagonists of steroid receptors. B. Internal activity of medicinal substances. The concept of agonists and antagonists of receptors The concept of specific receptor agonists and antagonists
Substances that have affinity may have intrinsic activity.
Internal Activity- the ability of a substance, when interacting with a 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 the Greek agonistes - rival, agon - fight) or mimetics- substances with affinity and internal activity. When interacting with specific receptors, they stimulate them, that is, they cause a change in the conformation of receptors, resulting in a chain of biochemical reactions and the development of certain pharmacological effects.
Full agonists, interacting with receptors, cause the maximum possible effect (have maximum internal activity).
Partial agonists when interacting with receptors, they cause an effect that is less than the maximum (do not have maximum internal activity).
Antagonists(from the Greek antagonisma - rivalry, anit - against, agon - struggle) - substances with affinity, but devoid of internal activity. By binding to receptors, they prevent the action of endogenous agonists (neurotransmitters, hormones) on these receptors. Therefore, antagonists are also called receptor blockers. The pharmacological effects of antagonists are due to the elimination or weakening of the action of endogenous agonists of these receptors. In this case, there are effects opposite to the effects of agonists. So, acetylcholine causes bradycardia, and the antagonist of M-cholinergic receptors atropine, eliminating the effect of acetylcholine on the heart, increases the heart rate.
If antagonists occupy the same binding sites as agonists, they can displace each other from binding to the receptors. this type of antagonism is referred to as competitive antagonism , and the antagonists are called competitive antagonists . Competitive antagonism depends on the relative affinity of competing substances for a given receptor and their concentration. At sufficiently high concentrations, even a low affinity substance can displace a higher affinity substance from binding to the receptor. That's why in competitive antagonism, the effect of an agonist can be fully restored by increasing its concentration in the medium. Competitive antagonism is often used to eliminate the toxic effects of drugs.
Partial antagonists can also compete with full agonists for binding sites. By displacing full agonists from binding to receptors, partial agonists reduce their effects and, therefore, can be used instead of antagonists in clinical practice. For example, partial agonists of b-adrenergic receptors (pindolol), as well as antagonists of these receptors (propranolol, atenolol), are used in the treatment of hypertension.
Noncompetitive antagonism develops when the antagonist occupies the so-called allosteric binding sites on the receptors (areas of the macromolecule that are not the binding sites of the agonist, but regulate the activity of the receptors). Non-competitive antagonists change the conformation of receptors so that they lose their ability to interact with agonists. At the same time, an increase in the concentration of an agonist cannot lead to a complete restoration of its effect. Non-competitive antagonism also occurs when the substance binds irreversibly (covalently) to the receptor.
Some drugs combine the ability to stimulate one receptor subtype and block another. Such substances are referred to as agonists - antagonists (for example, butorphenol is an antagonist μ and agonist to opioid receptors).
Other drug targets
Other "targets" include ion channels, enzymes, transport proteins.
ion channels. One of the main "targets" for drugs are voltage-gated ion channels that selectively conduct Na + , Ca 2+ , K + and other ions through the cell membrane. Unlike receptor-gated ion channels, which open when a substance interacts with a receptor, these channels are regulated by the action potential (open when the cell membrane is depolarized). Medicinal substances can either block voltage-dependent ion channels and thus disrupt the flow of ions through them, or activate, i.e., promote the passage of ion currents. Most drugs block ion channels.
Local anesthetics block voltage-dependent Na + channels. Many antiarrhythmic drugs (quinidine, lidocaine, procainamide) also belong to the number of Na + -channel blockers. Some antiepileptic drugs (phenytoin, carbamazepine) also block voltage-dependent Na + channels, and their anticonvulsant activity is associated with this. Sodium channel blockers disrupt the entry of Na + into the cell and thus prevent the depolarization of the cell membrane.
Very effective in the treatment of many cardiovascular diseases (hypertension, cardiac arrhythmias, angina pectoris) were Ca2+-channel blockers (nifedipine, verapamil, etc.). Calcium ions are involved in many physiological processes: in the contraction of smooth muscles, the generation of impulses in the sinoatrial node and the conduction of excitation through the atrioventricular node, platelet aggregation, etc. Blockers of slow calcium channels prevent the entry of calcium ions into the cell through voltage-dependent channels and cause relaxation of vascular smooth muscles, reducing the frequency of contractions heart and AV conduction, disrupt platelet aggregation. Some calcium channel blockers (nimodipine, cinnarizine) mainly dilate brain vessels and have a neuroprotective effect (prevent excess calcium ions from entering neurons).
Both activators and blockers of potassium channels are used as medicines. Potassium channel activators (minoxidil) have been used as antihypertensive agents. They contribute to the release of potassium ions from the cell, which leads to hyperpolarization of the cell membrane and a decrease in the tone of vascular smooth muscles. As a result, there is a decrease in blood pressure. Drugs that block voltage-dependent potassium channels (amiodarone, sotalol) have found application in the treatment of cardiac arrhythmias. They prevent the release of potassium ions from cardiomyocytes, as a result of which they increase the duration of the action potential and lengthen the effective refractory period (ERP). Blockade of ATP-dependent potassium channels in pancreatic b-cells leads to an increase in insulin secretion; blockers of these channels (sulfonylurea derivatives) are used as antidiabetic agents.
Enzymes. Many drugs are enzyme inhibitors. MAO inhibitors disrupt the metabolism (oxidative deamination) of catecholamines (norepinephrine, dopamine, serotonin) and increase their content in the central nervous system. The action of antidepressants - MAO inhibitors (for example, nialamide) is based on this principle. The mechanism of action of non-steroidal anti-inflammatory drugs is associated with the inhibition of cyclooxygenase, as a result, the biosynthesis of protaglandins E 2 and I 2 decreases and an anti-inflammatory effect develops. Acetylcholinesterase inhibitors (anticholinesterase agents) prevent the hydrolysis of acetylcholine and increase its content in the synaptic cleft. Preparations of this group are used to increase the tone of smooth muscle organs (GIT, Bladder and skeletal muscles).
Transport systems Medicinal substances can act on transport systems (transport proteins) that carry molecules of certain substances or ions through cell membranes. For example, tricyclic antidepressants block the transport proteins that carry norepinephrine and serotonin across the presynaptic membrane of the nerve ending (block the reuptake of norepinephrine and serotonin). Cardiac glycosides block Na + -, K + -ATPase of cardiomyocyte membranes, which transports Na + from cells in exchange for K + .
Other "targets" that drugs can act on are also possible. So, antacids neutralize the hydrochloric acid of the stomach, they are used for increased acidity of gastric juice (hyperacid gastritis, gastric ulcer).
A promising "target" for drugs are genes. With the help of selective drugs, it is possible to directly influence the function of certain genes.
Receptors (from Latin recipere - to receive) are biological macromolecules that are designed to bind to endogenous ligands (neurotransmitters, hormones, growth factors). Receptors can also interact with exogenous biologically active substances, incl. and with drugs.
When a drug interacts with a receptor, a chain of biochemical transformations develops, the end result of which is a pharmacological effect.
There are four types of receptors:
1. Receptors that directly control the function of the effector enzyme. They are associated with the plasma membrane of cells, phosphorylate cell proteins and change their activity. According to this principle, receptors for insulin, lymphokines, epidermal and platelet growth factors are arranged.
2. Receptors that control the function of ion channels. Ion channel receptors provide membrane permeability for ions. N-cholinergic receptors, glutamic and aspartic acid receptors increase membrane permeability for ions + + 2+
Na, K, Ca, causing depolarization and excitation of cell function. GABAA receptors, glycine receptors increase the permeability of membranes for Cl, causing hyperpolarization and inhibition of cell function.
3. Receptors associated with G-proteins. When these receptors are excited, the effect on the activity of intracellular enzymes is mediated through G-proteins. By changing the kinetics of ion channels and 2+ synthesis of second messengers (cAMP, cGMP, IP3, DAG, Ca), G-proteins regulate the activity of protein kinases, which provide intracellular phosphorylation of important regulatory proteins and the development of various effects. Among these receptors
include receptors for polypeptide hormones and mediators (m-cholinergic receptors, adrenoreceptors, histamine receptors). Receptors of types 1-3 are localized on the cytoplasmic membrane.
4. Receptors - regulators of DNA transcription. These receptors are intracellular and are soluble cytosolic or nuclear proteins. These receptors interact with steroid and thyroid hormones. The function of receptors is the activation or inhibition of gene transcription.
Receptors that provide the manifestation of the action of certain substances are called specific.
Substances that, when interacting with specific receptors, cause changes in them, leading to a biological effect, are called agonists. The stimulatory effect of an agonist on receptors can lead to activation or inhibition of cell function. If an agonist, interacting with receptors, causes the maximum effect, then this is a full agonist. In contrast to the latter, partial agonists, when interacting with the same receptors, do not cause the maximum effect.
Substances that bind to receptors but do not stimulate them are called antagonists. Their internal activity is zero. Their pharmacological effects are due to antagonism with endogenous ligands (mediators, hormones), as well as with exogenous agonist substances. If they occupy the same receptors that agonists interact with, then we are talking about competitive antagonists; if other parts of the macromolecule that are not related to a specific receptor, but are interconnected with it, then they speak of non-competitive antagonists.
Pharmacodynamics includes concepts of pharmacological effects, localization of action and mechanisms of drug action (i.e. ideas about how, where and how drugs act in the body). Pharmacodynamics also includes the concept of the types of drug action.
2.1. PHARMACOLOGICAL EFFECTS, LOCALIZATION AND MECHANISMS OF ACTION OF MEDICINAL SUBSTANCES
Pharmacological effects - changes in the function of organs and systems of the body caused by drugs. The pharmacological effects of drugs include, for example, an increase in heart rate, a decrease in blood pressure, an increase in the threshold of pain sensitivity, a decrease in body temperature, an increase in sleep duration, the elimination of delusions and hallucinations, etc. Each substance, as a rule, causes a number of specific pharmacological effects characteristic of it. At the same time, some pharmacological effects of drugs are useful - thanks to them, drugs are used in medical practice (main effects),
and others are not used and, moreover, are undesirable (side effects).
For many substances, the places of their predominant action in the body are known - i.e. action localization. Some substances mainly act on certain structures of the brain (antiparkinsonian, antipsychotic drugs), others mainly act on the heart (cardiac glycosides).
Thanks to modern methodological techniques, it is possible to determine the localization of the action of substances not only at the systemic 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 + -ATPase of cardiomyocyte membranes (molecular level).
The same pharmacological effects can be produced in different ways. So, there are substances that cause a decrease in blood pressure by reducing the synthesis of angiotensin II (ACE inhibitors), or by blocking the entry of Ca 2+ into smooth muscle cells (blockers of voltage-dependent calcium channels) or by reducing the release of norepinephrine from the endings of sympathetic nerves (sympatholytics). The ways in which drugs cause pharmacological effects are defined as mechanisms of action.
The pharmacological effects of most drugs are caused by their action on certain molecular substrates, the so-called "targets".
The main molecular "targets" for drugs include receptors, ion channels, enzymes, and transport systems.
Receptors
A. Properties and types of receptors. Interaction of receptors with enzymes and ion channels
Receptors are functionally active macromolecules or their fragments (mainly protein molecules - lipoproteins, glycoproteins, nucleoproteins, etc.). When substances (ligands) interact 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 endogenous biologically active substances), but they can also interact with exogenous biologically active substances, including drugs. Receptors interact only with certain substances (having a certain chemical structure and spatial orientation), i.e. are selective, hence they are called specific receptors.
Receptors are not stable, permanent cell structures. Their number may increase due to the predominance of the synthesis of receptor proteins or decrease due to the predominance of the process of their degradation. In addition, receptors may lose their functional activity (desensitization), as a result, when the receptor interacts with the ligand, biochemical reactions leading to a pharmacological effect do not occur. All these processes are regulated by the concentration of the ligand and the duration of its action on the receptors. With prolonged exposure to the ligand, desensitization of receptors and / or a decrease in their number develops. (down-regulation), and, conversely, the absence of a ligand (or a decrease in its concentration) leads to an increase in the number of receptors (up-regulation).
Receptors can be located in the cell membrane (membrane receptors) or inside cells - in the cytoplasm or nucleus (intracellular receptors) (Fig. 2-1).
membrane receptors. Membrane receptors have extracellular and intracellular domains. The extracellular domain has binding sites for ligands (substances that interact with receptors). Intracellular domains interact with effector proteins (enzymes or ion channels) or have enzymatic activity themselves.
Three types of membrane receptors are known.
1. Receptors that are directly coupled to enzymes. Since the intracellular domain of these receptors exhibits enzymatic activity, they are also called enzyme receptors or catalytic receptors. Most of the receptors in this group have tyrosine kinase activity. When the receptor binds to 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. Receptors directly associated with guanylate cyclase are known (when exposed to atrial natriuretic factor, guanylate cyclase is activated, and the content of cyclic guanosine monophosphate increases in cells).
2. Receptors that are directly coupled to ion channels consist of several subunits that penetrate the cell membrane and form an ion channel. When a substance binds to the extracellular domain of the receptor, ion channels open, resulting in a change in the permeability of cell membranes for various ions. These receptors include H-cholinergic receptors, gamma-aminobutyric acid (GABA) subtype A receptors, glycine receptors, and glutamate receptors.
The N-cholinergic receptor consists of five subunits penetrating the cell membrane. When two molecules of acetylcholine bind to two α-subunits of the receptor, the sodium channel opens and sodium ions enter the cell, causing depolarization of the cell membrane (in skeletal muscles, this leads to muscle contraction).
GABA A receptors are directly coupled to chloride channels. When receptors interact with GABA, chloride channels open and chloride ions enter the cell, causing
hyperpolarization of the cell membrane (this leads to increased inhibitory processes in the central nervous system). Glycine receptors function in the same way. 3. Receptors interacting with G-proteins. These receptors interact with enzymes and ion channels of cells through intermediary proteins (G proteins - guanosine triphosphate (GTP) binding proteins). When a substance acts on the receptor, the α-subunit of the G-protein binds to guanosine triphosphate. In this case, the G-protein-guanosine triphosphate complex interacts with enzymes or ion channels. As a rule, one receptor is coupled to several G proteins, and each G protein can simultaneously interact with several enzyme molecules or several ion channels. As a result of such an interaction, an increase (amplification) of the effect occurs.
The interaction of G-proteins with adenylate cyclase and phospholipase C has been well studied.
Adenylate cyclase is a membrane-bound enzyme that hydrolyzes ATP. As a result of ATP hydrolysis, cyclic adenosine monophosphate (cAMP) is formed, which activates cAMP-dependent protein kinases that phosphorylate cellular proteins. This changes the activity of proteins and the processes they regulate. According to the effect on the activity of adenylate cyclase, G proteins are divided into G s proteins that stimulate adenylate cyclase and G i proteins that inhibit this enzyme. An example of receptors that interact with G s proteins are β 1 -adrenergic receptors (mediate a stimulating effect on the heart of sympathetic innervation), and receptors that interact with G i proteins are M 2 -cholinergic receptors (mediate an inhibitory effect on the heart of parasympathetic innervation). These receptors are localized in the membrane of cardiomyocytes.
With stimulation of β 1 -adrenergic receptors, the activity of adenylate cyclase increases and the content of cAMP in cardiomyocytes increases. As a result, protein kinase is activated, which phosphorylates the calcium channels of cardiomyocyte membranes. Through these channels, calcium ions enter the cell. The entry of Ca 2+ into the cell increases, which leads to an increase in the automatism of the sinus node and an increase in the heart rate. Intracellular effects of the opposite direction develop with stimulation of M 2 -cholinergic receptors of cardiomyocytes, resulting in a decrease in the automatism of the sinus node and heart rate.
Phospholipase C interacts with G q -proteins, causing its activation. An example of G-coupled receptors q -proteins are adrenergic receptors of vascular smooth muscle cells (mediating the effect on the vessels of sympathetic innervation). When these receptors are stimulated, the activity of phospholipase C increases. Phospholipase C hydrolyzes phosphatidylinositol-4,5-diphosphate of cell membranes with the formation of a hydrophilic substance inositol-1,4,5-triphosphate, which interacts with calcium channels of the sarcoplasmic reticulum of the cell and causes the release of Ca 2 + into the cytoplasm. With an increase in Ca 2+ concentration in the cytoplasm of smooth muscle cells, the rate of formation of the Ca 2+ -calmodulin complex increases, which activates myosin light chain kinase. This enzyme phosphorylates myosin light chains, which facilitates the interaction of actin with myosin, and contraction of vascular smooth muscle occurs.
Receptors 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 regulatory action of substances for DNA transcription. Ligands of intracellular receptors are lipophilic substances (steroid and thyroid hormones, vitamins A, D).
The interaction of a ligand (for example, glucocorticoids) with cytosolic receptors causes their conformational change, as a result, the substance-receptor complex moves to the cell nucleus, where it binds to certain regions 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) in the synthesis of enzymes and other proteins leads to a change in the biochemical processes in the cell and the appearance of pharmacological effects. Thus, glucocorticoids, by activating the genes responsible for the synthesis of gluconeogenesis enzymes, stimulate the synthesis of glucose, which contributes to the development of hyperglycemia. As a result of repression 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 develop slowly (over several hours or even days).
Interaction with nuclear receptors is characteristic of thyroid hormones, vitamins A (retinoids) and D. A new subtype of nuclear receptors has been discovered - receptors activated by peroxisome proliferators. These receptors are involved in the regulation of lipid metabolism and other metabolic processes and are targets for clofibrate (a lipid-lowering drug).
B. Binding of a substance to a receptor. The concept of affinity
In order for a drug to act on a receptor, it must bind to it. As a result, a “substance-receptor” complex is formed. The formation of such a complex is carried out with the help of intermolecular bonds. There are several types of such connections.
Covalent bonds are the strongest type of intermolecular bonds. They are formed between two atoms due to a common pair of electrons. Covalent bonds most often provide irreversible binding substances, but they are not typical for the interaction of drugs with receptors.
Ionic bonds are less strong and arise between groups carrying opposite charges (electrostatic interaction).
Ion-dipole and dipole-dipole bonds are close in character to ionic bonds. In electrically neutral drug molecules that enter the electric field of cell membranes or are surrounded by ions, the formation of induced dipoles occurs. Ionic and dipole bonds are characteristic of the interaction of drugs with receptors.
Hydrogen bonds play a very significant role in the interaction of drugs with receptors. The hydrogen atom is able to bind the atoms of oxygen, nitrogen, sulfur, halogens. Hydrogen bonds are weak, for their formation it is necessary that the molecules are at a distance of no more than 0.3 nm from each other.
Van der Waals bonds are the weakest bonds that form between any two atoms if they are at a distance of no more than 0.2 nm. As the distance increases, these bonds weaken.
Hydrophobic bonds are formed during the interaction of non-polar molecules in an aqueous medium.
The term affinity is used to characterize the binding of a substance to a receptor.
Affinity (from lat. affinis- related) - the ability of a substance to bind to a receptor, resulting in the formation of a "substance-receptor" complex. In addition, the term "affinity" is used to characterize the strength of the binding of a substance to the receptor (ie, the duration of the existence of the "substance-receptor" complex). A quantitative measure of affinity as the strength of the binding of a substance to a receptor is dissociation constant(To d).
The dissociation constant is equal to the concentration of a substance at which half of the receptors in a given system are bound to the substance. This indicator is expressed in moles / l (M). Between affinity and dissociation constant there is an inversely proportional relationship: the smaller K d , the higher the affinity. For example, if K d substance A is 10 -3 M, and K d of substance B is 10 -10 M, the affinity of substance B is higher than the affinity of substance A.
B. Internal activity of medicinal substances. The concept of agonists and antagonists of receptors
Substances that have affinity may have intrinsic activity.
Internal activity - the ability of a substance, when interacting with a receptor, to stimulate it and thus cause certain effects.
Depending on the presence of internal activity, drugs are divided into agonists and antagonists receptors.
Agonists (from the Greek. agonistes- rival agon- wrestling) or mimetics- substances with affinity and internal activity. When interacting with specific receptors, they stimulate them, i.e. cause changes in the conformation of receptors, resulting in a chain of biochemical reactions and the development of certain pharmacological effects.
Full agonists, interacting with receptors, cause the maximum possible effect (they have maximum internal activity).
Partial agonists, when interacting with receptors, cause an effect that is less than the maximum (do not have maximum internal activity).
Antagonists (from the Greek. antagonism- rivalry, anti- against, agon- struggle) - substances with affinity, but devoid of internal activity. By binding to receptors, they prevent the action of endogenous agonists (neurotransmitters, hormones) on these receptors. Therefore, antagonists are also called receptor blockers. The pharmacological effects of antagonists are due to the elimination or weakening of the action of endogenous agonists of these receptors. In this case, there are effects opposite to the effects of agonists. Thus, acetylcholine causes bradycardia, and the antagonist of M-cholinergic receptors atropine, eliminating the effect of acetylcholine on the heart, increases the heart rate.
If antagonists occupy the same binding sites as agonists, they can displace each other from binding to the receptors. This type of antagonism is referred to as competitive antagonism, and antagonists are called competitive antagonists and. Competitive antagonism depends on the relative affinity of competing substances for a given receptor and their concentration. At sufficiently high concentrations, even a low affinity substance can displace a higher affinity substance from binding to the receptor. That's why in competitive antagonism, the effect of an agonist can be fully restored by increasing its concentration in the medium. Competitive antagonism is often used to eliminate the toxic effects of drugs.
Partial antagonists can also compete with full agonists for binding sites. By displacing full agonists from binding to receptors, partial agonists reduce their effects and, therefore, can be used instead of antagonists in clinical practice. For example, partial agonists of β-adrenergic receptors (pindolol) as well as antagonists of these receptors (propranolol, atenolol) are used in the treatment of hypertension.
Non-competitive antagonism develops when the antagonist occupies the so-called allosteric binding sites on the receptors (areas of the macromolecule that are not binding sites for the agonist, but regulate the activity of the receptors). Non-competitive antagonists change the conformation of receptors
so that they lose their ability to interact with agonists. At the same time, an increase in the concentration of an agonist cannot lead to a complete restoration of its effect. Non-competitive antagonism also occurs in the case of irreversible (covalent) binding of a substance to a receptor.
Some drugs combine the ability to stimulate one receptor subtype and block another. Such substances are referred to as antagonist agonists (for example, butorphanol is a µ antagonist and κ agonist of opioid receptors).
Other drug targets
Other "targets" include ion channels, enzymes, transport proteins.
ion channels.One of the main "targets" for drugs are voltage-gated ion channels that selectively conduct Na + , Ca 2+ , K + and other ions through the cell membrane. Unlike receptor-gated ion channels, which open when a substance interacts with a receptor, these channels are regulated by the action potential (open when the cell membrane is depolarized). Drugs can either block voltage-gated ion channels and thus disrupt the flow of ions through them, or activate, i.e. facilitate the passage of ionic currents. Most drugs block ion channels.
Local anesthetics block voltage-dependent Na + channels. Many antiarrhythmic drugs (quinidine, lidocaine, procainamide) also belong to the number of Na + -channel blockers. Some antiepileptic drugs (phenytoin, carbamazepine) also block voltage-dependent Na + channels, and their anticonvulsant activity is associated with this. Sodium channel blockers disrupt the entry of Na + into the cell and thus prevent the depolarization of the cell membrane.
Very effective in the treatment of many cardiovascular diseases (hypertension, cardiac arrhythmias, angina pectoris) were Ca 2+ channel blockers (nifedipine, verapamil, etc.). Calcium ions are involved in many physiological processes: smooth muscle contraction, generation of impulses in the sinoatrial node and conduction of excitation through the atrioventricular node, platelet aggregation, etc. Blockers of slow calcium
channels prevent the entry of calcium ions into the cell through voltage-dependent channels and cause relaxation of vascular smooth muscles, a decrease in the heart rate and AV conduction, and disrupt platelet aggregation. Some calcium channel blockers (nimodipine, cinnarizine) mainly dilate the brain vessels and have a neuroprotective effect (prevent excess Ca 2+ from entering neurons).
Both activators and blockers of potassium channels are used as medicines. Potassium channel activators (minoxidil) have been used as antihypertensive agents. They contribute to the release of potassium ions from the cell, which leads to hyperpolarization of the cell membrane and a decrease in the tone of vascular smooth muscles. As a result, there is a decrease in blood pressure. Drugs that block voltage-dependent potassium channels (amiodarone, sotalol) have found application in the treatment of cardiac arrhythmias. They prevent the release of K + from cardiomyocytes, as a result of which they increase the duration of the action potential and lengthen the effective refractory period (ERP). Blockade of ATP-dependent potassium channels in pancreatic β-cells leads to an increase in insulin secretion; blockers of these channels (sulfonylurea derivatives) are used as antidiabetic agents.
Enzymes.Many drugs are enzyme inhibitors. MAO inhibitors disrupt the metabolism (oxidative deamination) of catecholamines (norepinephrine, dopamine, serotonin) and increase their content in the central nervous system. The action of antidepressants - MAO inhibitors (for example, nialamide) is based on this principle. The mechanism of action of non-steroidal anti-inflammatory drugs is associated with the inhibition of cyclooxygenase, as a result, the biosynthesis of prostaglandins E 2 and I 2 decreases and a pro-inflammatory effect develops. Acetylcholinesterase inhibitors (anticholinesterase agents) prevent the hydrolysis of acetylcholine and increase its content in the synaptic cleft. Preparations of this group are used to increase the tone of smooth muscle organs (GIT, bladder) and skeletal muscles.
Transport systems. Drugs can act on transport systems (transport proteins) that carry molecules of certain substances or ions through cell membranes. For example, tricyclic antidepressants block the transport proteins that carry norepinephrine and serotonin across the presynaptic membrane.
wound of the nerve ending (block the reverse neuronal uptake of norepinephrine and serotonin). Cardiac glycosides block the K + -ATPase of cardiomyocyte membranes, which transports Na + from the cell in exchange for K + .
Other "targets" that drugs can act on are also possible. So, antacids neutralize the hydrochloric acid of the stomach, they are used for increased acidity of gastric juice (hyperacid gastritis, gastric ulcer).
A promising "target" for drugs are genes. With the help of selectively acting drugs, it is possible to directly influence the function of certain genes.
2.2. TYPES OF ACTION OF MEDICINAL SUBSTANCES
The following types of action are distinguished: local and resorptive, reflex, direct and indirect, main and side, and some others.
The local action of the drug is in contact with the tissues at the site of its application (usually the skin or mucous membranes). For example, with surface anesthesia, a local anesthetic acts on the endings of sensory nerves only at the site of application to the mucous membrane. To provide local action, drugs are prescribed in the form of ointments, lotions, rinses, patches. When prescribing some drugs in the form of eye or ear drops, they also rely on their local action. However, a certain amount of the drug is usually absorbed from the site of application into the blood and has a general (resorptive) effect. With topical application of drugs, a reflex action is also possible.
Resorptive action (from lat. resorbeo- absorb) - the effects caused by a drug after absorption into the blood or direct injection into a blood vessel and distribution in the body. With a resorptive action, as with a local one, a substance can excite sensitive receptors and cause reflex reactions.
reflex action. Some drugs are able to excite the endings of the sensory nerves of the skin, mucous membranes (exteroreceptors), vascular chemoreceptors (interoreceptors) and cause reflex reactions from organs located at a distance from the place of direct contact of the substance with sensitive receptors. An example of excitation of exteroreceptors
skin essential mustard oil is the action of mustard plasters. Lobelin, when administered intravenously, excites vascular chemoreceptors, which leads to reflex stimulation of the respiratory and vasomotor centers.
The direct (primary) effect of the drug on the heart, blood vessels, intestines and other organs develops with a direct impact on these organs. For example, cardiac glycosides cause a cardiotonic effect (increased myocardial contractions) due to their direct effect on cardiomyocytes. The increase in diuresis caused by cardiac glycosides in patients with heart failure is due to an increase in cardiac output and improved hemodynamics. Such an action, in which the drug changes the function of some organs, affecting other organs, is referred to as an indirect (secondary) action.
Main action. The action for which the drug is used in the treatment of this disease. For example, phenytoin has anticonvulsant and antiarrhythmic properties. In a patient with epilepsy, the main action of phenytoin is anticonvulsant, and in a patient with cardiac arrhythmia caused by an overdose of cardiac glycosides, it is antiarrhythmic.
All other (except the main) effects of the drug that occur when it is taken in therapeutic doses are regarded as a side effect. These effects are often unfavorable (negative) (see the chapter "Adverse and toxic effects of drugs"). For example, acetylsalicylic acid can cause ulceration of the gastric mucosa, antibiotics from the aminoglycoside group (kanamycin, gentamicin, etc.) can cause hearing loss. Negative side effects often serve as a reason for limiting the use of a particular drug and even excluding it from the list of drugs.
The selective action of the drug is directed mainly to one organ or system of the body. Thus, cardiac glycosides have a selective effect on the myocardium, oxytocin - on the uterus, hypnotics - on the central nervous system.
The central action develops due to the direct influence of the drug on the central nervous system. The central action is characteristic of substances that penetrate the BBB. For hypnotics, antidepressants, anxiolytics, anesthetics, this is the main action. At the same time, the central action may be side (undesirable).
So, many antihistamines cause drowsiness due to the central action.
Peripheral action is due to the influence of drugs on the peripheral part of the nervous system or on organs and tissues. Curare-like drugs (peripherally acting muscle relaxants) relax skeletal muscles by blocking the transmission of excitation in neuromuscular synapses, some peripheral vasodilators dilate blood vessels, acting directly on smooth muscle cells. For substances with a primary central action, peripheral effects are usually side effects. For example, the antipsychotic drug chlorpromazine causes vasodilation and a decrease in blood pressure (undesirable effect) by blocking peripheral α-adrenergic receptors.
The reversible action is a consequence of the reversible binding of drugs to "targets" (receptors, enzymes). The action of such a substance can be stopped by displacing it from its connection with the "target" of another drug.
Irreversible action occurs, as a rule, as a result of strong (covalent) binding of the drug to the "targets". For example, acetylsalicylic acid irreversibly blocks cyclooxygenase, so the effect of the drug stops only after the synthesis of a new enzyme.
Agonists are able to attach to receptor proteins, changing the function of the cell, i.e., they have internal activity. The biological effect of an agonist (i.e., change in cell function) depends on the efficiency of intracellular signal transduction as a result of receptor activation. The maximum effect of agonists develops even when only a part of the available receptors is bound.
Another agonist, which has the same affinity, but less ability to activate receptors and the corresponding intracellular signaling (i.e., having less internal activity), will cause a less pronounced maximum effect, even if all receptors are bound, i.e., it has less efficiency. Agonist B is a partial agonist. The activity of agonists is characterized by a concentration at which half of the maximum effect (EC 50) is achieved.
Antagonists weaken the effect of agonists, counteracting them. Competitive antagonists have the ability to bind to receptors, but the function of the cell does not change. In other words, they are devoid of inner activity. While in the body at the same time, the agonist and competitive antagonist compete for binding to the receptor. The chemical affinity and concentration of both competitors determine who will bind more actively: the agonist or antagonist.
Increasing agonist concentration, it is possible to overcome the block on the part of the antagonist: in this case, the dependence of the effect on the concentration shifts to the right, to a higher concentration while maintaining the maximum effectiveness of the drug.
Models of molecular mechanisms of action of agonists and antagonists
Agonist causes the receptor to switch to an activated conformation. The agonist binds to the receptor in an inactivated conformation and causes it to transition to an activated state. The antagonist attaches to the inactive receptor and will not change its conformation.
Agonist stabilizes the spontaneously appeared activated conformation. The receptor is able to spontaneously switch to an activated conformation. However, usually the statistical probability of such a transition is so small that spontaneous excitation of cells cannot be determined. Selective binding of the agonist occurs only to the receptor in the activated conformation and thus favors this state.
Antagonist is able to bind to a receptor that is only in an inactive state, prolonging its existence. If the system has low spontaneous activity, the addition of an antagonist has little effect. However, if the system exhibits high spontaneous activity, the antagonist may produce an effect opposite to that of the agonist, the so-called inverse agonist. A "true" agonist without intrinsic activity (neutral agonist) has the same affinity for activated and non-activated receptor conformations and does not change the basal activity of the cell.
According to this models, the partial agonist is less selective for the activated state: however, it also binds to some extent to the receptor in the inactivated state.
Other types of antagonism. allosteric antagonism. The antagonist binds outside the site of attachment of the agonist to the receptor and causes a decrease in the affinity of the agonist. The latter increases in the case of allosteric synergism.
Functional antagonism. Two agonists acting through different receptors change the same variable (diameter) in opposite directions (adrenaline causes expansion, histamine causes constriction).
Agonist-antagonists and partial agonists stimulate some types of receptors (agonistic action) and block others (antagonistic action). In medical practice, in addition to morphine, its derivatives, which are semi-synthetic or synthetic drugs, have been used. These include pentazocine, buprenorphine, butorphanol, nalbuphine.
It was taken into account that some previously synthesized compounds close to morphine, but not containing an oxygen bridge (levorphanol or lemoran, etc.), have high analgesic activity, and at the same time, the dimethylallyl residue is an important part of the nalorphine molecule, which has a significant least morphine antagonist properties. This modification of the morphine molecule was expected to result in a compound with greater analgesic activity than nalorphine but fewer side effects than morphine (Lasagna, 1964). Pentazocine satisfies these requirements to a certain extent. It has analgesic activity, although to a somewhat lesser extent than morphine, but less depresses respiration, less often causes constipation and urinary retention (Iwatsuki et al., 1969).
More potent agonist-antagonists have now been synthesized, such as nalbuphine (Gear et al., 1999).
The listed properties and features of the action of the drugs described above give reason to believe that their use is limited due to the emergence of dependence on them. Narcotic analgesics should be used only for the treatment of acute pain and for a short time. Most often they are used for injuries, burns, myocardial infarction, peritonitis (after the diagnosis has been clarified and the issue of surgery resolved) (Savyuk, 1997). In addition, chronic pain is a contraindication to drug use, except in advanced forms of malignant tumors (
